@article{HiguchiSerflingRoweetal.2022,
  author    = {Higuchi, Takahiro and Serfling, Sebastian E. and Rowe, Steven P. and Werner, Rudolf A.},
  title     = {Therapeutic effects of lipid lowering medications on myocardial blood flow, inflammation, and sympathetic nerve activity using nuclear techniques},
  series = {Current Cardiology Reports},
  volume    = {24},
  journal   = {Current Cardiology Reports},
  number    = {12},
  doi       = {10.1007/s11886-022-01792-4},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324599},
  pages     = {1849-1853},
  year      = {2022},
  abstract  = {Purpose of Review Statins are routinely applied in patients with coronary artery disease, as they allow significantly to reduce blood cholesterol levels. Although those drugs are endorsed by current guidelines and prescribed routinely, a substantial portion of patients are still statin-intolerant and image-piloted strategies may then be helpful to identify patients that need further intensified treatment, e.g., to initiate treatment with proprotein convertase subtilisin / kexin type 9 inhibitors (PCSK9i). In addition, it has also been advocated that statins exhibit nonlipid, cardio-protective effects including improved cardiac nerve integrity, blood flow, and anti-inflammatory effects in congestive heart failure (HF) patients. Recent Findings In subjects after myocardial infarction treated with statins, \(^{123}\)I-metaiodobenzylguanidine (MIBG) scintigraphy has already revealed enhanced cardiac nerve function relative to patients without statins. In addition, all of those aforementioned statin-targeted pathways in HF can be visualized and monitored using dedicated cardiac radiotracers, e.g., \(^{123}\)I-MIBG or \(^{18}\)F-AF78 (for cardiac nerve function), \(^{18}\)F-flurpiridaz (to determine coronary flow) or \(^{68}\)Ga-PentixaFor (to detect inflammation). Summary Statins exhibit various cardio-beneficial effects, including improvement of cardiac nerve function, blood flow, and reduction of inflammation, which can all be imaged using dedicated nuclear cardiac radiotracers. This may allow for in vivo monitoring of statin-induced cardioprotection beyond lipid profiling in HF patients.},
  language  = {en}
}
@article{OuhaddiCharbonnierPorgeetal.2023,
  author    = {Ouhaddi, Yassine and Charbonnier, Baptiste and Porge, Juliette and Zhang, Yu-Ling and Garcia, Isadora and Gbureck, Uwe and Grover, Liam and Gilardino, Mirko and Harvey, Edward and Makhoul, Nicholas and Barralet, Jake},
  title     = {Development of neovasculature in axially vascularized calcium phosphate cement scaffolds},
  series = {Journal of Functional Biomaterials},
  volume    = {14},
  journal   = {Journal of Functional Biomaterials},
  number    = {2},
  issn      = {2079-4983},
  doi       = {10.3390/jfb14020105},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304026},
  year      = {2023},
  abstract  = {Augmenting the vascular supply to generate new tissues, a crucial aspect in regenerative medicine, has been challenging. Recently, our group showed that calcium phosphate can induce the formation of a functional neo-angiosome without the need for microsurgical arterial anastomosis. This was a preclinical proof of concept for biomaterial-induced luminal sprouting of large-diameter vessels. In this study, we investigated if sprouting was a general response to surgical injury or placement of an inorganic construct around the vessel. Cylindrical biocement scaffolds of differing chemistries were placed around the femoral vein. A contrast agent was used to visualize vessel ingrowth into the scaffolds. Cell populations in the scaffold were mapped using immunohistochemistry. Calcium phosphate scaffolds induced 2.7-3 times greater volume of blood vessels than calcium sulphate or magnesium phosphate scaffolds. Macrophage and vSMC populations were identified that changed spatially and temporally within the scaffold during implantation. NLRP3 inflammasome activation peaked at weeks 2 and 4 and then declined; however, IL-1β expression was sustained over the course of the experiment. IL-8, a promoter of angiogenesis, was also detected, and together, these responses suggest a role of sterile inflammation. Unexpectedly, the effect was distinct from an injury response as a result of surgical placement and also was not simply a foreign body reaction as a result of placing a rigid bioceramic next to a vein, since, while the materials tested had similar microstructures, only the calcium phosphates tested elicited an angiogenic response. This finding then reveals a potential path towards a new strategy for creating better pro-regenerative biomaterials.},
  language  = {en}
}
@phdthesis{Krampert2024,
  author    = {Krampert, Laura},
  title     = {Dynamics of cardiac neutrophil diversity in murine myocardial infarction},
  doi       = {10.25972/OPUS-34957},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-349576},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2024},
  abstract  = {After myocardial infarction, an inflammatory response is induced characterized by a sterile inflammation, followed by a reparative phase in order to induce cardiac healing. Neutrophils are the first immune cells that enter the ischemic tissue. Neutrophils have various functions in the ischemic heart, such as phagocytosis, production of reactive oxygen species or release of granule components. These functions can not only directly damage cardiac tissue, but are also necessary for initiating reparative effects in post-ischemic healing, indicating a dual role of neutrophils in cardiac healing after infarction. In recent years, evidence has been growing that neutrophils show phenotypic and functional differences in distinct homeostatic and pathogenic settings. Preliminary data of my working group using single-cell RNA-sequencing revealed the time- dependent heterogeneity of neutrophils, with different populations showing distinct gene expression profiles in ischemic hearts of mice, including the time-dependent appearance of a SiglecFhigh neutrophil population. To better understand the dynamics of neutrophil heterogeneity in the ischemic heart, my work aimed to validate previous findings at the protein level, as well as to investigate whether the distinct neutrophil populations show functional differences. Furthermore, in vivo depletion experiments were performed in order to modulate circulating neutrophil levels. Hearts, blood, bone marrow and spleens were processed and analyzed from mice after 1 day and 3 days after the onset of cardiac ischemia and analyzed using flow cytometry. Results showed that the majority of cardiac neutrophils isolated at day 3 after myocardial infarction were SiglecFhigh, whereas nearly no SiglecFhigh neutrophils could be isolated from ischemic hearts at day 1 after myocardial infarction. No SiglecFhigh neutrophils could be found in the blood, spleen and bone marrow either after 1 day or 3 days after myocardial infarction, indicating that the SiglecFhigh state of neutrophils is unique to the ischemic cardiac tissue. When I compared SiglecFhigh and SiglecFlow neutrophils regarding their phagocytosis activity and ROS production, SiglecFhigh neutrophils showed a higher phagocytosis ability than their SiglecFlow counterparts, as well as higher ROS production capacity. In vivo depletion experiments could not achieve successful and efficient depletion of cardiac neutrophils either 1 day or 3 days after myocardial infarction, but led to a shift of a higher percentage of SiglecFhigh expressing neutrophils in the depletion group. Bone marrow neutrophil levels only showed partial depletion at day 3 after MI. Regarding blood neutrophils, depletion efficiently reduced circulating neutrophils at both time points, 1 and 3 days after MI. To summarize, this work showed the time-dependent presence of different neutrophil states in the ischemic heart. The main population of neutrophils isolated 3 days after MI showed a high expression of SiglecF, a unique state that could not be detected at different time points or other organs. These SiglecFhigh neutrophils showed functional differences regarding their phagocytosis ability and ROS production. Further investigation is needed to reveal what role these SiglecFhigh neutrophils could play within the ischemic heart. To better target neutrophil depletion in vivo, more efficient or different anti-neutrophil strategies are needed.},
  subject      = {Neutrophiler Granulozyt},
  language  = {en}
}
@article{GarciaFernandezReinholdUeceyleretal.2023,
  author    = {Garc{\´i}a-Fern{\´a}ndez, Patricia and Reinhold, Colette and {\"U}{\c{c}}eyler, Nurcan and Sommer, Claudia},
  title     = {Local inflammatory mediators involved in neuropathic pain},
  series = {International Journal of Molecular Sciences},
  volume    = {24},
  journal   = {International Journal of Molecular Sciences},
  number    = {9},
  issn      = {1422-0067},
  doi       = {10.3390/ijms24097814},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-313613},
  year      = {2023},
  abstract  = {Polyneuropathy (PNP) is a term to describe diseases of the peripheral nervous system, 50\% of which present with neuropathic pain. In some types of PNP, pain is restricted to the skin distally in the leg, suggesting a local regulatory process leading to pain. In this study, we proposed a pro-inflammatory pathway mediated by NF-κB that might be involved in the development of pain in patients with painful PNP. To test this hypothesis, we have collected nerve and skin samples from patients with different etiologies and levels of pain. We performed RT-qPCR to analyze the gene expression of the proposed inflammatory pathway components in sural nerve and in distal and proximal skin samples. In sural nerve, we showed a correlation of TLR4 and TNFα to neuropathic pain, and an upregulation of TNFα in patients with severe pain. Patients with an inflammatory PNP also presented a lower expression of TRPV1 and SIRT1. In distal skin, we found a reduced expression of TLR4 and miR-146-5p, in comparison to proximal skin. Our findings thus support our hypothesis of local inflammatory processes involved in pain in PNP, and further show disturbed anti-inflammatory pathways involving TRPV1 and SIRT1 in inflammatory PNP.},
  language  = {en}
}
@article{GlaserKernSpeeretal.2023,
  author    = {Glaser, Kirsten and Kern, David and Speer, Christian P. and Schlegel, Nicolas and Schwab, Michael and Thome, Ulrich H. and H{\"a}rtel, Christoph and Wright, Clyde J.},
  title     = {Imbalanced inflammatory responses in preterm and term cord blood monocytes and expansion of the CD14\(^+\)CD16\(^+\) subset upon toll-like receptor stimulation},
  series = {International Journal of Molecular Sciences},
  volume    = {24},
  journal   = {International Journal of Molecular Sciences},
  number    = {5},
  issn      = {1422-0067},
  doi       = {10.3390/ijms24054919},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-311056},
  year      = {2023},
  abstract  = {Developmentally regulated features of innate immunity are thought to place preterm and term infants at risk of infection and inflammation-related morbidity. Underlying mechanisms are incompletely understood. Differences in monocyte function including toll-like receptor (TLR) expression and signaling have been discussed. Some studies point to generally impaired TLR signaling, others to differences in individual pathways. In the present study, we assessed mRNA and protein expression of pro- and anti-inflammatory cytokines in preterm and term cord blood (CB) monocytes compared with adult controls stimulated ex vivo with Pam3CSK4, zymosan, polyinosinic:polycytidylic acid, lipopolysaccharide, flagellin, and CpG oligonucleotide, which activate the TLR1/2, TLR2/6, TLR3, TLR4, TLR5, and TLR9 pathways, respectively. In parallel, frequencies of monocyte subsets, stimulus-driven TLR expression, and phosphorylation of TLR-associated signaling molecules were analyzed. Independent of stimulus, pro-inflammatory responses of term CB monocytes equaled adult controls. The same held true for preterm CB monocytes—except for lower IL-1β levels. In contrast, CB monocytes released lower amounts of anti-inflammatory IL-10 and IL-1ra, resulting in higher ratios of pro-inflammatory to anti-inflammatory cytokines. Phosphorylation of p65, p38, and ERK1/2 correlated with adult controls. However, stimulated CB samples stood out with higher frequencies of intermediate monocytes (CD14\(^+\)CD16\(^+\)). Both pro-inflammatory net effect and expansion of the intermediate subset were most pronounced upon stimulation with Pam3CSK4 (TLR1/2), zymosan (TR2/6), and lipopolysaccharide (TLR4). Our data demonstrate robust pro-inflammatory and yet attenuated anti-inflammatory responses in preterm and term CB monocytes, along with imbalanced cytokine ratios. Intermediate monocytes, a subset ascribed pro-inflammatory features, might participate in this inflammatory state.},
  language  = {en}
}
@article{SchanbacherHermannsLorenzetal.2023,
  author    = {Schanbacher, Constanze and Hermanns, Heike M. and Lorenz, Kristina and Wajant, Harald and Lang, Isabell},
  title     = {Complement 1q/tumor necrosis factor-related proteins (CTRPs): structure, receptors and signaling},
  series = {Biomedicines},
  volume    = {11},
  journal   = {Biomedicines},
  number    = {2},
  issn      = {2227-9059},
  doi       = {10.3390/biomedicines11020559},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304136},
  year      = {2023},
  abstract  = {Adiponectin and the other 15 members of the complement 1q (C1q)/tumor necrosis factor (TNF)-related protein (CTRP) family are secreted proteins composed of an N-terminal variable domain followed by a stalk region and a characteristic C-terminal trimerizing globular C1q (gC1q) domain originally identified in the subunits of the complement protein C1q. We performed a basic PubMed literature search for articles mentioning the various CTRPs or their receptors in the abstract or title. In this narrative review, we briefly summarize the biology of CTRPs and focus then on the structure, receptors and major signaling pathways of CTRPs. Analyses of CTRP knockout mice and CTRP transgenic mice gave overwhelming evidence for the relevance of the anti-inflammatory and insulin-sensitizing effects of CTRPs in autoimmune diseases, obesity, atherosclerosis and cardiac dysfunction. CTRPs form homo- and heterotypic trimers and oligomers which can have different activities. The receptors of some CTRPs are unknown and some receptors are redundantly targeted by several CTRPs. The way in which CTRPs activate their receptors to trigger downstream signaling pathways is largely unknown. CTRPs and their receptors are considered as promising therapeutic targets but their translational usage is still hampered by the limited knowledge of CTRP redundancy and CTRP signal transduction.},
  language  = {en}
}
@article{ThalSmetakHayashietal.2022,
  author    = {Thal, Serge C. and Smetak, Manuel and Hayashi, Kentaro and F{\"o}rster, Carola Y.},
  title     = {Hemorrhagic cerebral insults and secondary Takotsubo syndrome: findings in a novel in vitro model using human blood samples},
  series = {International Journal of Molecular Sciences},
  volume    = {23},
  journal   = {International Journal of Molecular Sciences},
  number    = {19},
  issn      = {1422-0067},
  doi       = {10.3390/ijms231911557},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-288305},
  year      = {2022},
  abstract  = {Intracranial hemorrhage results in devastating forms of cerebral damage. Frequently, these results also present with cardiac dysfunction ranging from ECG changes to Takotsubo syndrome (TTS). This suggests that intracranial bleeding due to subarachnoid hemorrhage (SAH) disrupts the neuro-cardiac axis leading to neurogenic stress cardiomyopathy (NSC) of different degrees. Following this notion, SAH and secondary TTS could be directly linked, thus contributing to poor outcomes. We set out to test if blood circulation is the driver of the brain-heart axis by investigating serum samples of TTS patients. We present a novel in vitro model combining SAH and secondary TTS to mimic the effects of blood or serum, respectively, on blood-brain barrier (BBB) integrity using in vitro monolayers of an established murine model. We consistently demonstrated decreased monolayer integrity and confirmed reduced Claudin-5 and Occludin levels by RT-qPCR and Western blot and morphological reorganization of actin filaments in endothelial cells. Both tight junction proteins show a time-dependent reduction. Our findings highlight a faster and more prominent disintegration of BBB in the presence of TTS and support the importance of the bloodstream as a causal link between intracerebral bleeding and cardiac dysfunction. This may represent potential targets for future therapeutic inventions in SAH and TTS.},
  language  = {en}
}
@article{MaglioccaMoneDiIorioetal.2022,
  author    = {Magliocca, Giorgia and Mone, Pasquale and Di Iorio, Biagio Raffaele and Heidland, August and Marzocco, Stefania},
  title     = {Short-chain fatty acids in Chronic Kidney Disease: focus on inflammation and oxidative stress regulation},
  series = {International Journal of Molecular Sciences},
  volume    = {23},
  journal   = {International Journal of Molecular Sciences},
  number    = {10},
  issn      = {1422-0067},
  doi       = {10.3390/ijms23105354},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284587},
  year      = {2022},
  abstract  = {Chronic Kidney Disease (CKD) is a debilitating disease associated with several secondary complications that increase comorbidity and mortality. In patients with CKD, there is a significant qualitative and quantitative alteration in the gut microbiota, which, consequently, also leads to reduced production of beneficial bacterial metabolites, such as short-chain fatty acids. Evidence supports the beneficial effects of short-chain fatty acids in modulating inflammation and oxidative stress, which are implicated in CKD pathogenesis and progression. Therefore, this review will provide an overview of the current knowledge, based on pre-clinical and clinical evidence, on the effect of SCFAs on CKD-associated inflammation and oxidative stress.},
  language  = {en}
}
@article{DresenPimientoPateletal.2023,
  author    = {Dresen, Ellen and Pimiento, Jose M. and Patel, Jayshil J. and Heyland, Daren K. and Rice, Todd W. and Stoppe, Christian},
  title     = {Overview of oxidative stress and the role of micronutrients in critical illness},
  series = {Journal of Parenteral and Enteral Nutrition},
  volume    = {47},
  journal   = {Journal of Parenteral and Enteral Nutrition},
  doi       = {10.1002/jpen.2421},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318186},
  pages     = {S38 -- S49},
  year      = {2023},
  abstract  = {Inflammation and oxidative stress represent physiological response mechanisms to different types of stimuli and injury during critical illness. Its proper regulation is fundamental to cellular and organismal survival and are paramount to outcomes and recovery from critical illness. A proper maintenance of the delicate balance between inflammation, oxidative stress, and immune response is crucial for resolution from critical illness with important implications for patient outcome. The extent of inflammation and oxidative stress under normal conditions is limited by the antioxidant defense system of the human body, whereas the antioxidant capacity is commonly significantly compromised, and serum levels of micronutrients and vitamins significantly depleted in patients who are critically ill. Hence, the provision of antioxidants and anti-inflammatory nutrients may help to reduce the extent of oxidative stress and therefore improve clinical outcomes in patients who are critically ill. As existing evidence of the beneficial effects of antioxidant supplementation in patients who are critically ill is still unclear, actual findings about the most promising anti-inflammatory and antioxidative candidates selenium, vitamin C, zinc, and vitamin D will be discussed in this narrative review. The existing evidence provided so far demonstrates that several factors need to be considered to determine the efficacy of an antioxidant supplementation strategy in patients who are critically ill and indicates the need for adequately designed multicenter prospective randomized control trials to evaluate the clinical significance of different types and doses of micronutrients and vitamins in selected groups of patients with different types of critical illness.},
  language  = {en}
}
@article{WeiderSchlagenhaufSeefried2022,
  author    = {Weider, Margareta and Schlagenhauf, Ulrich and Seefried, Lothar},
  title     = {Oral health status of adult hypophosphatasia patients: A cross-sectional study},
  series = {Journal of Clinical Periodontology},
  volume    = {49},
  journal   = {Journal of Clinical Periodontology},
  number    = {12},
  doi       = {10.1111/jcpe.13718},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-293777},
  pages     = {1253 -- 1261},
  year      = {2022},
  abstract  = {Aim This study evaluated the oral health status of adult patients with hypophosphatasia (HPP). Materials and Methods Parameters of oral health assessment comprised decayed/missing/filled teeth (DMFT) index, probing pocket depth and clinical attachment level (CAL) as well as documentation of tooth loss and periodontal health status according to CCD/AAP criteria. Findings were compared with national reference data (DMS V survey) reporting oral health status in age-related controls. Within-group comparisons were made between the HPP patients harbouring one versus two alkaline phosphatase liver/bone/kidney type (ALPL) gene variants. Results Of 80 HPP patients (64 female) with a mean age of 46.4 years (range 24-78) and one (n = 55) or two (n = 18) variants (n = 7 lacking testing) within the ALPL gene, those with two variants displayed substantially higher tooth loss rate (14.0 ± 9.3) than those affected by only one ALPL variant (4.1 ± 5.4), who did not differ substantially from healthy DMS V controls. While DMFT score and severe periodontal diseases (PDs) of HPP patients with one variant only increased with progressing age, the two-variant sub-cohort age independently exhibited increased DMFT scores and a higher rate of severe PDs. Conclusions HPP patients affected by two variants of the ALPL gene exhibited a higher risk of periodontitis and tooth loss than the general population, while patients with one variant developed clinically relevant oral disease symptoms with progressing ageing.},
  language  = {en}
}
@article{BaumToykaBlueheretal.2021,
  author    = {Baum, Petra and Toyka, Klaus V. and Bl{\"u}her, Matthias and Kosacka, Joanna and Nowicki, Marcin},
  title     = {Inflammatory mechanisms in the pathophysiology of diabetic peripheral neuropathy (DN) — new aspects},
  series = {International Journal of Molecular Sciences},
  volume    = {22},
  journal   = {International Journal of Molecular Sciences},
  number    = {19},
  issn      = {1422-0067},
  doi       = {10.3390/ijms221910835},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284556},
  year      = {2021},
  abstract  = {The pathogenesis of diabetic neuropathy is complex, and various pathogenic pathways have been proposed. A better understanding of the pathophysiology is warranted for developing novel therapeutic strategies. Here, we summarize recent evidence from experiments using animal models of type 1 and type 2 diabetes showing that low-grade intraneural inflammation is a facet of diabetic neuropathy. Our experimental data suggest that these mild inflammatory processes are a likely common terminal pathway in diabetic neuropathy associated with the degeneration of intraepidermal nerve fibers. In contrast to earlier reports claiming toxic effects of high-iron content, we found the opposite, i.e., nutritional iron deficiency caused low-grade inflammation and fiber degeneration while in normal or high non-heme iron nutrition no or only extremely mild inflammatory signs were identified in nerve tissue. Obesity and dyslipidemia also appear to trigger mild inflammation of peripheral nerves, associated with neuropathy even in the absence of overt diabetes mellitus. Our finding may be the experimental analog of recent observations identifying systemic proinflammatory activity in human sensorimotor diabetic neuropathy. In a rat model of type 1 diabetes, a mild neuropathy with inflammatory components could be induced by insulin treatment causing an abrupt reduction in HbA1c. This is in line with observations in patients with severe diabetes developing a small fiber neuropathy upon treatment-induced rapid HbA1c reduction. If the inflammatory pathogenesis could be further substantiated by data from human tissues and intervention studies, anti-inflammatory compounds with different modes of action may become candidates for the treatment or prevention of diabetic neuropathy.},
  language  = {en}
}
@article{RajendranRajendranGiraldoVelasquezetal.2021,
  author    = {Rajendran, Ranjithkumar and Rajendran, Vinothkumar and Giraldo-Velasquez, Mario and Megalofonou, Fevronia-Foivi and Gurski, Fynn and Stadelmann, Christine and Karnati, Srikanth and Berghoff, Martin},
  title     = {Oligodendrocyte-specific deletion of FGFR1 reduces cerebellar inflammation and neurodegeneration in MOG\(_{35-55}\)-induced EAE},
  series = {International Journal of Molecular Sciences},
  volume    = {22},
  journal   = {International Journal of Molecular Sciences},
  number    = {17},
  issn      = {1422-0067},
  doi       = {10.3390/ijms22179495},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284296},
  year      = {2021},
  abstract  = {Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system (CNS). MS commonly affects the cerebellum causing acute and chronic symptoms. Cerebellar signs significantly contribute to clinical disability, and symptoms such as tremor, ataxia, and dysarthria are difficult to treat. Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in demyelinating pathologies such as MS. In autopsy tissue from patients with MS, increased expression of FGF1, FGF2, FGF9, and FGFR1 was found in lesion areas. Recent research using mouse models has focused on regions such as the spinal cord, and data on the expression of FGF/FGFR in the cerebellum are not available. In recent EAE studies, we detected that oligodendrocyte-specific deletion of FGFRs results in a milder disease course, less cellular infiltrates, and reduced neurodegeneration in the spinal cord. The objective of this study was to characterize the role of FGFR1 in oligodendrocytes in the cerebellum. Conditional deletion of FGFR1 in oligodendrocytes (Fgfr1\(^{ind-/-}\) was achieved by tamoxifen application, EAE was induced using the MOG\(_{35-55}\) peptide. The cerebellum was analyzed by histology, immunohistochemistry, and western blot. At day 62 p.i., Fgfr1\(^{ind-/-}\) mice showed less myelin and axonal degeneration compared to FGFR1-competent mice. Infiltration of CD3(+) T cells, Mac3(+) cells, B220(+) B cells and IgG(+) plasma cells in cerebellar white matter lesions (WML) was less in Fgfr1\(^{ind-/-}\)mice. There were no effects on the number of OPC or mature oligodendrocytes in white matter lesion (WML). Expression of FGF2 and FGF9 associated with less myelin and axonal degeneration, and of the pro-inflammatory cytokines IL-1β, IL-6, and CD200 was downregulated in Fgfr1\(^{ind-/-}\) mice. The FGF/FGFR signaling protein pAkt, BDNF, and TrkB were increased in Fgfr1\(^{ind-/-}\) mice. These data suggest that cell-specific deletion of FGFR1 in oligodendrocytes has anti-inflammatory and neuroprotective effects in the cerebellum in the EAE disease model of MS.},
  language  = {en}
}
@article{RapaDiIorioCampigliaetal.2019,
  author    = {Rapa, Shara Francesca and Di Iorio, Biagio Raffaele and Campiglia, Pietro and Heidland, August and Marzocco, Stefania},
  title     = {Inflammation and oxidative stress in chronic kidney disease — Potential therapeutic role of minerals, vitamins and plant-derived metabolites},
  series = {International Journal of Molecular Sciences},
  volume    = {21},
  journal   = {International Journal of Molecular Sciences},
  number    = {1},
  issn      = {1422-0067},
  doi       = {10.3390/ijms21010263},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284998},
  year      = {2019},
  abstract  = {Chronic kidney disease (CKD) is a debilitating pathology with various causal factors, culminating in end stage renal disease (ESRD) requiring dialysis or kidney transplantation. The progression of CKD is closely associated with systemic inflammation and oxidative stress, which are responsible for the manifestation of numerous complications such as malnutrition, atherosclerosis, coronary artery calcification, heart failure, anemia and mineral and bone disorders, as well as enhanced cardiovascular mortality. In addition to conventional therapy with anti-inflammatory and antioxidative agents, growing evidence has indicated that certain minerals, vitamins and plant-derived metabolites exhibit beneficial effects in these disturbances. In the current work, we review the anti-inflammatory and antioxidant properties of various agents which could be of potential benefit in CKD/ESRD. However, the related studies were limited due to small sample sizes and short-term follow-up in many trials. Therefore, studies of several anti-inflammatory and antioxidant agents with long-term follow-ups are necessary.},
  language  = {en}
}
@article{KoenigerKuerten2017,
  author    = {Koeniger, Tobias and Kuerten, Stefanie},
  title     = {Splitting the "unsplittable": Dissecting resident and infiltrating macrophages in experimental autoimmune encephalomyelitis},
  series = {International Journal of Molecular Sciences},
  volume    = {18},
  journal   = {International Journal of Molecular Sciences},
  number    = {10},
  issn      = {1422-0067},
  doi       = {10.3390/ijms18102072},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285067},
  year      = {2017},
  abstract  = {Macrophages predominate the inflammatory landscape within multiple sclerosis (MS) lesions, not only regarding cellularity but also with respect to the diverse functions this cell fraction provides during disease progression and remission. Researchers have been well aware of the fact that the macrophage pool during central nervous system (CNS) autoimmunity consists of a mixture of myeloid cells. Yet, separating these populations to define their unique contribution to disease pathology has long been challenging due to their similar marker expression. Sophisticated lineage tracing approaches as well as comprehensive transcriptome analysis have elevated our insight into macrophage biology to a new level enabling scientists to dissect the roles of resident (microglia and non-parenchymal macrophages) and infiltrating macrophages with unprecedented precision. To do so in an accurate way, researchers have to know their toolbox, which has been filled with diverse, discriminating approaches from decades of studying neuroinflammation in animal models. Every method has its own strengths and weaknesses, which will be addressed in this review. The focus will be on tools to manipulate and/or identify different macrophage subgroups within the injured murine CNS.},
  language  = {en}
}
@article{UngernSternbergZerneckeSeizer2018,
  author    = {Ungern-Sternberg, Saskia N. I. von and Zernecke, Alma and Seizer, Peter},
  title     = {Extracellular matrix metalloproteinase inducer EMMPRIN (CD147) in cardiovascular disease},
  series = {International Journal of Molecular Sciences},
  volume    = {19},
  journal   = {International Journal of Molecular Sciences},
  number    = {2},
  issn      = {1422-0067},
  doi       = {10.3390/ijms19020507},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285014},
  year      = {2018},
  abstract  = {The receptor EMMPRIN is involved in the development and progression of cardiovascular diseases and in the pathogenesis of myocardial infarction. There are several binding partners of EMMPRIN mediating the effects of EMMPRIN in cardiovascular diseases. EMMPRIN interaction with most binding partners leads to disease progression by mediating cytokine or chemokine release, the activation of platelets and monocytes, as well as the formation of monocyte-platelet aggregates (MPAs). EMMPRIN is also involved in atherosclerosis by mediating the infiltration of pro-inflammatory cells. There is also evidence that EMMPRIN controls energy metabolism of cells and that EMMPRIN binding partners modulate intracellular glycosylation and trafficking of EMMPRIN towards the cell membrane. In this review, we systematically discuss these multifaceted roles of EMMPRIN and its interaction partners, such as Cyclophilins, in cardiovascular disease.},
  language  = {en}
}
@article{LauruschkatEtterSchnacketal.2021,
  author    = {Lauruschkat, Chris D. and Etter, Sonja and Schnack, Elisabeth and Ebel, Frank and Sch{\"a}uble, Sascha and Page, Lukas and R{\"u}mens, Dana and Dragan, Mariola and Schlegel, Nicolas and Panagiotou, Gianni and Kniemeyer, Olaf and Brakhage, Axel A. and Einsele, Hermann and Wurster, Sebastian and Loeffler, Juergen},
  title     = {Chronic occupational mold exposure drives expansion of Aspergillus-reactive type 1 and type 2 T-helper cell responses},
  series = {Journal of Fungi},
  volume    = {7},
  journal   = {Journal of Fungi},
  number    = {9},
  issn      = {2309-608X},
  doi       = {10.3390/jof7090698},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-245202},
  year      = {2021},
  abstract  = {Occupational mold exposure can lead to Aspergillus-associated allergic diseases including asthma and hypersensitivity pneumonitis. Elevated IL-17 levels or disbalanced T-helper (Th) cell expansion were previously linked to Aspergillus-associated allergic diseases, whereas alterations to the Th cell repertoire in healthy occupationally exposed subjects are scarcely studied. Therefore, we employed functional immunoassays to compare Th cell responses to A. fumigatus antigens in organic farmers, a cohort frequently exposed to environmental molds, and non-occupationally exposed controls. Organic farmers harbored significantly higher A. fumigatus-specific Th-cell frequencies than controls, with comparable expansion of Th1- and Th2-cell frequencies but only slightly elevated Th17-cell frequencies. Accordingly, Aspergillus antigen-induced Th1 and Th2 cytokine levels were strongly elevated, whereas induction of IL-17A was minimal. Additionally, increased levels of some innate immune cell-derived cytokines were found in samples from organic farmers. Antigen-induced cytokine release combined with Aspergillus-specific Th-cell frequencies resulted in high classification accuracy between organic farmers and controls. Aspf22, CatB, and CipC elicited the strongest differences in Th1 and Th2 responses between the two cohorts, suggesting these antigens as potential candidates for future bio-effect monitoring approaches. Overall, we found that occupationally exposed agricultural workers display a largely balanced co-expansion of Th1 and Th2 immunity with only minor changes in Th17 responses.},
  language  = {en}
}
@article{SpitzelWagnerBreyeretal.2022,
  author    = {Spitzel, Marlene and Wagner, Elise and Breyer, Maximilian and Henniger, Dorothea and Bayin, Mehtap and Hofmann, Lukas and Mauceri, Daniela and Sommer, Claudia and {\"U}{\c{c}}eyler, Nurcan},
  title     = {Dysregulation of immune response mediators and pain-related ion channels is associated with pain-like behavior in the GLA KO mouse model of Fabry disease},
  series = {Cells},
  volume    = {11},
  journal   = {Cells},
  number    = {11},
  issn      = {2073-4409},
  doi       = {10.3390/cells11111730},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-275186},
  year      = {2022},
  abstract  = {Fabry disease (FD) is a rare life-threatening disorder caused by deficiency of the alpha-galactosidase A (GLA) enzyme with a characteristic pain phenotype. Impaired GLA production or function leads to the accumulation of the cell membrane compound globotriaosylceramide (Gb3) in the neurons of the dorsal root ganglia (DRG) of FD patients. Applying immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT PCR) analysis on DRG tissue of the GLA knockout (KO) mouse model of FD, we address the question of how Gb3 accumulation may contribute to FD pain and focus on the immune system and pain-associated ion channel gene expression. We show a higher Gb3 load in the DRG of young (<6 months) (p < 0.01) and old (≥12 months) (p < 0.001) GLA KO mice compared to old wildtype (WT) littermates, and an overall suppressed immune response in the DRG of old GLA KO mice, represented by a reduced number of CD206\(^+\) macrophages (p < 0.01) and lower gene expression levels of the inflammation-associated targets interleukin(IL)1b (p < 0.05), IL10 (p < 0.001), glial fibrillary acidic protein (GFAP) (p < 0.05), and leucine rich alpha-2-glycoprotein 1 (LRG1) (p < 0.01) in the DRG of old GLA KO mice compared to old WT. Dysregulation of immune-related genes may be linked to lower gene expression levels of the pain-associated ion channels calcium-activated potassium channel 3.1 (KCa3.1) and transient receptor potential ankyrin 1 channel (TRPA1). Ion channel expression might further be disturbed by impaired sphingolipid recruitment mediated via the lipid raft marker flotillin-1 (FLOT1). This impairment is represented by an increased number of FLOT1\(^+\) DRG neurons with a membranous expression pattern in old GLA KO mice compared to young GLA KO, young WT, and old WT mice (p < 0.001 each). Further, we provide evidence for aberrant behavior of GLA KO mice, which might be linked to dysregulated ion channel gene expression levels and disturbed FLOT1 distribution patterns. Behavioral testing revealed mechanical hypersensitivity in young (p < 0.01) and old (p < 0.001) GLA KO mice compared to WT, heat hypersensitivity in young GLA KO mice (p < 0.001) compared to WT, age-dependent heat hyposensitivity in old GLA KO mice (p < 0.001) compared to young GLA KO mice, and cold hyposensitivity in young (p < 0.001) and old (p < 0.001) GLA KO mice compared to WT, which well reflects the clinical phenotype observed in FD patients.},
  language  = {en}
}
@article{SchapovalovaGorlovadeMunteretal.2022,
  author    = {Schapovalova, Olesia and Gorlova, Anna and de Munter, Johannes and Sheveleva, Elisaveta and Eropkin, Mikhail and Gorbunov, Nikita and Sicker, Michail and Umriukhin, Aleksei and Lyubchyk, Sergiy and Lesch, Klaus-Peter and Strekalova, Tatyana and Schroeter, Careen A.},
  title     = {Immunomodulatory effects of new phytotherapy on human macrophages and TLR4- and TLR7/8-mediated viral-like inflammation in mice},
  series = {Frontiers in Medicine},
  volume    = {9},
  journal   = {Frontiers in Medicine},
  issn      = {2296-858X},
  doi       = {10.3389/fmed.2022.952977},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-286301},
  year      = {2022},
  abstract  = {Background While all efforts have been undertaken to propagate the vaccination and develop remedies against SARS-CoV-2, no satisfactory management of this infection is available yet. Moreover, poor availability of any preventive and treatment measures of SARS-CoV-2 in economically disadvantageous communities aggravates the course of the pandemic. Here, we studied a new immunomodulatory phytotherapy (IP), an extract of blackberry, chamomile, garlic, cloves, and elderberry as a potential low-cost solution for these problems given the reported efficacy of herbal medicine during the previous SARS virus outbreak. Methods The key feature of SARS-CoV-2 infection, excessive inflammation, was studied in in vitro and in vivo assays under the application of the IP. First, changes in tumor-necrosis factor (TNF) and lnteurleukin-1 beta (IL-1β) concentrations were measured in a culture of human macrophages following the lipopolysaccharide (LPS) challenge and treatment with IP or prednisolone. Second, chronically IP-pre-treated CD-1 mice received an agonist of Toll-like receptors (TLR)-7/8 resiquimod and were examined for lung and spleen expression of pro-inflammatory cytokines and blood formula. Finally, chronically IP-pre-treated mice challenged with LPS injection were studied for "sickness" behavior. Additionally, the IP was analyzed using high-potency-liquid chromatography (HPLC)-high-resolution-mass-spectrometry (HRMS). Results LPS-induced in vitro release of TNF and IL-1β was reduced by both treatments. The IP-treated mice displayed blunted over-expression of SAA-2, ACE-2, CXCL1, and CXCL10 and decreased changes in blood formula in response to an injection with resiquimod. The IP-treated mice injected with LPS showed normalized locomotion, anxiety, and exploration behaviors but not abnormal forced swimming. Isoquercitrin, choline, leucine, chlorogenic acid, and other constituents were identified by HPLC-HRMS and likely underlie the IP immunomodulatory effects. Conclusions Herbal IP-therapy decreases inflammation and, partly, "sickness behavior," suggesting its potency to combat SARS-CoV-2 infection first of all via its preventive effects.},
  language  = {en}
}
@article{HungDreherDiessneretal.2022,
  author    = {Hung, Sophia and Dreher, Liane and Diessner, Joachim and Schwarz, Stefan and Ohlsen, Knut and Hertlein, Tobias},
  title     = {MRSA infection in the thigh muscle leads to systemic disease, strong inflammation, and loss of human monocytes in humanized mice},
  series = {Frontiers in Immunology},
  volume    = {13},
  journal   = {Frontiers in Immunology},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2022.892053},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-278050},
  year      = {2022},
  abstract  = {MRSA (Methicillin-resistant Staphylococcus aureus) is the second-leading cause of deaths by antibiotic-resistant bacteria globally, with more than 100,000 attributable deaths annually. Despite the high urgency to develop a vaccine to control this pathogen, all clinical trials with pre-clinically effective candidates failed so far. The recent development of "humanized" mice might help to edge the pre-clinical evaluation closer to the clinical situation and thus close this gap. We infected humanized NSG mice (huNSG: (NOD)-scid IL2R\(_γ\)\(^{null}\) mice engrafted with human CD34+ hematopoietic stem cells) locally with S. aureus USA300 LAC* lux into the thigh muscle in order to investigate the human immune response to acute and chronic infection. These mice proved not only to be more susceptible to MRSA infection than wild-type or "murinized" mice, but displayed furthermore inferior survival and signs of systemic infection in an otherwise localized infection model. The rate of humanization correlated directly with the severity of disease and survival of the mice. Human and murine cytokine levels in blood and at the primary site of infection were strongly elevated in huNSG mice compared to all control groups. And importantly, differences in human and murine immune cell lineages surfaced during the infection, with human monocyte and B cell numbers in blood and bone marrow being significantly reduced at the later time point of infection. Murine monocytes in contrast behaved conversely by increasing cell numbers. This study demonstrates significant differences in the in vivo behavior of human and murine cells towards S. aureus infection, which might help to sharpen the translational potential of pre-clinical models for future therapeutic approaches.},
  language  = {en}
}
@article{SaintFleurLominyMausVaethetal.2018,
  author    = {Saint Fleur-Lominy, Shella and Maus, Mate and Vaeth, Martin and Lange, Ingo and Zee, Isabelle and Suh, David and Liu, Cynthia and Wu, Xiaojun and Tikhonova, Anastasia and Aifantis, Iannis and Feske, Stefan},
  title     = {STIM1 and STIM2 Mediate Cancer-Induced Inflammation in T Cell Acute Lymphoblastic Leukemia},
  series = {Cell Reports},
  volume    = {24},
  journal   = {Cell Reports},
  number    = {11},
  doi       = {10.1016/j.celrep.2018.08.030},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227259},
  pages     = {3045-3060},
  year      = {2018},
  abstract  = {T cell acute lymphoblastic leukemia (T-ALL) is commonly associated with activating mutations in the NOTCH1 pathway. Recent reports have shown a link between NOTCH1 signaling and intracellular Ca2+ homeostasis in T-ALL. Here, we investigate the role of store-operated Ca2+ entry (SOCE) mediated by the Ca2+ channel ORAI1 and its activators STIM1 and STIM2 in T-ALL. Deletion of STIM1 and STIM2 in leukemic cells abolishes SOCE and significantly prolongs the survival of mice in a NOTCH1-dependent model of T-ALL. The survival advantage is unrelated to the leukemic cell burden but is associated with the SOCE-dependent ability of malignant T lymphoblasts to cause inflammation in leukemia-infiltrated organs. Mice with STIM1/STIM2-deficient T-ALL show a markedly reduced necroinflammatory response in leukemia-infiltrated organs and downregulation of signaling pathways previously linked to cancer-induced inflammation. Our study shows that leukemic T lymphoblasts cause inflammation of leukemia-infiltrated organs that is dependent on SOCE.},
  language  = {en}
}
@article{KarnatiGuntasRajendranetal.2022,
  author    = {Karnati, Srikanth and Guntas, Gulcan and Rajendran, Ranjithkumar and Shityakov, Sergey and H{\"o}ring, Marcus and Liebisch, Gerhard and Kosanovic, Djuro and Erg{\"u}n, S{\"u}leyman and Nagai, Michiaki and F{\"o}rster, Carola Y.},
  title     = {Quantitative lipidomic analysis of Takotsubo syndrome patients' serum},
  series = {Frontiers in Cardiovascular Medicine},
  volume    = {9},
  journal   = {Frontiers in Cardiovascular Medicine},
  number    = {797154},
  issn      = {2297-055X},
  doi       = {10.3389/fcvm.2022.797154},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-270832},
  year      = {2022},
  abstract  = {Takotsubo syndrome (TTS), also known as the transient left ventricular apical ballooning syndrome, is in contemporary times known as novel acute cardiac syndrome. It is characterized by transient left ventricular apical akinesis and hyperkinesis of the basal left ventricular portions. Although the precise etiology of TTS is unknown, events like the sudden release of stress hormones, such as the catecholamines and the increased inflammatory status might be plausible causes leading to the cardiovascular pathologies. Recent studies have highlighted that an imbalance in lipid accumulation might promote a deviant immune response as observed in TTS. However, there is no information on comprehensive profiling of serum lipids of TTS patients. Therefore, we investigated a detailed quantitative lipid analysis of TTS patients using ES-MSI. Our results showed significant differences in the majority of lipid species composition in the TTS patients compared to the control group. Furthermore, the computational analyses presented was able to link the altered lipids to the pro-inflammatory cytokines and disseminate possible mechanistic pathways involving TNFα and IL-6. Taken together, our study provides an extensive quantitative lipidome of TTS patients, which may provide a valuable Pre-diagnostic tool. This would facilitate the elucidation of the underlying mechanisms of the disease and to prevent the development of TTS in the future.},
  language  = {en}
}
@article{Freitag‐WolfMunzJungeetal.2021,
  author    = {Freitag-Wolf, Sandra and Munz, Matthias and Junge, Olaf and Graetz, Christian and Jockel-Schneider, Yvonne and Staufenbiel, Ingmar and Bruckmann, Corinna and Lieb, Wolfgang and Franke, Andre and Loos, Bruno G. and Jepsen, S{\o}ren and Dommisch, Henrik and Schaefer, Arne S.},
  title     = {Sex-specific genetic factors affect the risk of early-onset periodontitis in Europeans},
  series = {Journal of Clinical Periodontology},
  volume    = {48},
  journal   = {Journal of Clinical Periodontology},
  number    = {11},
  doi       = {10.1111/jcpe.13538},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-262445},
  pages     = {1404 -- 1413},
  year      = {2021},
  abstract  = {Aims Various studies have reported that young European women are more likely to develop early-onset periodontitis compared to men. A potential explanation for the observed variations in sex and age of disease onset is the natural genetic variation within the autosomal genomes. We hypothesized that genotype-by-sex (G × S) interactions contribute to the increased prevalence and severity. Materials and methods Using the case-only design, we tested for differences in genetic effects between men and women in 896 North-West European early-onset cases, using imputed genotypes from the OmniExpress genotyping array. Population-representative 6823 controls were used to verify that the interacting variables G and S were uncorrelated in the general population. Results In total, 20 loci indicated G × S associations (P < 0.0005), 3 of which were previously suggested as risk genes for periodontitis (ABLIM2, CDH13, and NELL1). We also found independent G × S interactions of the related gene paralogs MACROD1/FLRT1 (chr11) and MACROD2/FLRT3 (chr20). G × S-associated SNPs at CPEB4, CDH13, MACROD1, and MECOM were genome-wide-associated with heel bone mineral density (CPEB4, MECOM), waist-to-hip ratio (CPEB4, MACROD1), and blood pressure (CPEB4, CDH13). Conclusions Our results indicate that natural genetic variation affects the different heritability of periodontitis among sexes and suggest genes that contribute to inter-sex phenotypic variation in early-onset periodontitis.},
  language  = {en}
}
@article{GrassingerFlorenMuelleretal.2021,
  author    = {Grassinger, Julia Maria and Floren, Andreas and M{\"u}ller, Tobias and Cerezo-Echevarria, Argi{\~n}e and Beitzinger, Christoph and Conrad, David and T{\"o}rner, Katrin and Staudacher, Marlies and Aupperle-Lellbach, Heike},
  title     = {Digital lesions in dogs: a statistical breed analysis of 2912 cases},
  series = {Veterinary Sciences},
  volume    = {8},
  journal   = {Veterinary Sciences},
  number    = {7},
  issn      = {2306-7381},
  doi       = {10.3390/vetsci8070136},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-242690},
  year      = {2021},
  abstract  = {Breed predispositions to canine digital neoplasms are well known. However, there is currently no statistical analysis identifying the least affected breeds. To this end, 2912 canine amputated digits submitted from 2014-2019 to the Laboklin GmbH \& Co. KG for routine diagnostics were statistically analyzed. The study population consisted of 155 different breeds (most common: 634 Mongrels, 411 Schnauzers, 197 Labrador Retrievers, 93 Golden Retrievers). Non-neoplastic processes were present in 1246 (43\%), tumor-like lesions in 138 (5\%), and neoplasms in 1528 cases (52\%). Benign tumors (n = 335) were characterized by 217 subungual keratoacanthomas, 36 histiocytomas, 35 plasmacytomas, 16 papillomas, 12 melanocytomas, 9 sebaceous gland tumors, 6 lipomas, and 4 bone tumors. Malignant neoplasms (n = 1193) included 758 squamous cell carcinomas (SCC), 196 malignant melanomas (MM), 76 soft tissue sarcomas, 52 mast cell tumors, 37 non-specified sarcomas, 29 anaplastic neoplasms, 24 carcinomas, 20 bone tumors, and 1 histiocytic sarcoma. Predisposed breeds for SCC included the Schnauzer (log OR = 2.61), Briard (log OR = 1.78), Rottweiler (log OR = 1.54), Poodle (log OR = 1.40), and Dachshund (log OR = 1.30). Jack Russell Terriers (log OR = -2.95) were significantly less affected by SCC than Mongrels. Acral MM were significantly more frequent in Rottweilers (log OR = 1.88) and Labrador Retrievers (log OR = 1.09). In contrast, Dachshunds (log OR = -2.17), Jack Russell Terriers (log OR = -1.88), and Rhodesian Ridgebacks (log OR = -1.88) were rarely affected. This contrasted with the well-known predisposition of Dachshunds and Rhodesian Ridgebacks to oral and cutaneous melanocytic neoplasms. Further studies are needed to explain the underlying reasons for breed predisposition or "resistance" to the development of specific acral tumors and/or other sites.},
  language  = {en}
}
@article{SchaeferZernecke2020,
  author    = {Sch{\"a}fer, Sarah and Zernecke, Alma},
  title     = {CD8\(^+\) T cells in atherosclerosis},
  series = {Cells},
  volume    = {10},
  journal   = {Cells},
  number    = {1},
  issn      = {2073-4409},
  doi       = {10.3390/cells10010037},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-220170},
  year      = {2020},
  abstract  = {Atherosclerotic lesions are populated by cells of the innate and adaptive immune system, including CD8\(^+\) T cells. The CD8\(^+\) T cell infiltrate has recently been characterized in mouse and human atherosclerosis and revealed activated, cytotoxic, and possibly dysfunctional and exhausted cell phenotypes. In mouse models of atherosclerosis, antibody-mediated depletion of CD8\(^+\) T cells ameliorates atherosclerosis. CD8\(^+\) T cells control monopoiesis and macrophage accumulation in early atherosclerosis. In addition, CD8\(^+\) T cells exert cytotoxic functions in atherosclerotic plaques and contribute to macrophage cell death and necrotic core formation. CD8\(^+\) T cell activation may be antigen-specific, and epitopes of atherosclerosis-relevant antigens may be targets of CD8\(^+\) T cells and their cytotoxic activity. CD8\(^+\) T cell functions are tightly controlled by costimulatory and coinhibitory immune checkpoints. Subsets of regulatory CD25\(^+\)CD8\(^+\) T cells with immunosuppressive functions can inhibit atherosclerosis. Importantly, local cytotoxic CD8\(^+\) T cell responses may trigger endothelial damage and plaque erosion in acute coronary syndromes. Understanding the complex role of CD8\(^+\) T cells in atherosclerosis may pave the way for defining novel treatment approaches in atherosclerosis. In this review article, we discuss these aspects, highlighting the emerging and critical role of CD8\(^+\) T cells in atherosclerosis.},
  language  = {en}
}
@article{LauruschkatPageWhiteetal.2021,
  author    = {Lauruschkat, Chris D. and Page, Lukas and White, P. Lewis and Etter, Sonja and Davies, Helen E. and Duckers, Jamie and Ebel, Frank and Schnack, Elisabeth and Backx, Matthijs and Dragan, Mariola and Schlegel, Nicolas and Kniemeyer, Olaf and Brakhage, Axel A. and Einsele, Hermann and Loeffler, Juergen and Wurster, Sebastian},
  title     = {Development of a simple and robust whole blood assay with dual co-stimulation to quantify the release of T-cellular signature cytokines in response to Aspergillus fumigatus antigens},
  series = {Journal of Fungi},
  volume    = {7},
  journal   = {Journal of Fungi},
  number    = {6},
  issn      = {2309-608X},
  doi       = {10.3390/jof7060462},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-241025},
  year      = {2021},
  abstract  = {Deeper understanding of mold-induced cytokine signatures could promote advances in the diagnosis and treatment of invasive mycoses and mold-associated hypersensitivity syndromes. Currently, most T-cellular immunoassays in medical mycology require the isolation of mononuclear cells and have limited robustness and practicability, hampering their broader applicability in clinical practice. Therefore, we developed a simple, cost-efficient whole blood (WB) assay with dual α-CD28 and α-CD49d co-stimulation to quantify cytokine secretion in response to Aspergillus fumigatus antigens. Dual co-stimulation strongly enhanced A. fumigatus-induced release of T-cellular signature cytokines detectable by enzyme-linked immunosorbent assay (ELISA) or a multiplex cytokine assay. Furthermore, T-cell-dependent activation and cytokine response of innate immune cells was captured by the assay. The protocol consistently showed little technical variation and high robustness to pre-analytic delays of up to 8 h. Stimulation with an A. fumigatus lysate elicited at least 7-fold greater median concentrations of key T-helper cell signature cytokines, including IL-17 and the type 2 T-helper cell cytokines IL-4 and IL-5 in WB samples from patients with Aspergillus-associated lung pathologies versus patients with non-mold-related lung diseases, suggesting high discriminatory power of the assay. These results position WB-ELISA with dual co-stimulation as a simple, accurate, and robust immunoassay for translational applications, encouraging further evaluation as a platform to monitor host immunity to opportunistic pathogens.},
  language  = {en}
}
@article{OelschlaegelWeissSadanSalpeteretal.2020,
  author    = {Oelschlaegel, Diana and Weiss Sadan, Tommy and Salpeter, Seth and Krug, Sebastian and Blum, Galia and Schmitz, Werner and Schulze, Almut and Michl, Patrick},
  title     = {Cathepsin inhibition modulates metabolism and polarization of tumor-associated macrophages},
  series = {Cancers},
  volume    = {12},
  journal   = {Cancers},
  number    = {9},
  issn      = {2072-6694},
  doi       = {10.3390/cancers12092579},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-213040},
  year      = {2020},
  abstract  = {Stroma-infiltrating immune cells, such as tumor-associated macrophages (TAM), play an important role in regulating tumor progression and chemoresistance. These effects are mostly conveyed by secreted mediators, among them several cathepsin proteases. In addition, increasing evidence suggests that stroma-infiltrating immune cells are able to induce profound metabolic changes within the tumor microenvironment. In this study, we aimed to characterize the impact of cathepsins in maintaining the TAM phenotype in more detail. For this purpose, we investigated the molecular effects of pharmacological cathepsin inhibition on the viability and polarization of human primary macrophages as well as its metabolic consequences. Pharmacological inhibition of cathepsins B, L, and S using a novel inhibitor, GB111-NH\(_2\), led to changes in cellular recycling processes characterized by an increased expression of autophagy- and lysosome-associated marker genes and reduced adenosine triphosphate (ATP) content. Decreased cathepsin activity in primary macrophages further led to distinct changes in fatty acid metabolites associated with increased expression of key modulators of fatty acid metabolism, such as fatty acid synthase (FASN) and acid ceramidase (ASAH1). The altered fatty acid profile was associated with an increased synthesis of the pro-inflammatory prostaglandin PGE\(_2\), which correlated with the upregulation of numerous NF\(_k\)B-dependent pro-inflammatory mediators, including interleukin-1 (IL-1), interleukin-6 (IL-6), C-C motif chemokine ligand 2 (CCL2), and tumor necrosis factor-alpha (TNFα). Our data indicate a novel link between cathepsin activity and metabolic reprogramming in macrophages, demonstrated by a profound impact on autophagy and fatty acid metabolism, which facilitates a pro-inflammatory micromilieu generally associated with enhanced tumor elimination. These results provide a strong rationale for therapeutic cathepsin inhibition to overcome the tumor-promoting effects of the immune-evasive tumor micromilieu.},
  language  = {en}
}
@article{BuddeHassounTangosetal.2021,
  author    = {Budde, Heidi and Hassoun, Roua and Tangos, Melina and Zhazykbayeva, Saltanat and Herwig, Melissa and Varatnitskaya, Marharyta and Sieme, Marcel and Delalat, Simin and Sultana, Innas and Kolijn, Detmar and G{\"o}m{\"o}ri, Kamilla and Jarkas, Muhammad and L{\´o}di, M{\´a}ria and Jaquet, Kornelia and Kov{\´a}cs, {\´A}rp{\´a}d and Mannherz, Hans Georg and Sequeira, Vasco and M{\"u}gge, Andreas and Leichert, Lars I. and Sossalla, Samuel and Hamdani, Nazha},
  title     = {The interplay between S-glutathionylation and phosphorylation of cardiac troponin I and myosin binding protein C in end-stage human failing hearts},
  series = {Antioxidants},
  volume    = {10},
  journal   = {Antioxidants},
  number    = {7},
  issn      = {2076-3921},
  doi       = {10.3390/antiox10071134},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-242701},
  year      = {2021},
  abstract  = {Oxidative stress is defined as an imbalance between the antioxidant defense system and the production of reactive oxygen species (ROS). At low levels, ROS are involved in the regulation of redox signaling for cell protection. However, upon chronical increase in oxidative stress, cell damage occurs, due to protein, DNA and lipid oxidation. Here, we investigated the oxidative modifications of myofilament proteins, and their role in modulating cardiomyocyte function in end-stage human failing hearts. We found altered maximum Ca\(^{2+}\)-activated tension and Ca\(^{2+}\) sensitivity of force production of skinned single cardiomyocytes in end-stage human failing hearts compared to non-failing hearts, which was corrected upon treatment with reduced glutathione enzyme. This was accompanied by the increased oxidation of troponin I and myosin binding protein C, and decreased levels of protein kinases A (PKA)- and C (PKC)-mediated phosphorylation of both proteins. The Ca\(^{2+}\) sensitivity and maximal tension correlated strongly with the myofilament oxidation levels, hypo-phosphorylation, and oxidative stress parameters that were measured in all the samples. Furthermore, we detected elevated titin-based myocardial stiffness in HF myocytes, which was reversed by PKA and reduced glutathione enzyme treatment. Finally, many oxidative stress and inflammation parameters were significantly elevated in failing hearts compared to non-failing hearts, and corrected upon treatment with the anti-oxidant GSH enzyme. Here, we provide evidence that the altered mechanical properties of failing human cardiomyocytes are partially due to phosphorylation, S-glutathionylation, and the interplay between the two post-translational modifications, which contribute to the development of heart failure.},
  language  = {en}
}
@article{WeilandBeezWestermaieretal.2021,
  author    = {Weiland, Judith and Beez, Alexandra and Westermaier, Thomas and Kunze, Ekkehard and Sir{\´e}n, Anna-Leena and Lilla, Nadine},
  title     = {Neuroprotective strategies in aneurysmal subarachnoid hemorrhage (aSAH)},
  series = {International Journal of Molecular Sciences},
  volume    = {22},
  journal   = {International Journal of Molecular Sciences},
  number    = {11},
  issn      = {1422-0067},
  doi       = {10.3390/ijms22115442},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260755},
  year      = {2021},
  abstract  = {Aneurysmal subarachnoid hemorrhage (aSAH) remains a disease with high mortality and morbidity. Since treating vasospasm has not inevitably led to an improvement in outcome, the actual emphasis is on finding neuroprotective therapies in the early phase following aSAH to prevent secondary brain injury in the later phase of disease. Within the early phase, neuroinflammation, thromboinflammation, disturbances in brain metabolism and early neuroprotective therapies directed against delayed cerebral ischemia (DCI) came into focus. Herein, the role of neuroinflammation, thromboinflammation and metabolism in aSAH is depicted. Potential neuroprotective strategies regarding neuroinflammation target microglia activation, metalloproteases, autophagy and the pathway via Toll-like receptor 4 (TLR4), high mobility group box 1 (HMGB1), NF-κB and finally the release of cytokines like TNFα or IL-1. Following the link to thromboinflammation, potential neuroprotective therapies try to target microthrombus formation, platelets and platelet receptors as well as clot clearance and immune cell infiltration. Potential neuroprotective strategies regarding metabolism try to re-balance the mismatch of energy need and supply following aSAH, for example, in restoring fuel to the TCA cycle or bypassing distinct energy pathways. Overall, this review addresses current neuroprotective strategies in aSAH, hopefully leading to future translational therapy options to prevent secondary brain injury.},
  language  = {en}
}
@article{MorbachBeyersdorfKerkauetal.2021,
  author    = {Morbach, Caroline and Beyersdorf, Niklas and Kerkau, Thomas and Ramos, Gustavo and Sahiti, Floran and Albert, Judith and Jahns, Roland and Ertl, Georg and Angermann, Christiane E. and Frantz, Stefan and Hofmann, Ulrich and St{\"o}rk, Stefan},
  title     = {Adaptive anti-myocardial immune response following hospitalization for acute heart failure},
  series = {ESC Heart Failure},
  volume    = {8},
  journal   = {ESC Heart Failure},
  number    = {4},
  doi       = {10.1002/ehf2.13376},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258907},
  pages     = {3348-3353},
  year      = {2021},
  abstract  = {Aims It has been hypothesized that cardiac decompensation accompanying acute heart failure (AHF) episodes generates a pro-inflammatory environment boosting an adaptive immune response against myocardial antigens, thus contributing to progression of heart failure (HF) and poor prognosis. We assessed the prevalence of anti-myocardial autoantibodies (AMyA) as biomarkers reflecting adaptive immune responses in patients admitted to the hospital for AHF, followed the change in AMyA titres for 6 months after discharge, and evaluated their prognostic utility. Methods and results AMyA were determined in n = 47 patients, median age 71 (quartiles 60; 80) years, 23 (49\%) female, and 24 (51\%) with HF with preserved ejection fraction, from blood collected at baseline (time point of hospitalization) and at 6 month follow-up (visit F6). Patients were followed for 18 months (visit F18). The prevalence of AMyA increased from baseline (n = 21, 45\%) to F6 (n = 36, 77\%; P < 0.001). At F6, the prevalence of AMyA was higher in patients with HF with preserved ejection fraction (n = 21, 88\%) compared with patients with reduced ejection fraction (n = 14, 61\%; P = 0.036). During the subsequent 12 months after F6, that is up to F18, patients with newly developed AMyA at F6 had a higher risk for the combined endpoint of death or rehospitalization for HF (hazard ratio 4.79, 95\% confidence interval 1.13-20.21; P = 0.033) compared with patients with persistent or without AMyA at F6. Conclusions Our results support the hypothesis that AHF may induce patterns of adaptive immune responses. More studies in larger populations and well-defined patient subgroups are needed to further clarify the role of the adaptive immune system in HF progression.},
  language  = {en}
}
@article{HeitmannFringsGeieretal.2021,
  author    = {Heitmann, Johanna and Frings, Verena G. and Geier, Andreas and Goebeler, Matthias and Kerstan, Andreas},
  title     = {Non-alcoholic fatty liver disease and psoriasis - is there a shared proinflammatory network?},
  series = {Journal der Deutschen Dermatologischen Gesellschaft},
  volume    = {19},
  journal   = {Journal der Deutschen Dermatologischen Gesellschaft},
  number    = {4},
  doi       = {10.1111/ddg.14425},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258424},
  pages     = {517-528},
  year      = {2021},
  abstract  = {Psoriasis is an immune-mediated systemic inflammatory disease that is not limited to the skin but may be associated with arthritis, cardiovascular diseases, metabolic syndrome including diabetes and obesity and, as identified more recently, non-alcoholic fatty liver disease (NAFLD) that occurs in approximately 50 \% of all patients with psoriasis. NAFLD is characterized by accumulation of fat in hepatocytes in the absence of excessive alcohol consumption. Over the last two decades, NAFLD has developed to the most common chronic liver disease with an estimated prevalence of 25 \% in the Western population. NAFLD ranges from non-inflammatory or bland hepatic steatosis to inflammation of hepatic tissue (non-alcoholic steatohepatitis, NASH) and consecutive liver fibrosis. It is controversial whether the underlying systemic inflammation of psoriasis is contributing to development of NAFLD or if comorbid diseases such as obesity enhance NAFLD development. Recent findings indicate that cytokine-mediated inflammation through TNFα, interleukin (IL)-6 and IL-17 might be the common link between psoriasis and NAFLD. Considering the shared inflammatory pathways, IL-17 pharmacological blockade, which is already well-established for psoriasis, may be a promising strategy to treat both psoriasis and NAFLD. Therefore, early detection of NAFLD and a better understanding of its pathophysiology in the context of the systemic inflammation in psoriasis is important with regard to individualized treatment approaches.},
  language  = {en}
}
@article{GraserLiedtkeJakob2021,
  author    = {Graser, Stephanie and Liedtke, Daniel and Jakob, Franz},
  title     = {TNAP as a new player in chronic inflammatory conditions and metabolism},
  series = {International Journal of Molecular Sciences},
  volume    = {22},
  journal   = {International Journal of Molecular Sciences},
  number    = {2},
  issn      = {1422-0067},
  doi       = {10.3390/ijms22020919},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258888},
  year      = {2021},
  abstract  = {This review summarizes important information on the ectoenzyme tissue-nonspecific alkaline phosphatase (TNAP) and gives a brief insight into the symptoms, diagnostics, and treatment of the rare disease Hypophosphatasia (HPP), which is resulting from mutations in the TNAP encoding ALPL gene. We emphasize the role of TNAP beyond its well-known contribution to mineralization processes. Therefore, above all, the impact of the enzyme on central molecular processes in the nervous system and on inflammation is presented here.},
  language  = {en}
}
@phdthesis{Leinweber2022,
  author    = {Leinweber, Jonas},
  title     = {Untersuchung zur pathophysiologischen Rolle und therapeutischen Relevanz der neuen Inhibitoren der plasmatischen Blutgerinnung Agaphelin und Ixolaris im experimentellen Schlaganfallmodell der Maus},
  doi       = {10.25972/OPUS-25292},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-252921},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2022},
  abstract  = {Beim isch{\"a}mischen Schlaganfall f{\"u}hrt ein thrombotischer Verschluss von gehirnversorgenden Arterien zu einer akuten Durchblutungsst{\"o}rung, mit der Folge von neurologischen Defiziten. Prim{\"a}res Therapieziel ist es, diese Blutgerinnsel aufzul{\"o}sen, um die Sauerstoffversorgung des Gehirns wiederherzustellen und den isch{\"a}mischen Hirnschaden zu begrenzen. Dazu stehen die intraven{\"o}sen Thrombolyse mit rt-PA (rekombinanter Gewebe-Plasminogen-Aktivator) sowie die endovaskul{\"a}re mechanische Thrombektomie zur Verf{\"u}gung. H{\"a}ufig kann ein Schlaganfall, trotz erfolgreicher Rekanalisation der Gef{\"a}ße, zu einer weiteren Gr{\"o}ßenzunahme des Infarktes und neurologischen Defiziten bei den Patienten f{\"u}hren. Diese Gr{\"o}ßenzunahme beruht zum einen auf einem sich entwickelnden Hirn{\"o}dem und zum anderen auf entz{\"u}ndlichen Prozessen. Zahlreiche Hinweise deuten darauf hin, dass der Schlaganfall ein Zusammenspiel aus thrombotischen und entz{\"u}ndlichen Ereignissen ist, ein Ph{\"a}nomen, das als Thromboinflammation bezeichnet wird. Aufgrund der begrenzten Behandlungsm{\"o}glichkeiten ist die Entwicklung neuer Therapieans{\"a}tze f{\"u}r den isch{\"a}mischen Schlaganfall besonders wichtig. Agaphelin und Ixolaris sind Proteine aus den Speicheldr{\"u}sen von H{\"a}matophagen, f{\"u}r welche in fr{\"u}heren Studien eine starke antithrombotische Wirkung bei gleichzeitig geringem Blutungsrisiko nachgewiesen wurde. Diese m{\"o}glichen antithrombotischen Effekte wurden in dieser Studie im Hinblick auf ihre Wirksamkeit und Sicherheit im Mausmodell der zerebralen Isch{\"a}mie untersucht. Die Behandlung der M{\"a}use mit Agaphelin 1 Stunde nach transienter Okklusion der Arteria cerebri media (tMCAO) f{\"u}hrte zu kleineren Schlaganfallvolumina und geringeren neurologischen Defiziten an Tag 1 nach dem Schlaganfall. Die Mortalit{\"a}t der M{\"a}use war bis Tag 7 deutlich gesunken. Aus klinischer Sicht ist ebenfalls relevant, dass der starke antithrombotische Effekt von Agaphelin im Mausmodell nicht mit einem erh{\"o}hten Risiko f{\"u}r intrazerebrale Blutungen einherging. Diesem protektiven Effekt von Agaphelin lagen eine verminderte intrazerebrale Thrombusbildung, eine abgeschw{\"a}chte Entz{\"u}ndungsantwort und eine Stabilisierung der Blut-Hirn-Schranke sowie eine Reduzierung der Apoptose zugrunde. Nach der Gabe von Ixolaris 1 Stunde nach tMCAO waren zwar signifikant geringere Infarktgr{\"o}ßen messbar, diese f{\"u}hrten allerdings nicht zu einer Verbesserung der neurologischen Defizite. Zudem verursachte die Gabe von Ixolaris schon 24 Stunden nach tMCAO erhebliche intrazerebrale Blutungen und auch die Mortalit{\"a}t der M{\"a}use war zu diesem Zeitpunkt bereits erh{\"o}ht. Aufgrund dieser massiven Nebenwirkungen scheint Ixolaris kein geeigneter Kandidat f{\"u}r eine humane Anwendung zu sein. Bei Agaphelin hingegen k{\"o}nnte es sich um einen vielversprechenden Kandidaten f{\"u}r die Behandlung des isch{\"a}mischen Schlaganfalls handeln. Vor einer m{\"o}glichen Testung von Agaphelin in klinischen Studien, sind weitere translationale Untersuchungen notwendig, um ein noch pr{\"a}ziseres Verst{\"a}ndnis f{\"u}r die Wirksamkeit und Sicherheit von Agaphelin zu gewinnen. Insgesamt stellt die Hemmung thromboinflammatorischer Prozesse, ohne eine Erh{\"o}hung der Blutungskomplikationen, eine vielversprechende Option zur Behandlung des isch{\"a}mischen Schlaganfalls dar.},
  subject      = {Schlaganfall},
  language  = {de}
}
@article{BurkardMeirKannapinetal.2021,
  author    = {Burkard, Natalie and Meir, Michael and Kannapin, Felix and Otto, Christoph and Petzke, Maximilian and Germer, Christoph-Thomas and Waschke, Jens and Schlegel, Nicolas},
  title     = {Desmoglein2 Regulates Claudin2 Expression by Sequestering PI-3-Kinase in Intestinal Epithelial Cells},
  series = {Frontiers in Immunology},
  volume    = {12},
  journal   = {Frontiers in Immunology},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2021.756321},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-247059},
  year      = {2021},
  abstract  = {Inflammation-induced reduction of intestinal desmosomal cadherin Desmoglein 2 (Dsg2) is linked to changes of tight junctions (TJ) leading to impaired intestinal epithelial barrier (IEB) function by undefined mechanisms. We characterized the interplay between loss of Dsg2 and upregulation of pore-forming TJ protein Claudin2. Intraperitoneal application of Dsg2-stablising Tandem peptide (TP) attenuated impaired IEB function, reduction of Dsg2 and increased Claudin2 in DSS-induced colitis in C57Bl/6 mice. TP blocked loss of Dsg2-mediated adhesion and upregulation of Claudin2 in Caco2 cells challenged with TNFα. In Dsg2-deficient Caco2 cells basal expression of Claudin2 was increased which was paralleled by reduced transepithelial electrical resistance and by augmented phosphorylation of AKT\(^{Ser473}\) under basal conditions. Inhibition of phosphoinositid-3-kinase proved that PI-3-kinase/AKT-signaling is critical to upregulate Claudin2. In immunostaining PI-3-kinase dissociated from Dsg2 under inflammatory conditions. Immunoprecipitations and proximity ligation assays confirmed a direct interaction of Dsg2 and PI-3-kinase which was abrogated following TNFα application. In summary, Dsg2 regulates Claudin2 expression by sequestering PI-3-kinase to the cell borders in intestinal epithelium.},
  language  = {en}
}
@article{FroehlichSerflingHiguchietal.2021,
  author    = {Fr{\"o}hlich, Matthias and Serfling, Sebastian and Higuchi, Takahiro and Pomper, Martin G. and Rowe, Steven P. and Schmalzing, Marc and Tony, Hans-Peter and Gernert, Michael and Strunz, Patrick-Pascal and Portegys, Jan and Schwaneck, Eva-Christina and Gadeholt, Ottar and Weich, Alexander and Buck, Andreas K. and Bley, Thorsten A. and Guggenberger, Konstanze V. and Werner, Rudolf A.},
  title     = {Whole-Body [\(^{18}\)F]FDG PET/CT Can Alter Diagnosis in Patients with Suspected Rheumatic Disease},
  series = {Diagnostics},
  volume    = {11},
  journal   = {Diagnostics},
  number    = {11},
  issn      = {2075-4418},
  doi       = {10.3390/diagnostics11112073},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250227},
  year      = {2021},
  abstract  = {The 2-deoxy-d-[\(^{18}\)F]fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) is widely utilized to assess the vascular and articular inflammatory burden of patients with a suspected diagnosis of rheumatic disease. We aimed to elucidate the impact of [\(^{18}\)F]FDG PET/CT on change in initially suspected diagnosis in patients at the time of the scan. Thirty-four patients, who had undergone [\(^{18}\)F]FDG PET/CT, were enrolled and the initially suspected diagnosis prior to [18F]FDG PET/CT was compared to the final diagnosis. In addition, a semi-quantitative analysis including vessel wall-to-liver (VLR) and joint-to-liver (JLR) ratios was also conducted. Prior to [\(^{18}\)F]FDG PET/CT, 22/34 (64.7\%) of patients did not have an established diagnosis, whereas in 7/34 (20.6\%), polymyalgia rheumatica (PMR) was suspected, and in 5/34 (14.7\%), giant cell arteritis (GCA) was suspected by the referring rheumatologists. After [\(^{18}\)F]FDG PET/CT, the diagnosis was GCA in 19/34 (55.9\%), combined GCA and PMR (GCA + PMR) in 9/34 (26.5\%) and PMR in the remaining 6/34 (17.6\%). As such, [\(^{18}\)F]FDG PET/CT altered suspected diagnosis in 28/34 (82.4\%), including in all unclear cases. VLR of patients whose final diagnosis was GCA tended to be significantly higher when compared to VLR in PMR (GCA, 1.01 ± 0.08 (95\%CI, 0.95-1.1) vs. PMR, 0.92 ± 0.1 (95\%CI, 0.85-0.99), p = 0.07), but not when compared to PMR + GCA (1.04 ± 0.14 (95\%CI, 0.95-1.13), p = 1). JLR of individuals finally diagnosed with PMR (0.94 ± 0.16, (95\%CI, 0.83-1.06)), however, was significantly increased relative to JLR in GCA (0.58 ± 0.04 (95\%CI, 0.55-0.61)) and GCA + PMR (0.64 ± 0.09 (95\%CI, 0.57-0.71); p < 0.0001, respectively). In individuals with a suspected diagnosis of rheumatic disease, an inflammatory-directed [\(^{18}\)F]FDG PET/CT can alter diagnosis in the majority of the cases, particularly in subjects who were referred because of diagnostic uncertainty. Semi-quantitative assessment may be helpful in establishing a final diagnosis of PMR, supporting the notion that a quantitative whole-body read-out may be useful in unclear cases.},
  language  = {en}
}
@article{OckermannHeadleyLizioetal.2021,
  author    = {Ockermann, Philipp and Headley, Laura and Lizio, Rosario and Hansmann, Jan},
  title     = {A Review of the Properties of Anthocyanins and Their Influence on Factors Affecting Cardiometabolic and Cognitive Health},
  series = {Nutrients},
  volume    = {13},
  journal   = {Nutrients},
  number    = {8},
  issn      = {2072-6643},
  doi       = {10.3390/nu13082831},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-245116},
  year      = {2021},
  abstract  = {The incidence of cardiovascular and metabolic diseases has increased over the last decades and is an important cause of death worldwide. An upcoming ingredient on the nutraceutical market are anthocyanins, a flavonoid subgroup, abundant mostly in berries and fruits. Epidemiological studies have suggested an association between anthocyanin intake and improved cardiovascular risk, type 2 diabetes and myocardial infarct. Clinical studies using anthocyanins have shown a significant decrease in inflammation markers and oxidative stress, a beneficial effect on vascular function and hyperlipidemia by decreasing low-density lipoprotein and increasing high-density lipoprotein. They have also shown a potential effect on glucose homeostasis and cognitive decline. This review summarizes the effects of anthocyanins in in-vitro, animal and human studies to give an overview of their application in medical prevention or as a dietary supplement.},
  language  = {en}
}
@article{PoppSchmittBoehrerLangeretal.2021,
  author    = {Popp, Sandy and Schmitt-B{\"o}hrer, Angelika and Langer, Simon and Hofmann, Ulrich and Hommers, Leif and Schuh, Kai and Frantz, Stefan and Lesch, Klaus-Peter and Frey, Anna},
  title     = {5-HTT Deficiency in Male Mice Affects Healing and Behavior after Myocardial Infarction},
  series = {Journal of Clinical Medicine},
  volume    = {10},
  journal   = {Journal of Clinical Medicine},
  number    = {14},
  issn      = {2077-0383},
  doi       = {10.3390/jcm10143104},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-242739},
  year      = {2021},
  abstract  = {Anxiety disorders and depression are common comorbidities in cardiac patients. Mice lacking the serotonin transporter (5-HTT) exhibit increased anxiety-like behavior. However, the role of 5-HTT deficiency on cardiac aging, and on healing and remodeling processes after myocardial infarction (MI), remains unclear. Cardiological evaluation of experimentally na{\"i}ve male mice revealed a mild cardiac dysfunction in ≥4-month-old 5-HTT knockout (-/-) animals. Following induction of chronic cardiac dysfunction (CCD) by MI vs. sham operation 5-HTT-/- mice with infarct sizes >30\% experienced 100\% mortality, while 50\% of 5-HTT+/- and 37\% of 5-HTT+/+ animals with large MI survived the 8-week observation period. Surviving (sham and MI < 30\%) 5-HTT-/- mutants displayed reduced exploratory activity and increased anxiety-like behavior in different approach-avoidance tasks. However, CCD failed to provoke a depressive-like behavioral response in either 5-Htt genotype. Mechanistic analyses were performed on mice 3 days post-MI. Electrocardiography, histology and FACS of inflammatory cells revealed no abnormalities. However, gene expression of inflammation-related cytokines (TGF-β, TNF-α, IL-6) and MMP-2, a protein involved in the breakdown of extracellular matrix, was significantly increased in 5-HTT-/- mice after MI. This study shows that 5-HTT deficiency leads to age-dependent cardiac dysfunction and disrupted early healing after MI probably due to alterations of inflammatory processes in mice.},
  language  = {en}
}
@article{AndelovicWinterJakobetal.2021,
  author    = {Andelovic, Kristina and Winter, Patrick and Jakob, Peter Michael and Bauer, Wolfgang Rudolf and Herold, Volker and Zernecke, Alma},
  title     = {Evaluation of plaque characteristics and inflammation using magnetic resonance imaging},
  series = {Biomedicines},
  volume    = {9},
  journal   = {Biomedicines},
  number    = {2},
  issn      = {2227-9059},
  doi       = {10.3390/biomedicines9020185},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228839},
  year      = {2021},
  abstract  = {Atherosclerosis is an inflammatory disease of large and medium-sized arteries, characterized by the growth of atherosclerotic lesions (plaques). These plaques often develop at inner curvatures of arteries, branchpoints, and bifurcations, where the endothelial wall shear stress is low and oscillatory. In conjunction with other processes such as lipid deposition, biomechanical factors lead to local vascular inflammation and plaque growth. There is also evidence that low and oscillatory shear stress contribute to arterial remodeling, entailing a loss in arterial elasticity and, therefore, an increased pulse-wave velocity. Although altered shear stress profiles, elasticity and inflammation are closely intertwined and critical for plaque growth, preclinical and clinical investigations for atherosclerosis mostly focus on the investigation of one of these parameters only due to the experimental limitations. However, cardiovascular magnetic resonance imaging (MRI) has been demonstrated to be a potent tool which can be used to provide insights into a large range of biological parameters in one experimental session. It enables the evaluation of the dynamic process of atherosclerotic lesion formation without the need for harmful radiation. Flow-sensitive MRI provides the assessment of hemodynamic parameters such as wall shear stress and pulse wave velocity which may replace invasive and radiation-based techniques for imaging of the vascular function and the characterization of early plaque development. In combination with inflammation imaging, the analyses and correlations of these parameters could not only significantly advance basic preclinical investigations of atherosclerotic lesion formation and progression, but also the diagnostic clinical evaluation for early identification of high-risk plaques, which are prone to rupture. In this review, we summarize the key applications of magnetic resonance imaging for the evaluation of plaque characteristics through flow sensitive and morphological measurements. The simultaneous measurements of functional and structural parameters will further preclinical research on atherosclerosis and has the potential to fundamentally improve the detection of inflammation and vulnerable plaques in patients.},
  language  = {en}
}
@article{FrischholzBerberichBoecketal.2020,
  author    = {Frischholz, Sebastian and Berberich, Oliver and B{\"o}ck, Thomas and Meffert, Rainer H. and Blunk, Torsten},
  title     = {Resveratrol counteracts IL-1β-mediated impairment of extracellular matrix deposition in 3D articular chondrocyte constructs},
  series = {Journal of Tissue Engineering and Regenerative Medicine},
  volume    = {14},
  journal   = {Journal of Tissue Engineering and Regenerative Medicine},
  number    = {7},
  doi       = {10.1002/term.3031},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-215471},
  pages     = {897 -- 908},
  year      = {2020},
  abstract  = {When aiming at cell-based therapies in osteoarthritis (OA), proinflammatory conditions mediated by cytokines such as IL-1β need to be considered. In recent studies, the phytoalexin resveratrol (RSV) has exhibited potent anti-inflammatory properties. However, long-term effects on 3D cartilaginous constructs under inflammatory conditions with regard to tissue quality, especially extracellular matrix (ECM) composition, have remained unexplored. Therefore, we employed long-term model cultures for cell-based therapies in an in vitro OA environment and evaluated effects of RSV. Pellet constructs made from expanded porcine articular chondrocytes were cultured with either IL-1β (1-10 ng/ml) or RSV (50 μM) alone, or a cotreatment with both agents. Treatments were applied for 14 days, either directly after pellet formation or after a preculture period of 7 days. Culture with IL-1β (10 ng/ml) decreased pellet size and DNA amount and severely compromised glycosaminoglycan (GAG) and collagen content. Cotreatment with RSV distinctly counteracted the proinflammatory catabolism and led to partial rescue of the ECM composition in both culture systems, with especially strong effects on GAG. Marked MMP13 expression was detected in IL-1β-treated pellets, but none upon RSV cotreatment. Expression of collagen type I was increased upon IL-1β treatment and still observed when adding RSV, whereas collagen type X, indicating hypertrophy, was detected exclusively in pellets treated with RSV alone. In conclusion, RSV can counteract IL-1β-mediated degradation and distinctly improve cartilaginous ECM deposition in 3D long-term inflammatory cultures. Nevertheless, potential hypertrophic effects should be taken into account when considering RSV as cotreatment for articular cartilage repair techniques.},
  language  = {en}
}
@article{SchmidFalterWeberetal.2017,
  author    = {Schmid, Tobias and Falter, Lena and Weber, Sabine and M{\"u}ller, Nils and Molitor, Konstantin and Zeller, David and Weber-Steffens, Dorothea and Hehlgans, Thomas and Wajant, Harald and Mostb{\"o}ck, Sven and M{\"a}nnel, Daniela N.},
  title     = {Chronic inflammation increases the sensitivity of mouse Treg for TNFR2 costimulation},
  series = {Frontiers in Immunology},
  volume    = {8},
  journal   = {Frontiers in Immunology},
  doi       = {10.3389/fimmu.2017.01471},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173259},
  year      = {2017},
  abstract  = {TNF receptor type 2 (TNFR2) has gained attention as a costimulatory receptor for T cells and as critical factor for the development of regulatory T cells (Treg) and myeloid suppressor cells. Using the TNFR2-specific agonist TNCscTNF80, direct effects of TNFR2 activation on myeloid cells and T cells were investigated in mice. \(In\) \(vitro\), TNCscTNF80 induced T cell proliferation in a costimulatory fashion, and also supported \(in\) \(vitro\) expansion of Treg cells. In addition, activation of TNFR2 retarded differentiation of bone marrow-derived immature myeloid cells in culture and reduced their suppressor function. \(In\) \(vivo\) application of TNCscTNF80-induced mild myelopoiesis in na{\"i}ve mice without affecting the immune cell composition. Already a single application expanded Treg cells and improved suppression of CD4 T cells in mice with chronic inflammation. By contrast, multiple applications of the TNFR2 agonist were required to expand Treg cells in na{\"i}ve mice. Improved suppression of T cell proliferation depended on expression of TNFR2 by T cells in mice repeatedly treated with TNCscTNF80, without a major contribution of TNFR2 on myeloid cells. Thus, TNFR2 activation on T cells in na{\"i}ve mice can lead to immune suppression \(in\) \(vivo\). These findings support the important role of TNFR2 for Treg cells in immune regulation.},
  language  = {en}
}
@article{HofmannBoettgerRangeetal.2017,
  author    = {Hofmann, Sigrun Ruth and B{\"o}ttger, Fanny and Range, Ursula and L{\"u}ck, Christian and Morbach, Henner and Girschick, Hermann Joseph and Suttorp, Meinolf and Hedrich, Christian Michael},
  title     = {Serum interleukin-6 and CCL11/eotaxin may be suitable biomarkers for the diagnosis of chronic nonbacterial osteomyelitis},
  series = {Frontiers in Pediatrics},
  volume    = {5},
  journal   = {Frontiers in Pediatrics},
  doi       = {10.3389/fped.2017.00256},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172744},
  year      = {2017},
  abstract  = {Objectives: Chronic recurrent multifocal osteomyelitis (CRMO), the most severe form of chronic nonbacterial osteomyelitis (CNO), is an autoinflammatory bone disorder. In the absence of diagnostic criteria or biomarkers, CNO/CRMO remains a diagnosis of exclusion. The aim of this study was to identify biomarkers for diagnosing multifocal disease (CRMO). Study design: Sera from 71 pediatric CRMO patients, 11 patients with osteoarticular infections, 62 patients with juvenile idiopathic arthritis (JIA), 7 patients with para-infectious or reactive arthritis, and 43 patients with acute leukemia or lymphoma, as well as 59 healthy individuals were collected. Multiplex analysis of 18 inflammation- and/or bone remodeling-associated serum proteins was performed. Statistical analysis included univariate ANOVA, discriminant analysis, univariate receiver operating characteristic (ROC) analysis, and logistic regression analyses. Results: For 14 of 18 blood serum proteins, significant differences were determined between CRMO patients, at least one alternative diagnosis, or healthy controls. Multi-component discriminant analysis delivered five biomarkers (IL-6, CCL11/eotaxin, CCL5/RANTES, collagen Iα, sIL-2R) for the diagnosis of CRMO. ROC analysis allowed further reduction to a core set of 2 biomarkers (CCL11/eotaxin, IL-6) that are sufficient to discern between CRMO, healthy controls, and alternative diagnoses. Conclusion: Serum biomarkers CCL11/eotaxin and IL-6 differentiate between patients with CRMO, healthy controls, and alternative diagnoses (leukemia and lymphoma, osteoarticular infections, para-infectious arthritis, and JIA). Easily accessible biomarkers may aid in diagnosing CRMO. Further studies testing biomarkers in larger unrelated cohorts are warranted.},
  language  = {en}
}
@phdthesis{Frischholz2021,
  author    = {Frischholz, Sebastian},
  title     = {Resveratrol Counteracts IL-1β-mediated Impairment of Extracellular Matrix Deposition in 3D Articular Chondrocyte Constructs},
  doi       = {10.25972/OPUS-23745},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237453},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2021},
  abstract  = {Articular cartilage is an exceptional connective tissue which by a network of fibrillar collagen and glycosaminoglycan (GAG) molecules allows both low- friction articulation and distribution of loads to the subchondral bone (Armiento et al., 2018, Ulrich-Vinther et al., 2003). Because of its very limited ability to self-repair, chondral defects following traumatic injury increase the risk for secondary osteoarthritis (OA) (Muthuri et al., 2011). Still, current OA treatments such as common nonsteroidal anti-inflammatory drugs (NSAIDs) and joint replacement primarily address end-stage symptoms (Tonge et al., 2014). As low-grade inflammation plays a pivotal role in the pathogenesis of OA (Robinson et al., 2016), there is a strong demand for novel therapeutic concepts, such as integrating application of anti-inflammatory agents into cartilage cell- based therapies in order to effectively treat OA affected joints in early disease stages. The polyphenolic phytoalexin resveratrol (RSV), found in the skin of red grapes, berries, and peanuts, has been shown to have effective anti-inflammatory properties (Shen et al., 2012). However, its long-term effects on 3D chondrocyte constructs cultured in an inflammatory environment with regard to tissue quality have remained unexplored so far. Therefore, in this study, pellets made from expanded porcine articular chondrocytes were cultured for 14 days with either the pro-inflammatory cytokine interleukin-1β (IL-1β) (1 - 10 ng/ml) or RSV (50 μM) alone, or a co-treatment with both agents. Constructs treated with chondrocyte medium only served as control. Treatment with IL-1β at 10 ng/ml resulted in a significantly smaller pellet size and reduced DNA content. However, RSV counteracted the IL-1β-induced decrease and significantly enhanced diameter and DNA content. Also, in terms of GAG deposition, treatment with IL-1β at 10 ng/ml resulted in a tremendous depletion of absolute GAG content and GAG/DNA. Again, RSV co-treatment counteracted the inflammatory stimulus and led to a partial recovery of GAG content. Histological analysis utilizing safranin-O staining confirmed these findings. Marked expression of the cartilage-degrading enzyme matrix metalloproteinase 13 (MMP13) was detected in IL-1β-treated pellets, but none upon RSV co- treatment. Moreover, co-treatment of IL-1β-challenged constructs with RSV significantly increased absolute collagen content. However, under non- inflammatory conditions, RSV induced gene expression and protein accumulation of collagen type X, a marker for undesirable hypertrophy. Taken together, in the present thesis, RSV was demonstrated to elicit marked beneficial effects on the extracellular matrix composition of 3D cartilaginous constructs in long-term inflammatory culture in vitro, but also induced hypertrophy under non-inflammatory conditions. Based on these findings, further experiments examining multiple concentrations of RSV under various inflammatory conditions appear desirable concerning potential therapeutic applicability in OA.},
  subject      = {Resveratrol},
  language  = {en}
}
@article{AlrefaiMuhammadRudolfetal.2016,
  author    = {Alrefai, Hani and Muhammad, Khalid and Rudolf, Ronald and Pham, Duong Anh Thuy and Klein-Hessling, Stefan and Patra, Amiya K. and Avots, Andris and Bukur, Valesca and Sahin,, Ugur and Tenzer, Stefan and Goebeler, Matthias and Kerstan, Andreas and Serfling, Edgar},
  title     = {NFATc1 supports imiquimod-induced skin inflammation by suppressing IL-10 synthesis in B cells},
  series = {Nature Communications},
  volume    = {7},
  journal   = {Nature Communications},
  doi       = {10.1038/ncomms11724},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173053},
  year      = {2016},
  abstract  = {Epicutaneous application of Aldara cream containing the TLR7 agonist imiquimod (IMQ) to mice induces skin inflammation that exhibits many aspects of psoriasis, an inflammatory human skin disease. Here we show that mice depleted of B cells or bearing interleukin (IL)-10-deficient B cells show a fulminant inflammation upon IMQ exposure, whereas ablation of NFATc1 in B cells results in a suppression of Aldara-induced inflammation. In vitro, IMQ induces the proliferation and IL-10 expression by B cells that is blocked by BCR signals inducing NFATc1. By binding to HDAC1, a transcriptional repressor, and to an intronic site of the Il10 gene, NFATc1 suppresses IL-10 expression that dampens the production of tumour necrosis factor-α and IL-17 by T cells. These data indicate a close link between NFATc1 and IL-10 expression in B cells and suggest NFATc1 and, in particular, its inducible short isoform, NFATc1/αA, as a potential target to treat human psoriasis.},
  language  = {en}
}
@article{GabbertDillingMeybohmetal.2020,
  author    = {Gabbert, Lydia and Dilling, Christina and Meybohm, Patrick and Burek, Malgorzata},
  title     = {Deletion of Protocadherin Gamma C3 Induces Phenotypic and Functional Changes in Brain Microvascular Endothelial Cells In Vitro},
  series = {Frontiers in Pharmacology},
  volume    = {11},
  journal   = {Frontiers in Pharmacology},
  issn      = {1663-9812},
  doi       = {10.3389/fphar.2020.590144},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-219828},
  year      = {2020},
  abstract  = {Inflammation of the central nervous system (CNS) is associated with diseases such as multiple sclerosis, stroke and neurodegenerative diseases. Compromised integrity of the blood-brain barrier (BBB) and increased migration of immune cells into the CNS are the main characteristics of brain inflammation. Clustered protocadherins (Pcdhs) belong to a large family of cadherin-related molecules. Pcdhs are highly expressed in the CNS in neurons, astrocytes, pericytes and epithelial cells of the choroid plexus and, as we have recently demonstrated, in brain microvascular endothelial cells (BMECs). Knockout of a member of the Pcdh subfamily, PcdhgC3, resulted in significant changes in the barrier integrity of BMECs. Here we characterized the endothelial PcdhgC3 knockout (KO) cells using paracellular permeability measurements, proliferation assay, wound healing assay, inhibition of signaling pathways, oxygen/glucose deprivation (OGD) and a pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) treatment. PcdhgC3 KO showed an increased paracellular permeability, a faster proliferation rate, an altered expression of efflux pumps, transporters, cellular receptors, signaling and inflammatory molecules. Serum starvation led to significantly higher phosphorylation of extracellular signal-regulated kinases (Erk) in KO cells, while no changes in phosphorylated Akt kinase levels were found. PcdhgC3 KO cells migrated faster in the wound healing assay and this migration was significantly inhibited by respective inhibitors of the MAPK-, β-catenin/Wnt-, mTOR- signaling pathways (SL327, XAV939, or Torin 2). PcdhgC3 KO cells responded stronger to OGD and TNFα by significantly higher induction of interleukin 6 mRNA than wild type cells. These results suggest that PcdhgC3 is involved in the regulation of major signaling pathways and the inflammatory response of BMECs.},
  language  = {en}
}
@article{NotzSchmalzingWedekinketal.2020,
  author    = {Notz, Quirin and Schmalzing, Marc and Wedekink, Florian and Schlesinger, Tobias and Gernert, Michael and Herrmann, Johannes and Sorger, Lena and Weismann, Dirk and Schmid, Benedikt and Sitter, Magdalena and Schlegel, Nicolas and Kranke, Peter and Wischhusen, J{\"o}rg and Meybohm, Patrick and Lotz, Christopher},
  title     = {Pro- and Anti-Inflammatory Responses in Severe COVID-19-Induced Acute Respiratory Distress Syndrome—An Observational Pilot Study},
  series = {Frontiers in Immunology},
  volume    = {11},
  journal   = {Frontiers in Immunology},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2020.581338},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-212815},
  year      = {2020},
  abstract  = {Objectives The severity of Coronavirus Disease 2019 (COVID-19) is largely determined by the immune response. First studies indicate altered lymphocyte counts and function. However, interactions of pro- and anti-inflammatory mechanisms remain elusive. In the current study we characterized the immune responses in patients suffering from severe COVID-19-induced acute respiratory distress syndrome (ARDS). Methods This was a single-center retrospective study in patients admitted to the intensive care unit (ICU) with confirmed COVID-19 between March 14th and May 28th 2020 (n = 39). Longitudinal data were collected within routine clinical care, including flow-cytometry of lymphocyte subsets, cytokine analysis and growth differentiation factor 15 (GDF-15). Antibody responses against the receptor binding domain (RBD) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike protein were analyzed. Results All patients suffered from severe ARDS, 30.8\% died. Interleukin (IL)-6 was massively elevated at every time-point. The anti-inflammatory cytokine IL-10 was concomitantly upregulated with IL-6. The cellular response was characterized by lymphocytopenia with low counts of CD8+ T cells, natural killer (NK) and na{\"i}ve T helper cells. CD8+ T and NK cells recovered after 8 to 14 days. The B cell system was largely unimpeded. This coincided with a slight increase in anti-SARS-CoV-2-Spike-RBD immunoglobulin (Ig) G and a decrease in anti-SARS-CoV-2-Spike-RBD IgM. GDF-15 levels were elevated throughout ICU treatment. Conclusions Massively elevated levels of IL-6 and a delayed cytotoxic immune defense characterized severe COVID-19-induced ARDS. The B cell response and antibody production were largely unimpeded. No obvious imbalance of pro- and anti-inflammatory mechanisms was observed, with elevated GDF-15 levels suggesting increased tissue resilience.},
  language  = {en}
}
@article{MahmoodSchmalzingDoerneretal.2020,
  author    = {Mahmood, Zafar and Schmalzing, Marc and D{\"o}rner, Thomas and Tony, Hans-Peter and Muhammad, Khalid},
  title     = {Therapeutic Cytokine Inhibition Modulates Activation and Homing Receptors of Peripheral Memory B Cell Subsets in Rheumatoid Arthritis Patients},
  series = {Frontiers in Immunology},
  volume    = {11},
  journal   = {Frontiers in Immunology},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2020.572475},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-212380},
  year      = {2020},
  abstract  = {Memory B cells have known to play an important role in the pathogenesis of rheumatoid arthritis (RA). With the emergence of B cell-targeted therapies, the modulation of memory B cells appears to be a key therapeutic target. Human peripheral memory B cells can be distinguished based on the phenotypic expression of CD27 and IgD, characterizing the three major B cell subpopulations: CD27+IgD+ pre-switch, CD27+IgD- post-switch, and CD27-IgD- double-negative memory B cells. We evaluated different memory cell populations for activation markers (CD95 and Ki-67) and chemokine receptors (CXCR3 and 4) expressing B cells in active RA, as well as under IL6-R blockade by tocilizumab (TCZ) and TNF-α blockade by adalimumab (ADA). Memory B cells were phenotypically analyzed from RA patients at baseline, week 12, and week 24 under TCZ or ADA treatment, respectively. Using flow cytometry, surface expression of CD95, intracellular Ki-67, and surface expressions of CXCR3 and CXCR4 were determined. Compared with healthy donors (n = 40), the phenotypic analysis of RA patients (n = 80) demonstrated that all three types of memory B cells were activated in RA patients. Surface and intracellular staining of B cells showed a significantly higher percentage of CD95+ (p < 0.0001) and Ki-67+ (p < 0.0001) cells, with numerically altered CXCR3+ and CXCR4+ cells in RA. CD95 and Ki-67 expressions were highest in post-switch memory B cells, whereas CD19+CXCR3+ and CD19+CXCR4+ expressing cells were substantially higher in the pre-switch compartment. In all subsets of the memory B cells, in vivo IL-6R, and TNF-α blockade significantly reduced the enhanced expressions of CD95 and Ki-67. Based on our findings, we conclude that the three major peripheral memory B cell populations, pre-, post-switch, and double-negative B cells, are activated in RA, demonstrating enhanced CD95 and Ki-67 expressions, and varied expression of CXCR3 and CXCR4 chemokine receptors when compared with healthy individuals. This activation can be efficaciously modulated under cytokine inhibition in vivo.},
  language  = {en}
}
@article{HowangyinZlatanovaPintoetal.2016,
  author    = {Howangyin, Kiave-Yune and Zlatanova, Ivana and Pinto, Cristina and Ngkelo, Anta and Cochain, Cl{\´e}ment and Rouanet, Marie and Vilar, Jos{\´e} and Lemitre, Mathilde and Stockmann, Christian and Fleischmann, Bernd K. and Mallat, Ziad and Silvestre, Jean-S{\´e}bastien},
  title     = {Myeloid-epithelial-reproductive receptor tyrosine kinase and milk fat globule epidermal growth factor 8 coordinately improve remodeling after myocardial infarction via local delivery of vascular endothelial growth factor},
  series = {Circulation},
  volume    = {133},
  journal   = {Circulation},
  number    = {9},
  doi       = {10.1161/CIRCULATIONAHA.115.020857},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-190755},
  pages     = {826-839},
  year      = {2016},
  abstract  = {Background: In infarcted heart, improper clearance of dying cells by activated neighboring phagocytes may precipitate the transition to heart failure. We analyzed the coordinated role of 2 major mediators of efferocytosis, the myeloid-epithelial-reproductive protein tyrosine kinase (Mertk) and the milk fat globule epidermal growth factor (Mfge8), in directing cardiac remodeling by skewing the inflammatory response after myocardial infarction. Methods and Results: We generated double-deficient mice for Mertk and Mfge8 (Mertk\(^{-/-}\)/Mfge8\(^{-/-}\)) and challenged them with acute coronary ligature. Compared with wild-type, Mertk-deficient (Mertk\(^{-/-}\)), or Mfge8-deficient (Mfge8\(^{-/-}\)) animals, Mertk\(^{-/-}\)/Mfge8\(^{-/-}\) mice displayed greater alteration in cardiac function and remodeling. Mertk and Mfge8 were expressed mainly by cardiac Ly6C\(^{High and Low}\) monocytes and macrophages. In parallel, Mertk\(^{-/-}\)/Mfge8\(^{-/-}\) bone marrow chimeras manifested increased accumulation of apoptotic cells, enhanced fibrotic area, and larger infarct size, as well as reduced angiogenesis. We found that the abrogation of efferocytosis affected neither the ability of circulating monocytes to infiltrate cardiac tissue nor the number of resident Ly6C\(^{High}\) and Ly6C\(^{Low}\) monocytes/macrophages populating the infarcted milieu. In contrast, combined Mertk and Mfge8 deficiency in Ly6C\(^{High}\)/Ly6C\(^{Low}\) monocytes/macrophages either obtained from in vitro differentiation of bone marrow cells or isolated from infarcted hearts altered their capacity of efferocytosis and subsequently blunted vascular endothelial growth factor A (VEGFA) release. Using LysMCre\(^+\)/VEGFA\(^{fl/fl}\) mice, we further identified an important role for myeloid-derived VEGFA in improving cardiac function and angiogenesis. Conclusions: After myocardial infarction, Mertk- and Mfge8-expressing monocyte/macrophages synergistically engage the clearance of injured cardiomyocytes, favoring the secretion of VEGFA to locally repair the dysfunctional heart.},
  language  = {en}
}
@article{SulimanSunPedersenetal.2016,
  author    = {Suliman, Salwa and Sun, Yang and Pedersen, Torbjorn O. and Xue, Ying and Nickel, Joachim and Waag, Thilo and Finne-Wistrand, Anna and Steinm{\"u}ller-Nethl, Doris and Krueger, Anke and Costea, Daniela E. and Mustafa, Kamal},
  title     = {In vivo host response and degradation of copolymer scaffolds functionalized with nanodiamonds and bone morphogenetic protein 2},
  series = {Advanced Healthcare Materials},
  volume    = {5},
  journal   = {Advanced Healthcare Materials},
  number    = {6},
  doi       = {10.1002/adhm.201500723},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189764},
  pages     = {730-742},
  year      = {2016},
  abstract  = {The aim is to evaluate the effect of modifying poly[(L-lactide)-co-(epsilon-caprolactone)] scaffolds (PLCL) with nanodiamonds (nDP) or with nDP+physisorbed BMP-2 (nDP+BMP-2) on in vivo host tissue response and degradation. The scaffolds are implanted subcutaneously in Balb/c mice and retrieved after 1, 8, and 27 weeks. Molecular weight analysis shows that modified scaffolds degrade faster than the unmodified. Gene analysis at week 1 shows highest expression of proinflammatory markers around nDP scaffolds; although the presence of inflammatory cells and foreign body giant cells is more prominent around the PLCL. Tissue regeneration markers are highly expressed in the nDP+BMP-2 scaffolds at week 8. A fibrous capsule is detectable by week 8, thinnest around nDP scaffolds and at week 27 thickest around PLCL scaffolds. mRNA levels of ALP, COL1 alpha 2, and ANGPT1 are signifi cantly upregulating in the nDP+BMP-2 scaffolds at week 1 with ectopic bone seen at week 8. Even when almost 90\% of the scaffold is degraded at week 27, nDP are observable at implantation areas without adverse effects. In conclusion, modifying PLCL scaffolds with nDP does not aggravate the host response and physisorbed BMP-2 delivery attenuates infl ammation while lowering the dose of BMP-2 to a relatively safe and economical level.},
  language  = {en}
}
@phdthesis{Burow2020,
  author    = {Burow, Wera Tamara},
  title     = {Die Rolle des CEACAM1-Molek{\"u}ls bei der Entstehung von neurogener Entz{\"u}ndung in den Atemwegen},
  doi       = {10.25972/OPUS-20933},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-209331},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2020},
  abstract  = {Neurogene Entz{\"u}ndung ist charakterisiert durch Vasodilatation, Plasmaextravasation und Leukozytenmigration. Im Zuge dieser Dissertationsarbeit konnte ein in vivo Versuchsmodell zur Quantifizierung neurogener Entz{\"u}ndungsreaktionen in den Atemwegen etabliert werden. Der bakterielle Bitterstoff Cycloheximid ist in der Lage, eine Erh{\"o}hung der Plasmaextravasation und Migration neutrophiler Granulozyten zu bewirken. Somit kann Cycloheximid nicht nur protektive Schutzreflexe ausl{\"o}sen, sondern f{\"u}hrt auch lokal zu einer neurogenen Entz{\"u}ndungsreaktion. Das carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1) ist an der Regulierung der endothelialen Barrierefunktion beteiligt. Die Versuche zeigen bei CC1-/--M{\"a}usen eine Verminderung der basalen Permeabilit{\"a}t in trachealen postkapill{\"a}ren Venolen. Nach Stimulation mit Cycloheximid zeigen CC1-/--M{\"a}use im Vergleich mit WT-M{\"a}usen eine verminderte Plasmaextravasation in bronchialen postkapill{\"a}ren Venolen. Auch die Permeabilit{\"a}t des Endothels f{\"u}r neutrophile Granulozyten scheint durch CEACAM1-Defizienz in trachealen und bronchialen Venolen herabgesetzt zu werden. Die Anwesenheit des CEACAM1-Molek{\"u}ls verursacht offenbar eine verminderte Stabilit{\"a}t der endothelialen Barriere in postkapill{\"a}ren Venolen der Atemwege. Diese Ergebnisse zeigen eine gegenteilige Funktion von CEACAM1 in postkapill{\"a}ren Venolen der Atemwege im Vergleich mit großen, herznahen Blutgef{\"a}ßen. Des Weiteren scheint sich die Rolle von CEACAM1 in der Entstehung von akuten und chronischen Entz{\"u}ndungsreaktionen zu unterscheiden. Das in dieser Arbeit etablierte Versuchsmodell stellt eine M{\"o}glichkeit dar, neurogene Entz{\"u}ndungsreaktionen als Reaktion auf verschiedene gustatorische Stimulanzien zu testen und zu quantifizieren.},
  subject      = {Entz{\"u}ndung},
  language  = {de}
}
@article{MuenstermannStrobelKlosetal.2019,
  author    = {Muenstermann, Marcel and Strobel, Lea and Klos, Andreas and Wetsel, Rick A. and Woodruff, Trent M. and K{\"o}hl, J{\"o}rg and Johswich, Kay O.},
  title     = {Distinct roles of the anaphylatoxin receptors C3aR, C5aR1 and C5aR2 in experimental meningococcal infections},
  series = {Virulence},
  volume    = {10},
  journal   = {Virulence},
  number    = {1},
  doi       = {10.1080/21505594.2019.1640035},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200496},
  pages     = {677-694},
  year      = {2019},
  abstract  = {The complement system is pivotal in the defense against invasive disease caused by Neisseria meningitidis (Nme, meningococcus), particularly via the membrane attack complex. Complement activation liberates the anaphylatoxins C3a and C5a, which activate three distinct G-protein coupled receptors, C3aR, C5aR1 and C5aR2 (anaphylatoxin receptors, ATRs). We recently discovered that C5aR1 exacerbates the course of the disease, revealing a downside of complement in Nme sepsis. Here, we compared the roles of all three ATRs during mouse nasal colonization, intraperitoneal infection and human whole blood infection with Nme. Deficiency of complement or ATRs did not alter nasal colonization, but significantly affected invasive disease: Compared to WT mice, the disease was aggravated in C3ar\(^{-/-}\) mice, whereas C5ar1\(^{-/-}\) and C5ar2\(^{-/-}\) mice showed increased resistance to meningococcal sepsis. Surprisingly, deletion of either of the ATRs resulted in lower cytokine/chemokine responses, irrespective of the different susceptibilities of the mice. This was similar in ex vivo human whole blood infection using ATR inhibitors. Neutrophil responses to Nme were reduced in C5ar1\(^{-/-}\) mouse blood. Upon stimulation with C5a plus Nme, mouse macrophages displayed reduced phosphorylation of ERK1/2, when C5aR1 or C5aR2 were ablated or inhibited, suggesting that both C5a-receptors prime an initial macrophage response to Nme. Finally, in vivo blockade of C5aR1 alone (PMX205) or along with C5aR2 (A8\(^{Δ71-73}\)) resulted in ameliorated disease, whereas neither antagonizing C3aR (SB290157) nor its activation with a "super-agonist" peptide (WWGKKYRASKLGLAR) demonstrated a benefit. Thus, C5aR1 and C5aR2 augment disease pathology and are interesting targets for treatment, whereas C3aR is protective in experimental meningococcal sepsis.},
  language  = {en}
}
@article{ScheurerBrandsElMeseryetal.2019,
  author    = {Scheurer, Mario Joachim Johannes and Brands, Roman Camillus and El-Mesery, Mohamed and Hartmann, Stefan and M{\"u}ller-Richter, Urs Dietmar Achim and K{\"u}bler, Alexander Christian and Seher, Axel},
  title     = {The selection of NFκB inhibitors to block inflammation and induce sensitisation to FasL-induced apoptosis in HNSCC cell lines is critical for their use as a prospective cancer therapy},
  series = {International Journal of Molecular Science},
  volume    = {20},
  journal   = {International Journal of Molecular Science},
  number    = {6},
  issn      = {1422-0067},
  doi       = {10.3390/ijms20061306},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201524},
  year      = {2019},
  abstract  = {Inflammation is a central aspect of tumour biology and can contribute significantly to both the origination and progression of tumours. The NFκB pathway is one of the most important signal transduction pathways in inflammation and is, therefore, an excellent target for cancer therapy. In this work, we examined the influence of four NFκB inhibitors — Cortisol, MLN4924, QNZ and TPCA1 — on proliferation, inflammation and sensitisation to apoptosis mediated by the death ligand FasL in the HNSCC cell lines PCI1, PCI9, PCI13, PCI52 and SCC25 and in the human dermal keratinocyte cell line HaCaT. We found that the selection of the inhibitor is critical to ensure that cells do not respond by inducing counteracting activities in the context of cancer therapy, e.g., the extreme IL-8 induction mediated by MLN4924 or FasL resistance mediated by Cortisol. However, TPCA1 was qualified by this in vitro study as an excellent therapeutic mediator in HNSCC by four positive qualities: (1) proliferation was inhibited at low μM-range concentrations; (2) TNFα-induced IL-8 secretion was blocked; (3) HNSCC cells were sensitized to TNFα-induced cell death; and (4) FasL-mediated apoptosis was not disrupted.},
  language  = {en}
}
@article{GlaserGradzkaLuczewskaSzymankiewiczBreborowiczetal.2019,
  author    = {Glaser, Kirsten and Gradzka-Luczewska, Anna and Szymankiewicz-Breborowicz, Marta and Kawczynska-Leda, Natalia and Henrich, Birgit and Waaga-Gasser, Ana Maria and Speer, Christian P.},
  title     = {Perinatal ureaplasma exposure is associated with increased risk of late onset sepsis and imbalanced inflammation in preterm infants and may add to lung injury},
  series = {Frontiers in Cellular and Infection Microbiology},
  volume    = {9},
  journal   = {Frontiers in Cellular and Infection Microbiology},
  number    = {68},
  doi       = {10.3389/fcimb.2019.00068},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201270},
  year      = {2019},
  abstract  = {Background: Controversy remains concerning the impact of Ureaplasma on preterm neonatal morbidity. Methods: Prospective single-center study in very low birth weight infants <30 weeks' gestation. Cord blood and initial nasopharyngeal swabs were screened for Ureaplasma parvum and U. urealyticum using culture technique and polymerase chain reaction. Neonatal outcomes were followed until death or discharge. Multi-analyte immunoassay provided cord blood levels of inflammatory markers. Using multivariate regression analyses, perinatal Ureaplasma exposure was evaluated as risk factor for the development of bronchopulmonary dysplasia (BPD), other neonatal morbidities until discharge and systemic inflammation at admission. Results: 40/103 (39\%) infants were positive for Ureaplasma in one or both specimens, with U. parvum being the predominant species. While exposure to Ureaplasma alone was not associated with BPD, we found an increased risk of BPD in Ureaplasma-positive infants ventilated ≥5 days (OR 1.64; 95\% CI 0.12-22.98; p = 0.009). Presence of Ureaplasma was associated with a 7-fold risk of late onset sepsis (LOS) (95\% CI 1.80-27.39; p = 0.014). Moreover, Ureaplasma-positive infants had higher I/T ratios (b 0.39; 95\% CI 0.08-0.71; p = 0.014), increased levels of interleukin (IL)-17 (b 0.16; 95\% CI 0.02-0.30; p = 0.025) and matrix metalloproteinase 8 (b 0.77; 95\% CI 0.10-1.44; p = 0.020), decreased levels of IL-10 (b -0.77; 95\% CI -1.58 to -0.01; p = 0.043) and increased ratios of Tumor necrosis factor-α, IL-8, and IL-17 to anti-inflammatory IL-10 (p = 0.003, p = 0.012, p < 0.001). Conclusions: Positive Ureaplasma screening was not associated with BPD. However, exposure contributed to BPD in infants ventilated ≥5 days and conferred an increased risk of LOS and imbalanced inflammatory cytokine responses.},
  language  = {en}
}
@article{KleefeldtBoemmelBroedeetal.2019,
  author    = {Kleefeldt, Florian and B{\"o}mmel, Heike and Broede, Britta and Thomsen, Michael and Pfeiffer, Verena and W{\"o}rsd{\"o}rfer, Philipp and Karnati, Srikanth and Wagner, Nicole and Rueckschloss, Uwe and Erg{\"u}n, S{\"u}leyman},
  title     = {Aging-related carcinoembryonic antigen-related cell adhesion molecule 1 signaling promotes vascular dysfunction},
  series = {Aging Cell},
  volume    = {2019},
  journal   = {Aging Cell},
  number    = {18},
  doi       = {10.1111/acel.13025},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201231},
  pages     = {e13025},
  year      = {2019},
  abstract  = {Aging is an independent risk factor for cardiovascular diseases and therefore of particular interest for the prevention of cardiovascular events. However, the mechanisms underlying vascular aging are not well understood. Since carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is crucially involved in vascular homeostasis, we sought to identify the role of CEACAM1 in vascular aging. Using human internal thoracic artery and murine aorta, we show that CEACAM1 is upregulated in the course of vascular aging. Further analyses demonstrated that TNF-α is CEACAM1-dependently upregulated in the aging vasculature. Vice versa, TNF-α induces CEACAM1 expression. This results in a feed-forward loop in the aging vasculature that maintains a chronic pro-inflammatory milieu. Furthermore, we demonstrate that age-associated vascular alterations, that is, increased oxidative stress and vascular fibrosis, due to increased medial collagen deposition crucially depend on the presence of CEACAM1. Additionally, age-dependent upregulation of vascular CEACAM1 expression contributes to endothelial barrier impairment, putatively via increased VEGF/VEGFR-2 signaling. Consequently, aging-related upregulation of vascular CEACAM1 expression results in endothelial dysfunction that may promote atherosclerotic plaque formation in the presence of additional risk factors. Our data suggest that CEACAM1 might represent an attractive target in order to delay physiological aging and therefore the transition to vascular disorders such as atherosclerosis.},
  language  = {en}
}
@article{BrodehlBelkeGarnettetal.2017,
  author    = {Brodehl, Andreas and Belke, Darrell D. and Garnett, Lauren and Martens, Kristina and Abdelfatah, Nelly and Rodriguez, Marcela and Diao, Catherine and Chen, Yong-Xiang and Gordon, Paul M. K. and Nygren, Anders and Gerull, Brenda},
  title     = {Transgenic mice overexpressing desmocollin-2 (DSC2) develop cardiomyopathy associated with myocardial inflammation and fibrotic remodeling},
  series = {PLoS ONE},
  volume    = {12},
  journal   = {PLoS ONE},
  number    = {3},
  doi       = {10.1371/journal.pone.0174019},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171084},
  pages     = {e0174019},
  year      = {2017},
  abstract  = {Background Arrhythmogenic cardiomyopathy is an inherited heart muscle disorder leading to ventricular arrhythmias and heart failure, mainly as a result of mutations in cardiac desmosomal genes. Desmosomes are cell-cell junctions mediating adhesion of cardiomyocytes; however, the molecular and cellular mechanisms underlying the disease remain widely unknown. Desmocollin-2 is a desmosomal cadherin serving as an anchor molecule required to reconstitute homeostatic intercellular adhesion with desmoglein-2. Cardiac specific lack of desmoglein-2 leads to severe cardiomyopathy, whereas overexpression does not. In contrast, the corresponding data for desmocollin-2 are incomplete, in particular from the view of protein overexpression. Therefore, we developed a mouse model overexpressing desmocollin-2 to determine its potential contribution to cardiomyopathy and intercellular adhesion pathology. Methods and results We generated transgenic mice overexpressing DSC2 in cardiac myocytes. Transgenic mice developed a severe cardiac dysfunction over 5 to 13 weeks as indicated by 2D-echocardiography measurements. Corresponding histology and immunohistochemistry demonstrated fibrosis, necrosis and calcification which were mainly localized in patches near the epi- and endocardium of both ventricles. Expressions of endogenous desmosomal proteins were markedly reduced in fibrotic areas but appear to be unchanged in non-fibrotic areas. Furthermore, gene expression data indicate an early up-regulation of inflammatory and fibrotic remodeling pathways between 2 to 3.5 weeks of age. Conclusion Cardiac specific overexpression of desmocollin-2 induces necrosis, acute inflammation and patchy cardiac fibrotic remodeling leading to fulminant biventricular cardiomyopathy.},
  language  = {en}
}
@article{JannaschGaetznerWeigeletal.2017,
  author    = {Jannasch, Maren and Gaetzner, Sabine and Weigel, Tobias and Walles, Heike and Schmitz, Tobias and Hansmann, Jan},
  title     = {A comparative multi-parametric in vitro model identifies the power of test conditions to predict the fibrotic tendency of a biomaterial},
  series = {Scientific Reports},
  volume    = {7},
  journal   = {Scientific Reports},
  number    = {1689},
  doi       = {10.1038/s41598-017-01584-9},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170908},
  year      = {2017},
  abstract  = {Despite growing effort to advance materials towards a low fibrotic progression, all implants elicit adverse tissue responses. Pre-clinical biomaterial assessment relies on animals testing, which can be complemented by in vitro tests to address the Russell and Burch's 3R aspect of reducing animal burden. However, a poor correlation between in vitro and in vivo biomaterial assessments confirms a need for suitable in vitro biomaterial tests. The aim of the study was to identify a test setting, which is predictive and might be time- and cost-efficient. We demonstrated how sensitive in vitro biomaterial assessment based on human primary macrophages depends on test conditions. Moreover, possible clinical scenarios such as lipopolysaccharide contamination, contact to autologous blood plasma, and presence of IL-4 in an immune niche influence the outcome of a biomaterial ranking. Nevertheless, by using glass, titanium, polytetrafluorethylene, silicone, and polyethylene representing a specific material-induced fibrotic response and by comparison to literature data, we were able to identify a test condition that provides a high correlation to state-of-the-art in vivo studies. Most important, biomaterial ranking obtained under native plasma test conditions showed a high predictive accuracy compared to in vivo assessments, strengthening a biomimetic three-dimensional in vitro test platform.},
  language  = {en}
}
@article{GlaserSilwedelFehrholzetal.2017,
  author    = {Glaser, Kirsten and Silwedel, Christine and Fehrholz, Markus and Waaga-Gasser, Ana M. and Henrich, Birgit and Claus, Heike and Speer, Christian P.},
  title     = {Ureaplasma Species Differentially Modulate Pro- and Anti-Inflammatory Cytokine Responses in Newborn and Adult Human Monocytes Pushing the State Toward Pro-Inflammation},
  series = {Frontiers in Cellular and Infection Microbiology},
  volume    = {7},
  journal   = {Frontiers in Cellular and Infection Microbiology},
  number    = {484},
  doi       = {10.3389/fcimb.2017.00484},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-169958},
  year      = {2017},
  abstract  = {Background: Ureaplasma species have been associated with chorioamnionitis and preterm birth and have been implicated in the pathogenesis of neonatal short and long-term morbidity. However, being mostly commensal bacteria, controversy remains on the pro-inflammatory capacity of Ureaplasma. Discussions are ongoing on the incidence and impact of prenatal, perinatal, and postnatal infection. The present study addressed the impact of Ureaplasma isolates on monocyte-driven inflammation. Methods: Cord blood monocytes of term neonates and adult monocytes, either native or LPS-primed, were cultured with Ureaplasma urealyticum (U. urealyticum) serovar 8 (Uu8) and Ureaplasma parvum serovar 3 (Up3). Using qRT-PCR, cytokine flow cytometry, and multi-analyte immunoassay, we assessed mRNA and protein expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-8, IL-12p40, IL-10, and IL-1 receptor antagonist (IL-1ra) as well as Toll-like receptor (TLR) 2 and TLR4. Results: Uu8 and Up3 induced mRNA expression and protein release of TNF-α, IL-1β and IL-8 in term neonatal and adult monocytes (p < 0.01 and p < 0.05). Intracellular protein expression of TNF-α, IL-1β and IL-8 in Ureaplasma-stimulated cells paralleled those results. Ureaplasma-induced cytokine levels did not significantly differ from LPS-mediated levels except for lower intracellular IL-1β in adult monocytes (Uu8: p < 0.05). Remarkably, ureaplasmas did not induce IL-12p40 response and promoted lower amounts of anti-inflammatory IL-10 and IL-1ra than LPS, provoking a cytokine imbalance more in favor of pro-inflammation (IL-1β/IL-10, IL-8/IL-10 and IL-8/IL-1ra: p < 0.01, vs. LPS). In contrast to LPS, both isolates induced TLR2 mRNA in neonatal and adult cells (p < 0.001 and p < 0.05) and suppressed TLR4 mRNA in adult monocytes (p < 0.05). Upon co-stimulation, Uu8 and Up3 inhibited LPS-induced intracellular IL-1β (p < 0.001 and p < 0.05) and IL-8 in adult monocytes (p < 0.01), while LPS-induced neonatal cytokines were maintained or aggravated (p < 0.05). Conclusion: Our data demonstrate a considerable pro-inflammatory capacity of Ureaplasma isolates in human monocytes. Stimulating pro-inflammatory cytokine responses while hardly inducing immunomodulatory and anti-inflammatory cytokines, ureaplasmas might push monocyte immune responses toward pro-inflammation. Inhibition of LPS-induced cytokines in adult monocytes in contrast to sustained inflammation in term neonatal monocytes indicates a differential modulation of host immune responses to a second stimulus. Modification of TLR2 and TLR4 expression may shape host susceptibility to inflammation.},
  language  = {en}
}
@article{JahnDorbathKircheretal.2019,
  author    = {Jahn, Daniel and Dorbath, Donata and Kircher, Stefan and Nier, Anika and Bergheim, Ina and Lenaerts, Kaatje and Hermanns, Heike M. and Geier, Andreas},
  title     = {Beneficial effects of vitamin D treatment in an obese mouse model of non-alcoholic steatohepatitis},
  series = {Nutrients},
  volume    = {11},
  journal   = {Nutrients},
  number    = {1},
  doi       = {10.3390/nu11010077},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177222},
  pages     = {77},
  year      = {2019},
  abstract  = {Serum vitamin D levels negatively correlate with obesity and associated disorders such as non-alcoholic steatohepatitis (NASH). However, the mechanisms linking low vitamin D (VD) status to disease progression are not completely understood. In this study, we analyzed the effect of VD treatment on NASH in mice. C57BL6/J mice were fed a high-fat/high-sugar diet (HFSD) containing low amounts of VD for 16 weeks to induce obesity, NASH and liver fibrosis. The effects of preventive and interventional VD treatment were studied on the level of liver histology and hepatic/intestinal gene expression. Interestingly, preventive and to a lesser extent also interventional VD treatment resulted in improvements of liver histology. This included a significant decrease of steatosis, a trend towards lower non-alcoholic fatty liver disease (NAFLD) activity score and a slight non-significant decrease of fibrosis in the preventive treatment group. In line with these changes, preventive VD treatment reduced the hepatic expression of lipogenic, inflammatory and pro-fibrotic genes. Notably, these beneficial effects occurred in conjunction with a reduction of intestinal inflammation. Together, our observations suggest that timely initiation of VD supplementation (preventive vs. interventional) is a critical determinant of treatment outcome in NASH. In the applied animal model, the improvements of liver histology occurred in conjunction with reduced inflammation in the gut, suggesting a potential relevance of vitamin D as a therapeutic agent acting on the gut-liver axis.},
  language  = {en}
}
@article{GrohHoernerMartini2018,
  author    = {Groh, Janos and H{\"o}rner, Michaela and Martini, Rudolf},
  title     = {Teriflunomide attenuates neuroinflammation-related neural damage in mice carrying human PLP1 mutations},
  series = {Journal of Neuroinflammation},
  volume    = {15},
  journal   = {Journal of Neuroinflammation},
  number    = {194},
  doi       = {10.1186/s12974-018-1228-z},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-176524},
  year      = {2018},
  abstract  = {Background: Genetically caused neurological disorders of the central nervous system (CNS) are mostly characterized by poor or even fatal clinical outcome and few or no causative treatments are available. Often, these disorders are associated with low-grade, disease-promoting inflammation, another feature shared by progressive forms of multiple sclerosis (PMS). We previously generated two mouse lines carrying distinct mutations in the oligodendrocytic PLP1 gene that have initially been identified in patients diagnosed with MS. These mutations cause a loss of PLP function leading to a histopathological and clinical phenotype common to both PMS and genetic CNS disorders, like hereditary spastic paraplegias. Importantly, neuroinflammation promotes disease progression in these models, suggesting that pharmacological modulation of inflammation might ameliorate disease outcome. Methods: We applied teriflunomide, an approved medication for relapsing-remitting MS targeting activated T-lymphocytes, in the drinking water (10 mg/kg body weight/day). Experimental long-term treatment of PLP mutant mice was non-invasively monitored by longitudinal optical coherence tomography and by rotarod analysis. Immunomodulatory effects were subsequently analyzed by flow cytometry and immunohistochemistry and treatment effects regarding neural damage, and neurodegeneration were assessed by histology and immunohistochemistry. Results: Preventive treatment with teriflunomide attenuated the increase in number of CD8+ cytotoxic effector T cells and fostered the proliferation of CD8+ CD122+ PD-1+ regulatory T cells in the CNS. This led to an amelioration of axonopathic features and neuron loss in the retinotectal system, also reflected by reduced thinning of the innermost retinal composite layer in longitudinal studies and ameliorated clinical outcome upon preventive long-term treatment. Treatment of immune-incompetent PLP mutants did not provide evidence for a direct, neuroprotective effect of the medication. When treatment was terminated, no rebound of neuroinflammation occurred and histopathological improvement was preserved for at least 75 days without treatment. After disease onset, teriflunomide halted ongoing axonal perturbation and enabled a recovery of dendritic arborization by surviving ganglion cells. However, neither neuron loss nor clinical features were ameliorated, likely due to already advanced neurodegeneration before treatment onset. Conclusions: We identify teriflunomide as a possible medication not only for PMS but also for inflammation-related genetic diseases of the nervous system for which causal treatment options are presently lacking.},
  language  = {en}
}
@article{HerrmannMuenstermannStrobeletal.2018,
  author    = {Herrmann, Johannes and Muenstermann, Marcel and Strobel, Lea and Schubert-Unkmeir, Alexandra and Woodruff, Trent M. and Gray-Owen, Scott D. and Klos, Andreas and Johswich, Kay O.},
  title     = {Complement C5a receptor 1 exacerbates the pathophysiology of N. meningitidis sepsis and is a potential target for disease treatment},
  series = {mBio},
  volume    = {9},
  journal   = {mBio},
  number    = {1},
  doi       = {10.1128/mBio.01755-17},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-175792},
  pages     = {e01755-17},
  year      = {2018},
  abstract  = {Sepsis caused by Neisseria meningitidis (meningococcus) is a rapidly progressing, life-threatening disease. Because its initial symptoms are rather unspecific, medical attention is often sought too late, i.e., when the systemic inflammatory response is already unleashed. This in turn limits the success of antibiotic treatment. The complement system is generally accepted as the most important innate immune determinant against invasive meningococcal disease since it protects the host through the bactericidal membrane attack complex. However, complement activation concomitantly liberates the C5a peptide, and it remains unclear whether this potent anaphylatoxin contributes to protection and/or drives the rapidly progressing immunopathogenesis associated with meningococcal disease. Here, we dissected the specific contribution of C5a receptor 1 (C5aR1), the canonical receptor for C5a, using a mouse model of meningococcal sepsis. Mice lacking C3 or C5 displayed susceptibility that was enhanced by >1,000-fold or 100-fold, respectively, consistent with the contribution of these components to protection. In clear contrast, C5ar1\(^{-/-}\) mice resisted invasive meningococcal infection and cleared N. meningitidis more rapidly than wild-type (WT) animals. This favorable outcome stemmed from an ameliorated inflammatory cytokine response to N. meningitidis in C5ar1\(^{-/-}\) mice in both in vivo and ex vivo whole-blood infections. In addition, inhibition of C5aR1 signaling without interference with the complement bactericidal activity reduced the inflammatory response also in human whole blood. Enticingly, pharmacologic C5aR1 blockade enhanced mouse survival and lowered meningococcal burden even when the treatment was administered after sepsis induction. Together, our findings demonstrate that C5aR1 drives the pathophysiology associated with meningococcal sepsis and provides a promising target for adjunctive therapy. Importance: The devastating consequences of N. meningitidis sepsis arise due to the rapidly arising and self-propagating inflammatory response that mobilizes antibacterial defenses but also drives the immunopathology associated with meningococcemia. The complement cascade provides innate broad-spectrum protection against infection by directly damaging the envelope of pathogenic microbes through the membrane attack complex and triggers an inflammatory response via the C5a peptide and its receptor C5aR1 aimed at mobilizing cellular effectors of immunity. Here, we consider the potential of separating the bactericidal activities of the complement cascade from its immune activating function to improve outcome of N. meningitidis sepsis. Our findings demonstrate that the specific genetic or pharmacological disruption of C5aR1 rapidly ameliorates disease by suppressing the pathogenic inflammatory response and, surprisingly, allows faster clearance of the bacterial infection. This outcome provides a clear demonstration of the therapeutic benefit of the use of C5aR1-specific inhibitors to improve the outcome of invasive meningococcal disease.},
  language  = {en}
}
@article{EbertBenischKrugetal.2015,
  author    = {Ebert, Regina and Benisch, Peggy and Krug, Melanie and Zeck, Sabine and Meißner-Weigl, Jutta and Steinert, Andre and Rauner, Martina and Hofbauer, Lorenz and Jakob, Franz},
  title     = {Acute phase serum amyloid A induces proinflammatory cytokines and mineralization via toll-like receptor 4 in mesenchymal stem cells},
  series = {Stem Cell Research},
  volume    = {15},
  journal   = {Stem Cell Research},
  doi       = {10.1016/j.scr.2015.06.008},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148491},
  pages     = {231-239},
  year      = {2015},
  abstract  = {The role of serum amyloid A (SAA) proteins, which are ligands for toll-like receptors, was analyzed in human bone marrow-derived mesenchymal stem cells (hMSCs) and their osteogenic offspring with a focus on senescence, differentiation andmineralization. In vitro aged hMSC developed a senescence-associated secretory phenotype (SASP), resulting in enhanced SAA1/2, TLR2/4 and proinflammatory cytokine (IL6, IL8, IL1\(\beta\), CXCL1, CXCL2) expression before entering replicative senescence. Recombinant human SAA1 (rhSAA1) induced SASP-related genes and proteins in MSC, which could be abolished by cotreatment with the TLR4-inhibitor CLI-095. The same pattern of SASP-resembling genes was stimulated upon induction of osteogenic differentiation, which is accompanied by autocrine SAA1/2 expression. In this context additional rhSAA1 enhanced the SASP-like phenotype, accelerated the proinflammatory phase of osteogenic differentiation and enhanced mineralization. Autocrine/paracrine and rhSAA1 via TLR4 stimulate a proinflammatory phenotype that is both part of the early phase of osteogenic differentiation and the development of senescence. This signaling cascade is tightly involved in bone formation and mineralization, but may also propagate pathological extraosseous calcification conditions such as calcifying inflammation and atherosclerosis.},
  language  = {en}
}
@article{SchuhmannBittnerMeuthetal.2015,
  author    = {Schuhmann, Michael K. and Bittner, Stefan and Meuth, Sven G. and Kleinschnitz, Christoph and Fluri, Felix},
  title     = {Fingolimod (FTY720-P) does not stabilize the blood-brain barrier under inflammatory conditions in an in vitro model},
  series = {International Journal of Molecular Sciences},
  volume    = {16},
  journal   = {International Journal of Molecular Sciences},
  doi       = {10.3390/ijms161226177},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-145047},
  pages     = {29454-29466},
  year      = {2015},
  abstract  = {Breakdown of the blood-brain barrier (BBB) is an early hallmark of multiple sclerosis (MS), a progressive inflammatory disease of the central nervous system. Cell adhesion in the BBB is modulated by sphingosine-1-phosphate (S1P), a signaling protein, via S1P receptors (S1P\(_1\)). Fingolimod phosphate (FTY720-P) a functional S1P\(_1\) antagonist has been shown to improve the relapse rate in relapsing-remitting MS by preventing the egress of lymphocytes from lymph nodes. However, its role in modulating BBB permeabilityin particular, on the tight junction proteins occludin, claudin 5 and ZO-1has not been well elucidated to date. In the present study, FTY720-P did not change the transendothelial electrical resistance in a rat brain microvascular endothelial cell (RBMEC) culture exposed to inflammatory conditions and thus did not decrease endothelial barrier permeability. In contrast, occludin was reduced in RBMEC culture after adding FTY720-P. Additionally, FTY720-P did not alter the amount of endothelial matrix metalloproteinase (MMP)-9 and MMP-2 in RBMEC cultures. Taken together, our observations support the assumption that S1P\(_1\) plays a dual role in vascular permeability, depending on its ligand. Thus, S1P\(_1\) provides a mechanistic basis for FTY720-P-associated disruption of endothelial barrierssuch as the blood-retinal barrierwhich might result in macular edema.},
  language  = {en}
}
@article{SchuhmannGunrebenKleinschnitzetal.2016,
  author    = {Schuhmann, Michael K. and Gunreben, Ignaz and Kleinschnitz, Christoph and Kraft, Peter},
  title     = {Immunohistochemical Analysis of Cerebral Thrombi Retrieved by Mechanical Thrombectomy from Patients with Acute Ischemic Stroke},
  series = {International Journal of Molecular Sciences},
  volume    = {17},
  journal   = {International Journal of Molecular Sciences},
  number    = {3},
  doi       = {10.3390/ijms17030298},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166206},
  pages     = {298},
  year      = {2016},
  abstract  = {Mechanical thrombectomy is a novel treatment option for patients with acute ischemic stroke (AIS). Only a few studies have previously suggested strategies to categorize retrieved clots according to their histologic composition. However, these reports did not analyze potential biomarkers that are of importance in stroke-related inflammation. We therefore histopathologically investigated 37 intracerebral thrombi mechanically retrieved from patients with AIS, and focused on the composition of immune cells and platelets. We also conducted correlation analyses of distinctive morphologic patterns (erythrocytic, serpentine, layered, red, white, mixed appearance) with clinical parameters. Most T cells and monocytes were detected in erythrocytic and red clots, in which the distribution of these cells was random. In contrast, von Willebrand factor (vWF)-positive areas co-localized with regions of fibrin and collagen. While clots with huge amounts of vWF seem to be associated with a high National Institute of Health Stroke Scale score at admission, histologic findings could not predict the clinical outcome at discharge. In summary, we provide the first histologic description of mechanically retrieved intracerebral thrombi regarding biomarkers relevant for inflammation in ischemic stroke.},
  language  = {en}
}
@article{GrimmigMoenchKreckeletal.2016,
  author    = {Grimmig, Tanja and Moench, Romana and Kreckel, Jennifer and Haack, Stephanie and Rueckert, Felix and Rehder, Roberta and Tripathi, Sudipta and Ribas, Carmen and Chandraker, Anil and Germer, Christoph T. and Gasser, Martin and Waaga-Gasser, Ana Maria},
  title     = {Toll Like Receptor 2, 4, and 9 Signaling Promotes Autoregulative Tumor Cell Growth and VEGF/PDGF Expression in Human Pancreatic Cancer},
  series = {International Journal of Molecular Sciences},
  volume    = {17},
  journal   = {International Journal of Molecular Sciences},
  number    = {12},
  doi       = {10.3390/ijms17122060},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165743},
  pages     = {2060},
  year      = {2016},
  abstract  = {Toll like receptor (TLR) signaling has been suggested to play an important role in the inflammatory microenvironment of solid tumors and through this inflammation-mediated tumor growth. Here, we studied the role of tumor cells in their process of self-maintaining TLR expression independent of inflammatory cells and cytokine milieu for autoregulative tumor growth signaling in pancreatic cancer. We analyzed the expression of TLR2, -4, and -9 in primary human cancers and their impact on tumor growth via induced activation in several established pancreatic cancers. TLR-stimulated pancreatic cancer cells were specifically investigated for activated signaling pathways of VEGF/PDGF and anti-apoptotic Bcl-xL expression as well as tumor cell growth. The primary pancreatic cancers and cell lines expressed TLR2, -4, and -9. TLR-specific stimulation resulted in activated MAP-kinase signaling, most likely via autoregulative stimulation of demonstrated TLR-induced VEGF and PDGF expression. Moreover, TLR activation prompted the expression of Bcl-xL and has been demonstrated for the first time to induce tumor cell proliferation in pancreatic cancer. These findings strongly suggest that pancreatic cancer cells use specific Toll like receptor signaling to promote tumor cell proliferation and emphasize the particular role of TLR2, -4, and -9 in this autoregulative process of tumor cell activation and proliferation in pancreatic cancer.},
  language  = {en}
}
@article{ZanuccoGoetzPotapenkoetal.2011,
  author    = {Zanucco, Emanuele and G{\"o}tz, Rudolf and Potapenko, Tamara and Carraretto, Irene and Ceteci, Semra and Ceteci, Fatih and Seeger, Werner and Savai, Rajkumar and Rapp, Ulf R.},
  title     = {Expression of B-RAF V600E in Type II Pneumocytes Causes Abnormalities in Alveolar Formation, Airspace Enlargement and Tumor Formation in Mice},
  series = {PLOS ONE},
  volume    = {6},
  journal   = {PLOS ONE},
  number    = {12},
  doi       = {10.1371/journal.pone.0029093},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-137061},
  pages     = {e29093},
  year      = {2011},
  abstract  = {Growth factor induced signaling cascades are key regulatory elements in tissue development, maintenance and regeneration. Perturbations of these cascades have severe consequences, leading to developmental disorders and neoplastic diseases. As a major function in signal transduction, activating mutations in RAF family kinases are the cause of human tumorigenesis, where B-RAF V600E has been identified as the prevalent mutant. In order to address the oncogenic function of B-RAF V600E, we have generated transgenic mice expressing the activated oncogene specifically in lung alveolar epithelial type II cells. Constitutive expression of B-RAF V600E caused abnormalities in alveolar epithelium formation that led to airspace enlargements. These lung lesions showed signs of tissue remodeling and were often associated with chronic inflammation and low incidence of lung tumors. The inflammatory cell infiltration did not precede the formation of the lung lesions but was rather accompanied with late tumor development. These data support a model where the continuous regenerative process initiated by oncogenic B-RAF-driven alveolar disruption provides a tumor-promoting environment associated with chronic inflammation.},
  language  = {en}
}
@article{WernerWakabayashiBaueretal.2018,
  author    = {Werner, Rudolf and Wakabayashi, Hiroshi and Bauer, Jochen and Sch{\"u}tz, Claudia and Zechmeister, Christina and Hayakawa, Nobuyuki and Javadi, Mehrbod S. and Lapa, Constantin and Jahns, Roland and Erg{\"u}n, S{\"u}leyman and Jahns, Valerie and Higuchi, Takahiro},
  title     = {Longitudinal \(^{18}\)F-FDG PET imaging in a Rat Model of Autoimmune Myocarditis},
  series = {European Heart Journal Cardiovascular Imaging},
  journal   = {European Heart Journal Cardiovascular Imaging},
  issn      = {2047-2404},
  doi       = {10.1093/ehjci/jey119},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165601},
  pages     = {1-8},
  year      = {2018},
  abstract  = {Aims: Although mortality rate is very high, diagnosis of acute myocarditis remains challenging with conventional tests. We aimed to elucidate the potential role of longitudinal 2-Deoxy-2-\(^{18}\)F-fluoro-D-glucose (\(^{18}\)F-FDG) positron emission tomography (PET) inflammation monitoring in a rat model of experimental autoimmune myocarditis. Methods and results: Autoimmune myocarditis was induced in Lewis rats by immunizing with porcine cardiac myosin emulsified in complete Freund's adjuvant. Time course of disease was assessed by longitudinal \(^{18}\)F-FDG PET imaging. A correlative analysis between in- and ex vivo \(^{18}\)F-FDG signalling and macrophage infiltration using CD68 staining was conducted. Finally, immunohistochemistry analysis of the cell-adhesion markers CD34 and CD44 was performed at different disease stages determined by longitudinal \(^{18}\)F-FDG PET imaging. After immunization, myocarditis rats revealed a temporal increase in 18F-FDG uptake (peaked at week 3), which was followed by a rapid decline thereafter. Localization of CD68 positive cells was well correlated with in vivo \(^{18}\)F-FDG PET signalling (R\(^2\) = 0.92) as well as with ex vivo 18F-FDG autoradiography (R\(^2\) = 0.9, P < 0.001, respectively). CD44 positivity was primarily observed at tissue samples obtained at acute phase (i.e. at peak 18F-FDG uptake), while CD34-positive staining areas were predominantly identified in samples harvested at both sub-acute and chronic phases (i.e. at \(^{18}\)F-FDG decrease). Conclusion: \(^{18}\)F-FDG PET imaging can provide non-invasive serial monitoring of cardiac inflammation in a rat model of acute myocarditis.},
  subject      = {Myokarditis},
  language  = {en}
}
@article{SchuhmannFluri2017,
  author    = {Schuhmann, Michael K. and Fluri, Felix},
  title     = {Effects of fullerenols on mouse brain microvascular endothelial cells},
  series = {International Journal of Molecular Sciences},
  volume    = {18},
  journal   = {International Journal of Molecular Sciences},
  number    = {8},
  issn      = {1422-0067},
  doi       = {10.3390/ijms18081783},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158072},
  year      = {2017},
  abstract  = {Fullerenols, water-soluble C60-fullerene derivatives, have been shown to exert neuroprotective effects in vitro and in vivo, most likely due to their capability to scavenge free radicals. However, little is known about the effects of fullerenols on the blood-brain barrier (BBB), especially on cerebral endothelial cells under inflammatory conditions. Here, we investigated whether the treatment of primary mouse brain microvascular endothelial cells with fullerenols impacts basal and inflammatory blood-brain barrier (BBB) properties in vitro. While fullerenols (1, 10, and 100 µg/mL) did not change transendothelial electrical resistance under basal and inflammatory conditions, 100 µg/mL of fullerenol significantly reduced erk1/2 activation and resulted in an activation of NFκB in an inflammatory milieu. Our findings suggest that fullerenols might counteract oxidative stress via the erk1/2 and NFκB pathways, and thus are able to protect microvascular endothelial cells under inflammatory conditions.},
  language  = {en}
}
@article{OehlerMohammadiPerpinaVicianoetal.2017,
  author    = {Oehler, Beatrice and Mohammadi, Milad and Perpina Viciano, Cristina and Hackel, Dagmar and Hoffmann, Carsten and Brack, Alexander and Rittner, Heike L.},
  title     = {Peripheral interaction of Resolvin D1 and E1 with opioid receptor antagonists for antinociception in inflammatory pain in rats},
  series = {Frontiers in Molecular Neuroscience},
  volume    = {10},
  journal   = {Frontiers in Molecular Neuroscience},
  number    = {242},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158642},
  year      = {2017},
  abstract  = {Antinociceptive pathways are activated in the periphery in inflammatory pain, for instance resolvins and opioid peptides. Resolvins are biosynthesized from omega-3 polyunsaturated fatty acids such as eicosapentaenoic acid and docosahexaenoic acid. Resolvin D1 (RvD1) and resolvin E1 (RvE1) initiate the resolution of inflammation and control of hypersensitivity via induction of anti-inflammatory signaling cascades. RvD1 binds to lipoxin A4/annexin-A1 receptor/formyl-peptide receptor 2 (ALX/FPR2), RvE1 to chemerin receptor 23 (ChemR23). Antinociception of RvD1 is mediated by interaction with transient receptor potential channels ankyrin 1 (TRPA1). Endogenous opioid peptides are synthesized and released from leukocytes in the tissue and bind to opioid receptors on nociceptor terminals. Here, we further explored peripheral mechanisms of RvD1 and chemerin (Chem), the ligand of ChemR23, in complete Freund's adjuvant (CFA)-induced hindpaw inflammation in male Wistar rats. RvD1 and Chem ameliorated CFA-induced hypersensitivity in early and late inflammatory phases. This was prevented by peripheral blockade of the μ-opioid peptide receptor (MOR) using low dose local naloxone or by local injection of anti-β-endorphin and anti-met-enkephalin (anti-ENK) antibodies. Naloxone also hindered antinociception by the TRPA1 inhibitor HC-030031. RvD1 did not stimulate the release of β-endorphin from macrophages and neutrophils, nor did RvD1 itself activate G-proteins coupled MOR or initiate β-arrestin recruitment to the membrane. TRPA1 blockade by HC-030031 in inflammation in vivo as well as inhibition of the TRPA1-mediated calcium influx in dorsal root ganglia neurons in vitro was hampered by naloxone. Peripheral application of naloxone alone in vivo already lowered mechanical nociceptive thresholds. Therefore, either a perturbation of the balance of endogenous pro- and antinociceptive mechanisms in early and late inflammation, or an interaction of TRPA1 and opioid receptors weaken the antinociceptive potency of RvD1 and TRPA1 blockers.},
  language  = {en}
}
@phdthesis{Karl2017,
  author    = {Karl, Franziska},
  title     = {The role of miR-21 in the pathophysiology of neuropathic pain using the model of B7-H1 knockout mice},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-156004},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2017},
  abstract  = {The impact of microRNA (miRNA) as key players in the regulation of immune and neuronal gene expression and their role as master switches in the pathophysiology of neuropathic pain is increasingly recognized. miR-21 is a promising candidate that could be linked to the immune and the nociceptive system. To further investigate the pathophysiological role of miR-21 in neuropathic pain, we assesed mice deficient of B7 homolog 1 (B7-H1 ko), a protein with suppressive effect on inflammatory responses. B7-H1 ko mice and wildtype littermates (WT) of three different age-groups, young (8 weeks), middle-aged (6 months), and old (12 months) received a spared nerve injury (SNI). Thermal withdrawal latencies and mechanical withdrawal thresholds were determined. Further, we investigated anxiety-, depression-like and cognitive behavior. Quantitative real time PCR was used to determine miR-21 relative expression in peripheral nerves, dorsal root ganglia and white blood cells (WBC) at distinct time points after SNI. Na{\"i}ve B7-H1 ko mice showed mechanical hyposensitivity with increasing age. Young and middle-aged B7-H1 ko mice displayed lower mechanical withdrawal thresholds compared to WT mice. From day three after SNI both genotypes developed mechanical and heat hypersensitivity, without intergroup differences. As supported by the results of three behavioral tests, no relevant differences were found for anxiety-like behavior after SNI in B7-H1 ko and WT mice. Also, there was no indication of depression-like behavior after SNI or any effect of SNI on cognition in both genotypes. The injured nerves of B7-H1 ko and WT mice showed higher miR-21 expression and invasion of macrophages and T cells 7 days after SNI without intergroup differences. Perineurial miR-21 inhibitor injection reversed SNI-induced mechanical and heat hypersensitivity in old B7-H1 ko and WT mice. This study reveals that reduced mechanical thresholds and heat withdrawal latencies are associated with miR-21 induction in the tibial and common peroneal nerve after SNI, which can be reversed by perineurial injection of a miR-21 inhibitor. Contrary to expectations, miR-21 expression levels were not higher in B7-H1 ko compared to WT mice. Thus, the B7-H1 ko mouse may be of minor importance for the study of miR-21 related pain. However, these results spot the contribution of miR-21 in the pathophysiology of neuropathic pain and emphasize the crucial role of miRNA in the regulation of neuronal and immune circuits that contribute to neuropathic pain.},
  subject      = {neuropathic pain},
  language  = {en}
}
@article{MacedoJavadiHiguchietal.2015,
  author    = {Macedo, Robson and Javadi, Som Mehrbod and Higuchi, Takahiro and Ferreira de Carvalho, Marilia Daniela and Lima Paiva Medeiros, Vanessa de F{\´a}tima and Azevedo, {\´I}talo Medeiros and Lima, Francisco Pignataro and Medeiros, Aldo Cunha},
  title     = {Heart and systemic effects of statin pretreatment in a rat model of abdominal sepsis. Assessment by Tc\(^{99m}\)-sestamibi biodistribition},
  series = {Acta Cir{\´u}rgica Brasileira},
  volume    = {30},
  journal   = {Acta Cir{\´u}rgica Brasileira},
  number    = {6},
  doi       = {10.1590/S0102-865020150060000003},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-151887},
  pages     = {388 -- 393},
  year      = {2015},
  abstract  = {PURPOSE: To evaluate the heart and the Tc-99m-sestamibi biodistribution after statin pretreatment in a rat model of abdominal sepsis. METHODS: Twenty-four Wistar rats were randomly distributed into four groups (n=6 per group): 1) sepsis with simvastatin treatment, 2) sepsis with vehicle, 3) sham control with simvastatin and 4) sham control with vehicle. 24 hours after cecal ligation and puncture rats received 1.0MBq of Tc-99m-sestamibi i.v. 30min after, animals were euthanized for ex-vivo tissue counting and myocardium histological analysis. RESULTS: Myocardial histologic alterations were not detected 24 hours post-sepsis. There was significantly increased cardiac Tc-99m-sestamibi activity in the sepsis group with simvastatin treatment (1.9\(\pm\)0.3\%ID/g, p<0.001) in comparison to the sepsis group+vehicle (1.0\(\pm\)0.2\% ID/g), control sham group+ simvastatin (1.2\(\pm\)0.3\% ID/g) and control sham group (1.3\(\pm\)0.2\% ID/g). Significant Tc-99m-sestamibi activity in liver, kidney and lungs was also detected in the sepsis group treated with simvastatinin comparison to the other groups. CONCLUSIONS: Statin treatment altered the biodistribution of Tc-99m-sestamibi with increased cardiac and solid organ activity in rats with abdominal sepsis, while no impact on controls. Increased myocardial tracer activity may be a result of a possible protection effect due to increased tissue perfusion mediated by statins.},
  language  = {en}
}
@article{RosenbaumSchickWollbornetal.2016,
  author    = {Rosenbaum, Corinna and Schick, Martin Alexander and Wollborn, Jakob and Heider, Andreas and Scholz, Claus-J{\"u}rgen and Cecil, Alexander and Niesler, Beate and Hirrlinger, Johannes and Walles, Heike and Metzger, Marco},
  title     = {Activation of Myenteric Glia during Acute Inflammation In Vitro and In Vivo},
  series = {PLoS One},
  volume    = {11},
  journal   = {PLoS One},
  number    = {3},
  doi       = {10.1371/journal.pone.0151335},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146544},
  pages     = {e0151335},
  year      = {2016},
  abstract  = {Background Enteric glial cells (EGCs) are the main constituent of the enteric nervous system and share similarities with astrocytes from the central nervous system including their reactivity to an inflammatory microenvironment. Previous studies on EGC pathophysiology have specifically focused on mucosal glia activation and its contribution to mucosal inflammatory processes observed in the gut of inflammatory bowel disease (IBD) patients. In contrast knowledge is scarce on intestinal inflammation not locally restricted to the mucosa but systemically affecting the intestine and its effect on the overall EGC network. Methods and Results In this study, we analyzed the biological effects of a systemic LPS-induced hyperinflammatory insult on overall EGCs in a rat model in vivo, mimicking the clinical situation of systemic inflammation response syndrome (SIRS). Tissues from small and large intestine were removed 4 hours after systemic LPS-injection and analyzed on transcript and protein level. Laser capture microdissection was performed to study plexus-specific gene expression alterations. Upon systemic LPS-injection in vivo we observed a rapid and dramatic activation of Glial Fibrillary Acidic Protein (GFAP)-expressing glia on mRNA level, locally restricted to the myenteric plexus. To study the specific role of the GFAP subpopulation, we established flow cytometry-purified primary glial cell cultures from GFAP promotor-driven EGFP reporter mice. After LPS stimulation, we analyzed cytokine secretion and global gene expression profiles, which were finally implemented in a bioinformatic comparative transcriptome analysis. Enriched GFAP+ glial cells cultured as gliospheres secreted increased levels of prominent inflammatory cytokines upon LPS stimulation. Additionally, a shift in myenteric glial gene expression profile was induced that predominantly affected genes associated with immune response. Conclusion and Significance Our findings identify the myenteric GFAP-expressing glial subpopulation as particularly susceptible and responsive to acute systemic inflammation of the gut wall and complement knowledge on glial involvement in mucosal inflammation of the intestine.},
  language  = {en}
}
@article{FehrholzGlaserSeidenspinneretal.2016,
  author    = {Fehrholz, Markus and Glaser, Kirsten and Seidenspinner, Silvia and Ottensmeier, Barbara and Curstedt, Tore and Speer, Christian P. and Kunzmann, Steffen},
  title     = {Impact of the New Generation Reconstituted Surfactant CHF5633 on Human CD4\(^+\) Lymphocytes},
  series = {PLoS One},
  volume    = {11},
  journal   = {PLoS One},
  number    = {4},
  doi       = {10.1371/journal.pone.0153578},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146419},
  pages     = {e0153578},
  year      = {2016},
  abstract  = {Background Natural surfactant preparations, commonly isolated from porcine or bovine lungs, are used to treat respiratory distress syndrome in preterm infants. Besides biophysical effectiveness, several studies have documented additional immunomodulatory properties. Within the near future, synthetic surfactant preparations may be a promising alternative. CHF5633 is a new generation reconstituted synthetic surfactant preparation with defined composition, containing dipalmitoyl-phosphatidylcholine, palmitoyl-oleoyl-phosphatidylglycerol and synthetic analogs of surfactant protein (SP-) B and SP-C. While its biophysical effectiveness has been demonstrated in vitro and in vivo, possible immunomodulatory abilities are currently unknown. Aim The aim of the current study was to define a potential impact of CHF5633 and its single components on pro- and anti-inflammatory cytokine responses in human CD4\(^+\) lymphocytes. Methods Purified human CD4\(^+\) T cells were activated using anti CD3/CD28 antibodies and exposed to CHF5633, its components, or to the well-known animal-derived surfactant Poractant alfa (Curosurf®). Proliferative response and cell viability were assessed using flow cytometry and a methylthiazolyldiphenyltetrazolium bromide colorimetric assay. The mRNA expression of IFNγ, IL-2, IL-17A, IL-22, IL-4, and IL-10 was measured by quantitative PCR, while intracellular protein expression was assessed by means of flow cytometry. Results Neither CHF5633 nor any of its phospholipid components with or without SP-B or SP-C analogs had any influence on proliferative ability and viability of CD4\(^+\) lymphocytes under the given conditions. IFNγ, IL-2, IL-17A, IL-22, IL-4, and IL-10 mRNA as well as IFNγ, IL-2, IL-4 and IL-10 protein levels were unaffected in both non-activated and activated CD4+ lymphocytes after exposure to CHF5633 or its constituents compared to non-exposed controls. However, in comparison to Curosurf®, expression levels of anti-inflammatory IL-4 and IL-10 mRNA were significantly increased in CHF5633 exposed CD4\(^+\) lymphocytes. Conclusion For the first time, the immunomodulatory capacity of CHF5633 on CD4\(^+\) lymphocytes was evaluated. CHF5633 did not show any cytotoxicity on CD4\(^+\) cells. Moreover, our in vitro data indicate that CHF5633 does not exert unintended pro-inflammatory effects on non-activated and activated CD4+ T cells. As far as anti-inflammatory cytokines are concerned, it might lack an overall reductive ability in comparison to animal-derived surfactants, potentially leaving pro- and anti-inflammatory cytokine response in balance.},
  language  = {en}
}
@article{BauneKonradGrotegerdetal.2012,
  author    = {Baune, Bernhard T. and Konrad, Carsten and Grotegerd, Dominik and Suslow, Thomas and Birosova, Eva and Ohrmann, Patricia and Bauer, Jochen and Arolt, Volker and Heindel, Walter and Domschke, Katharina and Sch{\"o}ning, Sonja and Rauch, Astrid V. and Uhlmann, Christina and Kugel, Harald and Dannlowski, Udo},
  title     = {Interleukin-6 gene (IL-6): a possible role in brain morphology in the healthy adult brain},
  series = {Journal of Neuroinflammation},
  volume    = {9},
  journal   = {Journal of Neuroinflammation},
  number    = {125},
  doi       = {10.1186/1742-2094-9-125},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130804},
  year      = {2012},
  abstract  = {Background: Cytokines such as interleukin 6 (IL-6) have been implicated in dual functions in neuropsychiatric disorders. Little is known about the genetic predisposition to neurodegenerative and neuroproliferative properties of cytokine genes. In this study the potential dual role of several IL-6 polymorphisms in brain morphology is investigated. Methodology: In a large sample of healthy individuals (N = 303), associations between genetic variants of IL-6 (rs1800795; rs1800796, rs2069833, rs2069840) and brain volume (gray matter volume) were analyzed using voxel-based morphometry (VBM). Selection of single nucleotide polymorphisms (SNPs) followed a tagging SNP approach (e. g., Stampa algorigthm), yielding a capture 97.08\% of the variation in the IL-6 gene using four tagging SNPs. Principal findings/results In a whole-brain analysis, the polymorphism rs1800795 (-174 C/G) showed a strong main effect of genotype (43 CC vs. 150 CG vs. 100 GG; x = 24, y = -10, z = -15; F(2,286) = 8.54, p(uncorrected) = 0.0002; p(AlphaSim-corrected) = 0.002; cluster size k = 577) within the right hippocampus head. Homozygous carriers of the G-allele had significantly larger hippocampus gray matter volumes compared to heterozygous subjects. None of the other investigated SNPs showed a significant association with grey matter volume in whole-brain analyses. Conclusions/significance: These findings suggest a possible neuroprotective role of the G-allele of the SNP rs1800795 on hippocampal volumes. Studies on the role of this SNP in psychiatric populations and especially in those with an affected hippocampus (e.g., by maltreatment, stress) are warranted.},
  language  = {en}
}
@article{WillemsUrlichsSeidenspinneretal.2012,
  author    = {Willems, Coen H. M. P. and Urlichs, Florian and Seidenspinner, Silvia and Kunzmann, Steffen and Speer, Christian P. and Kramer, Boris W.},
  title     = {Poractant alfa (Curosurf (R)) increases phagocytosis of apoptotic neutrophils by alveolar macrophages in vivo},
  series = {Respiratory Research},
  volume    = {13},
  journal   = {Respiratory Research},
  number    = {17},
  doi       = {10.1186/1465-9921-13-17},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130721},
  year      = {2012},
  abstract  = {Background: Clearance of apoptotic neutrophils in the lung is an essential process to limit inflammation, since they could become a pro-inflammatory stimulus themselves. The clearance is partially mediated by alveolar macrophages, which phagocytose these apoptotic cells. The phagocytosis of apoptotic immune cells by monocytes in vitro has been shown to be augmented by several constituents of pulmonary surfactant, e. g. phospholipids and hydrophobic surfactant proteins. In this study, we assessed the influence of exogenous poractant alfa (Curosurf (R)) instillation on the in vivo phagocytosis of apoptotic neutrophils by alveolar macrophages. Methods: Poractant alfa (200 mg/kg) was instilled intratracheally in the lungs of three months old adult male C57/Black 6 mice, followed by apoptotic neutrophil instillation. Bronchoalveloar lavage was performed and alveolar macrophages and neutrophils were counted. Phagocytosis of apoptotic neutrophils was quantified by determining the number of apoptotic neutrophils per alveolar macrophages. Results: Exogenous surfactant increased the number of alveolar macrophages engulfing apoptotic neutrophils 2.6 fold. The phagocytosis of apoptotic neutrophils was increased in the presence of exogenous surfactant by a 4.7 fold increase in phagocytosed apoptotic neutrophils per alveolar macrophage. Conclusions: We conclude that the anti-inflammatory properties of surfactant therapy may be mediated in part by increased numbers of alveolar macrophages and increased phagocytosis of apoptotic neutrophils by alveolar macrophages.},
  language  = {en}
}
@phdthesis{Panjwani2015,
  author    = {Panjwani, Priyadarshini},
  title     = {Induction, Imaging, Histo-morphological and Molecular Characterization of Myocarditis in the Rat to Explore Novel Diagnostic Strategies for the Detection of Myocardial Inflammation},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-122469},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2015},
  abstract  = {Fulminant myocarditis is rare but a potentially life-threatening disease. Acute or mild myocarditis following acute ischemia is generally associated with a profound activation of the host's immune system. On one hand this is mandatory to protect the host's heart by fighting the invading agents (i.e., bacteria, viruses or other microbial agents) and/or to induce healing and repair processes in the damaged myocardium. On other hand, uncontrolled activation of the immune system may result in the generation of auto-reactive (not always beneficial) immune cells. Myocarditis or inflammatory cardiomyopathy is characterized by focal or diffuse infiltrates, myocyte necrosis and/or apoptosis and subsequent fibrotic replacement of the heart muscle. In humans, about 30\% of the myocarditis-patients develop dilated cardiomyopathy. As the clinical picture of myocarditis is multifaceted, it is difficult to diagnose the disease. Therefore, the main goal of the present work was to test and further develop novel non-invasive methods for the detection of myocardial inflammation by employing both contrast enhanced MRI techniques as well as novel nuclear tracers that are suitable for in vivo PET/ SPECT imaging. As a part of this thesis, a pre-clinical animal model was successfully established by immunizing female Lewis rats with whole-porcine cardiac myosin (CM). Induction of Experimental Autoimmune Myocarditis (EAM) is considered successful when anti-myosin antibody titers are increased more than 100-fold over control animals and pericardial effusion develops. In addition, cardiac tissues from EAM-rats versus controls were analyzed for the expression of various pro-inflammatory and fibrosis markers. To further exploit non-invasive MRI techniques for the detection of myocarditis, our EAM-rats were injected either with (1) ultra-small Paramagnetic iron oxide particles (USPIO's; Feraheme®), allowing for in vivo imaging , (2) micron sized paramagnetic iron oxide particles (MPIO) for ex vivo inflammatory cell-tracking by cMRI, or (3) with different radioactive nuclear tracers (67gallium citrate, 68gallium-labeled somatostatin analogue, and 68gallium-labeled cyclic RGD-peptide) which in the present work have been employed for autoradiographic imaging, but in principle are also suitable for in vivo nuclear imaging (PET/SPECT). In order to compare imaging results with histology, consecutive heart sections were stained with hematoxylin \& eosin (HE, for cell infiltrates) and Masson Goldner trichrome (MGT, for fibrosis); in addition, immuno-stainings were performed with anti-CD68 (macrophages), anti-SSRT2A (somatostatin receptor type 2A), anti-CD61 (β3-integrins) and anti-CD31 (platelet endothelial cell adhesion molecule 1). Sera from immunized rats strongly reacted with cardiac myosin. In immunized rats, echocardiography and subsequent MRI revealed huge amounts of pericardial effusion (days 18-21). Analysis of the kinetics of myocardial infiltrates revealed maximal macrophage invasion between days 14 and 28. Disappearance of macrophages resulted in replacement-fibrosis in formerly cell-infiltrated myocardial areas. This finding was confirmed by the time-dependent differential expression of corresponding cytokines in the myocardium. Immunized animals reacted either with an early or a late pattern of post-inflammation fibrosis. Areas with massive cellular infiltrates were easily detectible in autoradiograms showing a high focal uptake of 67gallium-citrate and 68gallium labeled somatostatin analogues (68Ga DOTA-TATE). Myocardium with a loss of cardiomyocytes presented a high uptake of 68gallium labeled cyclic RGD-peptide (68Ga NOTA-RGD). MRI cell tracking experiments with Feraheme® as the contrast-agent were inconclusive; however, strikingly better results were obtained when MPIOs were used as a contrast-agent: histological findings correlated well with in vivo and ex vivo MPIO-enhanced MRI images. Imaging of myocardial inflammatory processes including the kinetics of macrophage invasion after microbial or ischemic damage is still a major challenge in, both animal models and in human patients. By applying a broad panel of biochemical, histological, molecular and imaging methods, we show here that different patterns of reactivity may occur upon induction of myocarditis using one and the same rat strain. In particular, immunized Lewis rats may react either with an early or a late pattern of macrophage invasion and subsequent post-inflammation fibrosis. Imaging results achieved in the acute inflammatory phase of the myocarditis with MPIOs, 67gallium citrate and 68gallium linked to somatostatin will stimulate further development of contrast agents and radioactive-nuclear tracers for the non-invasive detection of acute myocarditis and in the near future perhaps even in human patients.},
  subject      = {Ratte},
  language  = {en}
}
@article{SchreweLillLiuetal.2015,
  author    = {Schrewe, L. and Lill, C. M. and Liu, T. and Salmen, A. and Gerdes, L. A. and Guillot-Noel, L. and Akkad, D. A. and Blaschke, P. and Graetz, C. and Hoffjan, S. and Kroner, A. and Demir, S. and B{\"o}hme, A. and Rieckmann, P. and El Ali, A. and Hagemann, N. and Hermann, D. M. and Cournu-Rebeix, I. and Zipp, F. and K{\"u}mpfel, T. and Buttmann, M. and Zettl, U. K. and Fontaine, B. and Bertram, L. and Gold, R. and Chan, A.},
  title     = {Investigation of sex-specific effects of apolipoprotein E on severity of EAE and MS},
  series = {Journal of Neuroinflammation},
  volume    = {12},
  journal   = {Journal of Neuroinflammation},
  number    = {234},
  doi       = {10.1186/s12974-015-0429-y},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-136252},
  year      = {2015},
  abstract  = {Background: Despite pleiotropic immunomodulatory effects of apolipoprotein E (apoE) in vitro, its effects on the clinical course of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) are still controversial. As sex hormones modify immunomodulatory apoE functions, they may explain contentious findings. This study aimed to investigate sex-specific effects of apoE on disease course of EAE and MS. Methods: MOG\(_{35-55}\) induced EAE in female and male apoE-deficient mice was assessed clinically and histopathologically. apoE expression was investigated by qPCR. The association of the MS severity score (MSSS) and APOE rs429358 and rs7412 was assessed across 3237 MS patients using linear regression analyses. Results: EAE disease course was slightly attenuated in male apoE-deficient (apoE\(^{-/-}\)) mice compared to wildtype mice (cumulative median score: apoE\(^{-/-}\) = 2 [IQR 0.0-4.5]; wildtype = 4 [IQR 1.0-5.0]; n = 10 each group, p = 0.0002). In contrast, EAE was more severe in female apoE\(^{-/-}\) mice compared to wildtype mice (cumulative median score: apoE\(^{-/-}\) = 3 [IQR 2.0-4.5]; wildtype = 3 [IQR 0.0-4.0]; n = 10, p = 0.003). In wildtype animals, apoE expression during the chronic EAE phase was increased in both females and males (in comparison to naive animals; p < 0.001). However, in MS, we did not observe a significant association between MSSS and rs429358 or rs7412, neither in the overall analyses nor upon stratification for sex. Conclusions: apoE exerts moderate sex-specific effects on EAE severity. However, the results in the apoE knock-out model are not comparable to effects of polymorphic variants in the human APOE gene, thus pinpointing the challenge of translating findings from the EAE model to the human disease.},
  language  = {en}
}
@article{WeibelBasseLuesebrinkHessetal.2013,
  author    = {Weibel, Stephanie and Basse-Luesebrink, Thomas Christian and Hess, Michael and Hofmann, Elisabeth and Seubert, Carolin and Langbein-Laugwitz, Johanna and Gentschev, Ivaylo and Sturm, Volker J{\"o}rg Friedrich and Ye, Yuxiang and Kampf, Thomas and Jakob, Peter Michael and Szalay, Aladar A.},
  title     = {Imaging of Intratumoral Inflammation during Oncolytic Virotherapy of Tumors by \(^{19}\)F-Magnetic Resonance Imaging (MRI)},
  series = {PLoS ONE},
  volume    = {8},
  journal   = {PLoS ONE},
  number    = {3},
  doi       = {10.1371/journal.pone.0056317},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130311},
  pages     = {e56317},
  year      = {2013},
  abstract  = {Background Oncolytic virotherapy of tumors is an up-coming, promising therapeutic modality of cancer therapy. Unfortunately, non-invasive techniques to evaluate the inflammatory host response to treatment are rare. Here, we evaluate \(^{19}\)F magnetic resonance imaging (MRI) which enables the non-invasive visualization of inflammatory processes in pathological conditions by the use of perfluorocarbon nanoemulsions (PFC) for monitoring of oncolytic virotherapy. Methodology/Principal Findings The Vaccinia virus strain GLV-1h68 was used as an oncolytic agent for the treatment of different tumor models. Systemic application of PFC emulsions followed by \(^1H\)/\(^{19}\)F MRI of mock-infected and GLV-1h68-infected tumor-bearing mice revealed a significant accumulation of the \(^{19}\)F signal in the tumor rim of virus-treated mice. Histological examination of tumors confirmed a similar spatial distribution of the \(^{19}\)F signal hot spots and \(CD68^+\)-macrophages. Thereby, the \(CD68^+\)-macrophages encapsulate the GFP-positive viral infection foci. In multiple tumor models, we specifically visualized early inflammatory cell recruitment in Vaccinia virus colonized tumors. Furthermore, we documented that the \(^{19}\)F signal correlated with the extent of viral spreading within tumors. Conclusions/Significance These results suggest \(^{19}\)F MRI as a non-invasive methodology to document the tumor-associated host immune response as well as the extent of intratumoral viral replication. Thus, \(^{19}\)F MRI represents a new platform to non-invasively investigate the role of the host immune response for therapeutic outcome of oncolytic virotherapy and individual patient response.},
  language  = {en}
}
@article{PachelMathesBayeretal.2013,
  author    = {Pachel, Christina and Mathes, Denise and Bayer, Barbara and Dienesch, Charlotte and Wangorsch, Gaby and Heitzmann, Wolfram and Lang, Isabell and Ardehali, Hossein and Ertl, Georg and Dandekar, Thomas and Wajant, Harald and Frantz, Stefan},
  title     = {Exogenous Administration of a Recombinant Variant of TWEAK Impairs Healing after Myocardial Infarction by Aggravation of Inflammation},
  series = {PLoS ONE},
  volume    = {8},
  journal   = {PLoS ONE},
  number    = {11},
  doi       = {10.1371/journal.pone.0078938},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129889},
  pages     = {e78938},
  year      = {2013},
  abstract  = {Background: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factorinducible 14 (Fn14) are upregulated after myocardial infarction (MI) in both humans and mice. They modulate inflammation and the extracellular matrix, and could therefore be important for healing and remodeling after MI. However, the function of TWEAK after MI remains poorly defined. Methods and results: Following ligation of the left coronary artery, mice were injected twice per week with a recombinant human serum albumin conjugated variant of TWEAK (HSA-Flag-TWEAK), mimicking the activity of soluble TWEAK. Treatment with HSA-Flag-TWEAK resulted in significantly increased mortality in comparison to the placebo group due to myocardial rupture. Infarct size, extracellular matrix remodeling, and apoptosis rates were not different after MI. However, HSA-Flag-TWEAK treatment increased infiltration of proinflammatory cells into the myocardium. Accordingly, depletion of neutrophils prevented cardiac ruptures without modulating all-cause mortality. Conclusion: Treatment of mice with HSA-Flag-TWEAK induces myocardial healing defects after experimental MI. This is mediated by an exaggerated neutrophil infiltration into the myocardium.},
  language  = {en}
}
@article{BloemerPachelHofmannetal.2013,
  author    = {Bl{\"o}mer, Nadja and Pachel, Christina and Hofmann, Urlich and Nordbeck, Peter and Bauer, Wolfgang and Mathes, Denise and Frey, Anna and Bayer, Barbara and Vogel, Benjamin and Ertl, Georg},
  title     = {5-Lipoxygenase facilitates healing after myocardial infarction},
  series = {Basic Research in Cardiology},
  volume    = {108},
  journal   = {Basic Research in Cardiology},
  number    = {4},
  doi       = {10.1007/s00395-013-0367-8},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132602},
  year      = {2013},
  abstract  = {Early healing after myocardial infarction (MI) is characterized by a strong inflammatory reaction. Most leukotrienes are pro-inflammatory and are therefore potential mediators of healing and remodeling after myocardial ischemia. The enzyme 5-lipoxygenase (5-LOX) has a key role in the transformation of arachidonic acid in leukotrienes. Thus, we tested the effect of 5-LOX on healing after MI. After chronic coronary artery ligation, early mortality was significantly increased in 5-LOX\(^{-/-}\) when compared to matching wildtype (WT) mice due to left ventricular rupture. This effect could be reproduced in mice treated with the 5-LOX inhibitor Zileuton. A perfusion mismatch due to the vasoactive potential of leukotrienes is not responsible for left ventricular rupture since local blood flow assessed by magnetic resonance perfusion measurements was not different. However, after MI, there was an accentuation of the inflammatory reaction with an increase of pro-inflammatory macrophages. Yet, mortality was not changed in chimeric mice (WT vs. 5-LOX\(^{-/-}\) bone marrow in 5-LOX\(^{-/-}\) animals), indicating that an altered function of 5-LOX\(^{-/-}\) inflammatory cells is not responsible for the phenotype. Collagen production and accumulation of fibroblasts were significantly reduced in 5-LOX\(^{-/-}\) mice in vivo after MI. This might be due to an impaired migration of 5-LOX\(^{-/-}\) fibroblasts, as shown in vitro to serum. In conclusion, a lack or inhibition of 5-LOX increases mortality after MI because of healing defects. This is not mediated by a change in local blood flow, but through an altered inflammation and/or fibroblast function.},
  language  = {en}
}
@article{HedrichHofmannPabliketal.2013,
  author    = {Hedrich, Christian M. and Hofmann, Sigrun R. and Pablik, Jessica and Morbach, Henner and Girschick, Hermann J.},
  title     = {Autoinflammatory bone disorders with special focus on chronic recurrent multifocal osteomyelitis (CRMO)},
  series = {Pediatric Rheumatology},
  volume    = {11},
  journal   = {Pediatric Rheumatology},
  number    = {47},
  doi       = {10.1186/1546-0096-11-47},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132456},
  year      = {2013},
  abstract  = {Sterile bone inflammation is the hallmark of autoinflammatory bone disorders, including chronic nonbacterial osteomyelitis (CNO) with its most severe form chronic recurrent multifocal osteomyelitis (CRMO). Autoinflammatory osteopathies are the result of a dysregulated innate immune system, resulting in immune cell infiltration of the bone and subsequent osteoclast differentiation and activation. Interestingly, autoinflammatory bone disorders are associated with inflammation of the skin and/or the intestine. In several monogenic autoinflammatory bone disorders mutations in disease-causing genes have been reported. However, regardless of recent developments, the molecular pathogenesis of CNO/CRMO remains unclear. Here, we discuss the clinical presentation and molecular pathophysiology of human autoinflammatory osteopathies and animal models with special focus on CNO/CRMO. Treatment options in monogenic autoinflammatory bone disorders and CRMO will be illustrated.},
  language  = {en}
}
@article{WolfAkrapMargetal.2013,
  author    = {Wolf, Annette and Akrap, Nina and Marg, Berenice and Galliardt, Helena and Heiligentag, Martyna and Humpert, Fabian and Sauer, Markus and Kaltschmidt, Barbara and Kaltschmidt, Christian and Seidel, Thorsten},
  title     = {Elements of Transcriptional Machinery Are Compatible among Plants and Mammals},
  series = {PLoS ONE},
  volume    = {8},
  journal   = {PLoS ONE},
  number    = {1},
  doi       = {10.1371/journal.pone.0053737},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131203},
  pages     = {e53737},
  year      = {2013},
  abstract  = {In the present work, the objective has been to analyse the compatibility of plant and human transcriptional machinery. The experiments revealed that nuclear import and export are conserved among plants and mammals. Further it has been shown that transactivation of a human promoter occurs by human transcription factor NF-\(\kappa\) B in plant cells, demonstrating that the transcriptional machinery is highly conserved in both kingdoms. Functionality was also seen for regulatory elements of NF-\(\kappa\) B such as its inhibitor I\(\kappa\)B isoform \(\alpha\) that negatively regulated the transactivation activity of the p50/RelA heterodimer by interaction with NF-\(\kappa\)B in plant cells. Nuclear export of RelA could be demonstrated by FRAP-measurements so that RelA shows nucleo-cytoplasmic shuttling as reported for RelA in mammalian cells. The data reveals the high level of compatibility of human transcriptional elements with the plant transcriptional machinery. Thus, Arabidopsis thaliana mesophyll protoplasts might provide a new heterologous expression system for the investigation of the human NF-\(\kappa\)B signaling pathways. The system successfully enabled the controlled manipulation of NF-\(\kappa\)B activity. We suggest the plant protoplast system as a tool for reconstitution and analyses of mammalian pathways and for direct observation of responses to e. g. pharmaceuticals. The major advantage of the system is the absence of interference with endogenous factors that affect and crosstalk with the pathway.},
  language  = {en}
}
@article{HedrichHofmannPabliketal.2013,
  author    = {Hedrich, Christian M. and Hofmann, Sigrun R. and Pablik, Jessica and Morbach, Henner and Girschick, Hermann J.},
  title     = {Autoinflammatory bone disorders with special focus on chronic recurrent multifocal osteomyelitis (CRMO)},
  series = {Pediatric Rheumatology},
  volume    = {11},
  journal   = {Pediatric Rheumatology},
  number    = {47},
  issn      = {1546-0096},
  doi       = {10.1186/1546-0096-11-47},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125694},
  year      = {2013},
  abstract  = {Sterile bone inflammation is the hallmark of autoinflammatory bone disorders, including chronic nonbacterial osteomyelitis (CNO) with its most severe form chronic recurrent multifocal osteomyelitis (CRMO). Autoinflammatory osteopathies are the result of a dysregulated innate immune system, resulting in immune cell infiltration of the bone and subsequent osteoclast differentiation and activation. Interestingly, autoinflammatory bone disorders are associated with inflammation of the skin and/or the intestine. In several monogenic autoinflammatory bone disorders mutations in disease-causing genes have been reported. However, regardless of recent developments, the molecular pathogenesis of CNO/CRMO remains unclear. Here, we discuss the clinical presentation and molecular pathophysiology of human autoinflammatory osteopathies and animal models with special focus on CNO/CRMO. Treatment options in monogenic autoinflammatory bone disorders and CRMO will be illustrated.},
  language  = {en}
}
@article{SchickBaarBrunoetal.2015,
  author    = {Schick, Martin Alexander and Baar, Wolfgang and Bruno, Raphael Romano and Wollborn, Jakob and Held, Christopher and Schneider, Reinhard and Flemming, Sven and Schlegel, Nicolas and Roewer, Norbert and Neuhaus, Winfried and Wunder, Christian},
  title     = {Balanced hydroxyethylstarch (HES 130/0.4) impairs kidney function in-vivo without inflammation},
  series = {PLoS One},
  volume    = {10},
  journal   = {PLoS One},
  number    = {9},
  doi       = {10.1371/journal.pone.0137247},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126068},
  pages     = {e0137247},
  year      = {2015},
  abstract  = {Volume therapy is a standard procedure in daily perioperative care, and there is an ongoing discussion about the benefits of colloid resuscitation with hydroxyethylstarch (HES). In sepsis HES should be avoided due to a higher risk for acute kidney injury (AKI). Results of the usage of HES in patients without sepsis are controversial. Therefore we conducted an animal study to evaluate the impact of 6\% HES 130/0.4 on kidney integrity with sepsis or under healthy conditions Sepsis was induced by standardized Colon Ascendens Stent Peritonitis (sCASP). sCASP-group as well as control group (C) remained untreated for 24 h. After 18 h sCASP+HES group (sCASP+VOL) and control+HES (C+VOL) received 50 ml/KG balanced 6\% HES (VOL) 130/0.4 over 6h. After 24h kidney function was measured via Inulin- and PAH-Clearance in re-anesthetized rats, and serum urea, creatinine (crea), cystatin C and Neutrophil gelatinase-associated lipocalin (NGAL) as well as histopathology were analysed. In vitro human proximal tubule cells (PTC) were cultured +/- lipopolysaccharid (LPS) and with 0.1-4.0\% VOL. Cell viability was measured with XTT-, cell toxicity with LDH-test. sCASP induced severe septic AKI demonstrated divergent results regarding renal function by clearance or creatinine measure focusing on VOL. Soleley HES (C+VOL) deteriorated renal function without sCASP. Histopathology revealed significantly derangements in all HES groups compared to control. In vitro LPS did not worsen the HES induced reduction of cell viability in PTC cells. For the first time, we demonstrated, that application of 50 ml/KG 6\% HES 130/0.4 over 6 hours induced AKI without inflammation in vivo. Severity of sCASP induced septic AKI might be no longer susceptible to the way of volume expansion},
  language  = {en}
}
@article{LoefflerLoefflerKobsaretal.2015,
  author    = {Loeffler, Claudia and Loeffler, J{\"u}rgen and Kobsar, Anna and Speer, Christian P. and Eigenthaler, Martin},
  title     = {Septic Vs Colonizing Group B Streptococci Differentially Regulate Inflammation and Apoptosis in Human Coronary Artery Endothelial Cells - a Pilot Study},
  series = {Journal of Pediatrics and Neonatal Care},
  volume    = {2},
  journal   = {Journal of Pediatrics and Neonatal Care},
  number    = {2},
  doi       = {10.15406/jpnc.2015.02.00064},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125596},
  pages     = {00064},
  year      = {2015},
  abstract  = {In this pilot study, we exemplify differences between a septic and a colonizing GBS strain during their interaction with Endothelial Cells by evaluating cytokine levels, surface and apoptosis-related molecules. These preliminary results indicate that in vitro infection using an exemplary septic GBS strain results in diminished activation of the innate immune response.},
  language  = {en}
}
@article{WagnerAshbyKurtzetal.2015,
  author    = {Wagner, Martin and Ashby, Damien R. and Kurtz, Caroline and Alam, Ahsan and Busbridge, Mark and Raff, Ulrike and Zimmermann, Josef and Heuschmann, Peter U. and Wanner, Christoph and Schramm, Lothar},
  title     = {Hepcidin-25 in diabetic chronic kidney disease is predictive for mortality and progression to end stage renal disease},
  series = {PLoS One},
  volume    = {10},
  journal   = {PLoS One},
  number    = {4},
  doi       = {10.1371/journal.pone.0123072},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125514},
  pages     = {e0123072},
  year      = {2015},
  abstract  = {Background Anemia is common and is associated with impaired clinical outcomes in diabetic chronic kidney disease (CKD). It may be explained by reduced erythropoietin (EPO) synthesis, but recent data suggest that EPO-resistance and diminished iron availability due to inflammation contribute significantly. In this cohort study, we evaluated the impact of hepcidin-25—the key hormone of iron-metabolism—on clinical outcomes in diabetic patients with CKD along with endogenous EPO levels. Methods 249 diabetic patients with CKD of any stage, excluding end-stage renal disease (ESRD), were enrolled (2003-2005), if they were not on EPO-stimulating agent and iron therapy. Hepcidin-25 levels were measured by radioimmunoassay. The association of hepcidin-25 at baseline with clinical variables was investigated using linear regression models. All-cause mortality and a composite endpoint of CKD progression (ESRD or doubling of serum creatinine) were analyzed by Cox proportional hazards models. Results Patients (age 67 yrs, 53\% male, GFR 51 ml/min, hemoglobin 131 g/L, EPO 13.5 U/L, hepcidin-25 62.0 ng/ml) were followed for a median time of 4.2 yrs. Forty-nine patients died (19.7\%) and forty (16.1\%) patients reached the composite endpoint. Elevated hepcidin levels were independently associated with higher ferritin-levels, lower EPO-levels and impaired kidney function (all p<0.05). Hepcidin was related to mortality, along with its interaction with EPO, older age, greater proteinuria and elevated CRP (all p<0.05). Hepcidin was also predictive for progression of CKD, aside from baseline GFR, proteinuria, low albumin- and hemoglobin-levels and a history of CVD (all p<0.05). Conclusions We found hepcidin-25 to be associated with EPO and impaired kidney function in diabetic CKD. Elevated hepcidin-25 and EPO-levels were independent predictors of mortality, while hepcidin-25 was also predictive for progression of CKD. Both hepcidin-25 and EPO may represent important prognostic factors of clinical outcome and have the potential to further define "high risk" populations in CKD.},
  language  = {en}
}
@article{HuettenDhanasinghHessleretal.2014,
  author    = {H{\"u}tten, Mareike and Dhanasingh, Anandhan and Hessler, Roland and St{\"o}ver, Timo and Esser, Karl-Heinz and M{\"o}ller, Martin and Lenarz, Thomas and Jolly, Claude and Groll, J{\"u}rgen and Scheper, Verena},
  title     = {In Vitro and In Vivo Evaluation of a Hydrogel Reservoir as a Continuous Drug Delivery System for Inner Ear Treatment},
  series = {PLoS ONE},
  volume    = {9},
  journal   = {PLoS ONE},
  number    = {8},
  doi       = {10.1371/journal.pone.0104564},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119375},
  pages     = {e104564},
  year      = {2014},
  abstract  = {Fibrous tissue growth and loss of residual hearing after cochlear implantation can be reduced by application of the glucocorticoid dexamethasone-21-phosphate-disodium-salt (DEX). To date, sustained delivery of this agent to the cochlea using a number of pharmaceutical technologies has not been entirely successful. In this study we examine a novel way of continuous local drug application into the inner ear using a refillable hydrogel functionalized silicone reservoir. A PEG-based hydrogel made of reactive NCO-sP(EO-stat-PO) prepolymers was evaluated as a drug conveying and delivery system in vitro and in vivo. Encapsulating the free form hydrogel into a silicone tube with a small opening for the drug diffusion resulted in delayed drug release but unaffected diffusion of DEX through the gel compared to the free form hydrogel. Additionally, controlled DEX release over several weeks could be demonstrated using the hydrogel filled reservoir. Using a guinea-pig cochlear trauma model the reservoir delivery of DEX significantly protected residual hearing and reduced fibrosis. As well as being used as a device in its own right or in combination with cochlear implants, the hydrogel-filled reservoir represents a new drug delivery system that feasibly could be replenished with therapeutic agents to provide sustained treatment of the inner ear.},
  language  = {en}
}
@article{AlbertWeissenbergerMenclSchuhmannetal.2014,
  author    = {Albert-Weissenberger, Christiane and Mencl, Stine and Schuhmann, Michael K. and Salur, Irmak and G{\"o}b, Eva and Langhauser, Friederike and Hopp, Sarah and Hennig, Nelli and Meuth, Sven G. and Nolte, Marc W. and Sir{\´e}n, Anna-Leena and Kleinschnitz, Christoph},
  title     = {C1-Inhibitor protects from focal brain trauma in a cortical cryolesion mice model by reducing thrombo-inflammation},
  series = {Frontiers in Cellular Neuroscience},
  volume    = {8},
  journal   = {Frontiers in Cellular Neuroscience},
  issn      = {1662-5102},
  doi       = {10.3389/fncel.2014.00269},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119263},
  pages     = {269},
  year      = {2014},
  abstract  = {Traumatic brain injury (TBI) induces a strong inflammatory response which includes blood-brain barrier damage, edema formation and infiltration of different immune cell subsets. More recently, microvascular thrombosis has been identified as another pathophysiological feature of TBI. The contact-kinin system represents an interface between inflammatory and thrombotic circuits and is activated in different neurological diseases. C1-Inhibitor counteracts activation of the contact-kinin system at multiple levels. We investigated the therapeutic potential of C1-Inhibitor in a model of TBI. Male and female C57BL/6 mice were subjected to cortical cryolesion and treated with C1-Inhibitor after 1 h. Lesion volumes were assessed between day 1 and day 5 and blood-brain barrier damage, thrombus formation as well as the local inflammatory response were determined post TBI. Treatment of male mice with 15.0 IU C1-Inhibitor, but not 7.5 IU, 1 h after cryolesion reduced lesion volumes by ~75\% on day 1. This protective effect was preserved in female mice and at later stages of trauma. Mechanistically, C1-Inhibitor stabilized the blood-brain barrier and decreased the invasion of immune cells into the brain parenchyma. Moreover, C1-Inhibitor had strong antithrombotic effects. C1-Inhibitor represents a multifaceted anti-inflammatory and antithrombotic compound that prevents traumatic neurodegeneration in clinically meaningful settings.},
  language  = {en}
}
@article{CardaniSardiLaFerlaetal.2014,
  author    = {Cardani, Diego and Sardi, Claudia and La Ferla, Barbara and D'Orazio, Guiseppe and Sommariva, Michele and Marcucci, Fabrizio and Olivero, Daniela and Tagliabue, Elda and Koepsell, Hermann and Nicotra, Francesco and Balsari, Andrea and Rumio, Christiano},
  title     = {Sodium glucose cotransporter 1 ligand BLF501 as a novel tool for management of gastrointestinal mucositis},
  series = {Molecular Cancer},
  volume    = {13},
  journal   = {Molecular Cancer},
  number    = {23},
  issn      = {1476-4598},
  doi       = {10.1186/1476-4598-13-23},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117352},
  year      = {2014},
  abstract  = {Background: Recent studies demonstrated that engagement of sodium glucose transporter 1 (SGLT-1) by orally administered D-glucose protects the intestinal mucosa from lipopolysaccharide (LPS)-induced injury. We tested whether SGLT-1 engagement might protect the intestinal mucosa from doxorubicin (DXR)- and 5-fluorouracil (5-FU)-induced injury in animal models mimicking acute or chronic mucositis. Methods: Mice were treated intraperitoneally with DXR, alone or in combination with 5-FU, and orally with BLF501, a glucose-derived synthetic compound with high affinity for SGLT-1. Intestinal mucosal epithelium integrity was assessed by histological analysis, cellular proliferation assays, real-time PCR gene expression assays and Western blot assays. Student's t-test (paired two-tailed) and X-2 analyses were used for comparisons between groups. Differences were considered significant at p < 0.05. Results: BLF501 administration in mice treated with DXR and/or 5-FU decreased the injuries to the mucosa in terms of epithelial integrity and cellular proliferative ability. Co-treatment with BLF501 led to a normal expression and distribution of both zonula occludens-1 (ZO-1) and beta-catenin, which were underexpressed after treatment with either chemotherapeutic agent alone. BLF501 administration also restored normal expression of caspase-3 and ezrin/radixin/moesin (ERM), which were overexpressed after treatment with DXR and 5-FU. In SGLT1-/- mice, BLF501 had no detectable effects. BLF501 administration in wild-type mice with growing A431 tumors did not modify antitumor activity of DXR. Conclusions: BLF501-induced protection of the intestinal mucosa is a promising novel therapeutic approach to reducing the severity of chemotherapy-induced mucositis.},
  language  = {en}
}
@article{RittnerWangGehringeretal.2014,
  author    = {Rittner, Heike L. and Wang, Ying and Gehringer, Rebekka and Mousa, Shaaban A. and Hackel, Dagmar and Brack, Alexander},
  title     = {CXCL10 Controls Inflammatory Pain via Opioid Peptide- Containing Macrophages in Electroacupuncture},
  doi       = {10.1371/journal.pone.0094696},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-112979},
  year      = {2014},
  abstract  = {Acupuncture is widely used for pain treatment in patients with osteoarthritis or low back pain, but molecular mechanisms remain largely enigmatic. In the early phase of inflammation neutrophilic chemokines direct opioid-containing neutrophils in the inflamed tissue and stimulate opioid peptide release and antinociception. In this study the molecular pathway and neuroimmune connections in complete Freund's adjuvant (CFA)-induced hind paw inflammation and electroacupuncture for peripheral pain control were analyzed. Free moving Wistar rats with hind paw inflammation were treated twice with electroacupuncture at GB30 (Huan Tiao - gall bladder meridian) (day 0 and 1) and analyzed for mechanical and thermal nociceptive thresholds. The cytokine profiles as well as the expression of opioid peptides were quantified in the inflamed paw. Electroacupuncture elicited long-term antinociception blocked by local injection of anti-opioid peptide antibodies (beta-endorphin, met-enkephalin, dynorphin A). The treatment altered the cytokine profile towards an anti-inflammatory pattern but augmented interferon (IFN)-gamma and the chemokine CXCL10 (IP-10: interferon gamma-inducible protein) protein and mRNA expression with concomitant increased numbers of opioid peptide-containing CXCR3+ macrophages. In rats with CFA hind paw inflammation without acupuncture repeated injection of CXCL10 triggered opioid-mediated antinociception and increase opioid-containing macrophages. Conversely, neutralization of CXCL10 time-dependently decreased electroacupuncture-induced antinociception and the number of infiltrating opioid peptide-expressing CXCR3+ macrophages. In summary, we describe a novel function of the chemokine CXCL10 - as a regulator for an increase of opioid-containing macrophages and antinociceptive mediator in inflammatory pain and as a key chemokine regulated by electroacupuncture.},
  language  = {en}
}
@article{RittnerHackelPflueckeetal.2013,
  author    = {Rittner, Heike Lydia and Hackel, Dagmar and Pfl{\"u}cke, Diana and Neumann, Annick and Viebahn, Johannes and Mousa, Shaaban and Wischmeyer, Erhard and Roewer, Norbert and Brack, Alexander},
  title     = {The Connection of Monocytes and Reactive Oxygen Species in Pain},
  series = {PLoS ONE},
  journal   = {PLoS ONE},
  doi       = {10.1371/journal.pone.0063564},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-96669},
  year      = {2013},
  abstract  = {The interplay of specific leukocyte subpopulations, resident cells and proalgesic mediators results in pain in inflammation. Proalgesic mediators like reactive oxygen species (ROS) and downstream products elicit pain by stimulation of transient receptor potential (TRP) channels. The contribution of leukocyte subpopulations however is less clear. Local injection of neutrophilic chemokines elicits neutrophil recruitment but no hyperalgesia in rats. In meta-analyses the monocytic chemoattractant, CCL2 (monocyte chemoattractant protein-1; MCP-1), was identified as an important factor in the pathophysiology of human and animal pain. In this study, intraplantar injection of CCL2 elicited thermal and mechanical pain in Wistar but not in Dark Agouti (DA) rats, which lack p47phox, a part of the NADPH oxidase complex. Inflammatory hyperalgesia after complete Freund's adjuvant (CFA) as well as capsaicin-induced hyperalgesia and capsaicin-induced current flow in dorsal root ganglion neurons in DA were comparable to Wistar rats. Macrophages from DA expressed lower levels of CCR2 and thereby migrated less towards CCL2 and formed limited amounts of ROS in vitro and 4-hydroxynonenal (4-HNE) in the tissue in response to CCL2 compared to Wistar rats. Local adoptive transfer of peritoneal macrophages from Wistar but not from DA rats reconstituted CCL2-triggered hyperalgesia in leukocyte-depleted DA and Wistar rats. A pharmacological stimulator of ROS production (phytol) restored CCL2-induced hyperalgesia in vivo in DA rats. In Wistar rats, CCL2-induced hyperalgesia was completely blocked by superoxide dismutase (SOD), catalase or tempol. Likewise, inhibition of NADPH oxidase by apocynin reduced CCL2-elicited hyperalgesia but not CFA-induced inflammatory hyperalgesia. In summary, we provide a link between CCL2, CCR2 expression on macrophages, NADPH oxidase, ROS and the development CCL2-triggered hyperalgesia, which is different from CFA-induced hyperalgesia. The study further supports the impact of CCL2 and ROS as potential targets in pain therapy.},
  language  = {en}
}
@article{SchuppAliBeegametal.2013,
  author    = {Schupp, Nicole and Ali, Badreldin H. and Beegam, Sumyia and Al-Husseni, Isehaq and Al-Shukaili, Ahmed and Nemmar, Abderrahim and Schierling, Simone and Queisser, Nina},
  title     = {Effect of gum arabic on oxidative stress and inflammation in adenine-induced chronic renal failure in rats},
  series = {PLoS One},
  journal   = {PLoS One},
  doi       = {10.1371/journal.pone.0055242},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-95787},
  year      = {2013},
  abstract  = {Inflammation and oxidative stress are known to be involved in the pathogenesis of chronic kidney disease in humans, and in chronic renal failure (CRF) in rats. The aim of this work was to study the role of inflammation and oxidative stress in adenine-induced CRF and the effect thereon of the purported nephroprotective agent gum arabic (GA). Rats were divided into four groups and treated for 4 weeks as follows: control, adenine in feed (0.75\%, w/w), GA in drinking water (15\%, w/v) and adenine+GA, as before. Urine, blood and kidneys were collected from the rats at the end of the treatment for analysis of conventional renal function tests (plasma creatinine and urea concentration). In addition, the concentrations of the pro-inflammatory cytokine TNF-a and the oxidative stress markers glutathione and superoxide dismutase, renal apoptosis, superoxide formation and DNA double strand break frequency, detected by immunohistochemistry for c-H2AX, were measured. Adenine significantly increased the concentrations of urea and creatinine in plasma, significantly decreased the creatinine clearance and induced significant increases in the concentration of the measured inflammatory mediators. Further, it caused oxidative stress and DNA damage. Treatment with GA significantly ameliorated these actions. The mechanism of the reported salutary effect of GA in adenine-induced CRF is associated with mitigation of the adenine-induced inflammation and generation of free radicals.},
  language  = {en}
}
@phdthesis{Partheil2013,
  author    = {Partheil, Anna},
  title     = {Monozyten und Prostaglandine in der Schmerzentstehung},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-85091},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2013},
  abstract  = {Schmerz ist eine klassische Komponente von Entz{\"u}ndungsreaktionen. Im Rahmen des Entz{\"u}ndungsgeschehens werden Zytokine und Chemokine freigesetzt, die Leukozyten zum Entz{\"u}ndungsort rekrutieren. {\"U}ber die Freisetzung weiterer proalgetischer Mediatoren tragen diese zur Aktivierung und Sensitivierung von Nozizeptoren und damit zur Schmerzentstehung bei. Das Monozyten-rekrutierende Chemokin CCL2 verursachte in Verhaltensexperimenten eine Hyperalgesie bei Ratten. Die Hyperalgesie war durch den Cox-2 Inhibitor Parecoxib vollst{\"a}ndig reversibel. Daher wurde in dieser Arbeit die Rolle von Monozyten und Prostaglandinen in der Entstehung dieser Hyperalgesie untersucht. Dazu wurde in vitro die Cox-2 Expression und die Prostaglandin-Bildung in humanen Monozyten und Peritonealmakrophagen der Ratte nach CCL2 Stimulation bestimmt. Zudem wurde in vivo die Cox-2 Expression im R{\"u}ckenmark und in der Rattenpfote nach CCL2 Injektion in die Pfote untersucht.},
  subject      = {Schmerz},
  language  = {de}
}
@phdthesis{Rodenberg2011,
  author    = {Rodenberg, Hella Katharina},
  title     = {Inflammation und Mangelern{\"a}hrung bei Dialysepatienten mit Diabetes Mellitus Typ 2},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-71145},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2011},
  abstract  = {In der vorliegenden Arbeit wird der Einfluss von hs-CRP und Albumin auf die kardiovaskul{\"a}re Ereignisrate und das {\"U}berleben von Patienten mit Diabetes Mellitus Typ 2 an der H{\"a}modialyse untersucht. Grundlagen f{\"u}r die hier dargestellte Auswertung sind die in der 4D Studie erhobenen Daten. Die 4D Studie hat prospektiv, randomisiert, doppelblind und placebo-kontrolliert untersucht, ob die Behandlung mit Atorvastatin bei Patienten mit Diabetes Mellitus Typ 2 an der H{\"a}modialyse den prim{\"a}ren Endpunkt bestehend aus Herzinfarkt, kardialem Tod und Schlaganfall zu senken vermag. Die Daten zum hs-CRP und Albumin wurden bei Studienbeginn und nach sechs Monaten erhoben. In einer post-hoc Analyse mit Hilfe eines multivariaten Cox Regressionsmodels konnte best{\"a}tigt werden, dass ein erh{\"o}hter Spiegel an hs-CRP und ein verminderter Spiegel an Albumin im Zusammenhang mit einer vermehrten kardiovaskul{\"a}ren Ereignisrate und Mortalit{\"a}t stehen. Eine Behandlung mit Atorvastatin f{\"u}hrte zwar nicht zu einer Risikosenkung f{\"u}r den prim{\"a}ren Endpunkt oder die Mortalit{\"a}t, hatte aber einen stabilisierenden Effekt auf des hs-CRP Spiegel.},
  subject      = {H{\"a}modialyse},
  language  = {de}
}
@phdthesis{Rauh2011,
  author    = {Rauh, Katharina},
  title     = {Erythropoietin und Inflammation bei diabetischer Nephropathie},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-66637},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2011},
  abstract  = {Bei Patienten mit Diabetes mellitus Typ 2 und chronischer Niereninsuffizienz ist An{\"a}mie h{\"a}ufig. Zum Teil ist sie durch ungen{\"u}gende EPO-Produktion bedingt. Zus{\"a}tzlich wird die H{\"a}moglobinsynthese, wie bei der An{\"a}mie chronischer Krankheiten (anemia of chronic disease, ACD) beschrieben, durch entz{\"u}ndliche Vorg{\"a}nge unterdr{\"u}ckt. Der Stellenwert endogenen Erythropoietins bei Patienten mit diabetischer Nephropathie und ACD bleibt noch unsicher sowie auch der Zusammenhang zwischen EPO und der Nierenfunktion. Diese Querschnittsanalyse schloss 224 Patienten mit Typ 2-Diabetes in allen Stadien chronischer Niereninsuffizienz (CNI-Stadium 1-5) ein. Das mediane Alter betrug 67 Jahre, 54 \% waren m{\"a}nnlich und die mediane GFR lag bei 49 ml/min. Gem{\"a}ß den Definitionen der K/DOQI-Richtlinien waren 41 \% der Patienten an{\"a}misch. Von der Studie ausgeschlossen wurden wegen der An{\"a}mie behandelte Patienten und solche mit Eisenmangel. Pr{\"a}diktoren der log-transformierten EPO-Spiegel wurden unter Benutzung multivariater linearer Regressionsmodelle ausgewertet. Die univariate und inverse Beziehung zwischen GFR und EPO-Spiegeln (p = 0,009) wurde in der multivariaten Analyse nicht-signifikant. Erh{\"o}htes CRP (p < 0,001), niedriges Ferritin (p = 0,002), kardiovaskul{\"a}re Ereignisse in der Vorgeschichte (p = 0,02) und Hypertension (p = 0,04) waren nach Adjustierung f{\"u}r Alter, Geschlecht, Hb, GFR und andere klinische Faktoren unabh{\"a}ngig mit erh{\"o}hten EPO-Spiegeln assoziiert. In der untersuchten Population fand sich kein Zusammenhang zwischen EPO-Spiegeln und H{\"a}moglobin. Bei diabetischen Patienten mit chronischer Niereninsuffizienz werden die EPO-Spiegel trotz gleichzeitig niedriger H{\"a}moglobinspiegel vor allem durch Entz{\"u}ndungsparameter und den Eisenstatus vorhergesagt und sind dabei unabh{\"a}ngig von der Nierenfunktion. Deshalb k{\"o}nnte die An{\"a}mie bei Patienten mit diabetischer Nephropathie haupts{\"a}chlich durch Inflammation entstehen, die zu einem relativen Eisenmangel und einer Resistenz des Knochenmarks gegen{\"u}ber endogenem EPO f{\"u}hrt.},
  subject      = {Diabetes mellitus},
  language  = {de}
}
@phdthesis{Raab2010,
  author    = {Raab, Viktoria Maria},
  title     = {Histologische Charakterisierung Vaccinia-Virus infizierter humaner Tumore im Mausmodell},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-49024},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2010},
  abstract  = {Onkolytische Viren spielen eine immer bedeutendere Rolle f{\"u}r die Tumorforschung, weil in zahlreichen pr{\"a}klinischen Studien gezeigt werden konnte, dass viral bedingte Onkolyse zu einer Tumorregression f{\"u}hrt. Ein {\"a}ußerst vielversprechender Kandidat der onkolytischen Viren ist das Vaccinia-Virus. In der vorliegenden Arbeit wurde mit dem attenuierten Vaccinia-Virus GLV-1h68 gearbeitet, welches nach systemischer Applikation eine Regression von Tumoren verursacht. Obwohl bereits zahlreiche onkolytische Viren in klinischen Studien Anwendung finden, sind zugrunde liegende Abl{\"a}ufe bei einer Virusinfektion solider Tumore sowie Mechanismen, welche f{\"u}r die Tumorregression verantwortlich sind, immer noch nicht erschlossen. Um Aufschluss {\"u}ber notwendige Parameter f{\"u}r eine effiziente Infektion eines soliden Tumors mit GLV-1h68 zu erlangen, wurden im ersten Teil dieser Arbeit die uninfizierte Tumormikroumgebung sowie stromale Ver{\"a}nderungen in der fr{\"u}he Phase der Infektion untersucht. Als Tumormodell diente hierbei ein humanes autologes Melanomzellpaar (888-MEL und 1936-MEL). Diese beiden Zelllinien sind Teil einer Reihe von f{\"u}nf verschiedenen Melanomzelllinien, welche alle aus den widerkehrenden Metastasen eines einzelnen Patienten (Patient 888) isoliert wurden. 888-MEL zeigt nach Virusinfektion mit GLV-1h68 ein regredierendes Verhalten (therapeutischer Index: 88,0) und ist somit respondierend nach GLV-1h68-Infektion. 1936-MEL hingegen zeigte mit einem therapeutischen Index von 13,7 ein nur schwach verlangsamtes Wachstum solider Tumore, und ist somit schwach-respondierend nach GLV-1h68-Infektion. Als ein Grund, weshalb diese beiden autologen Melanomzelllinien unterschiedlich auf GLV-1h68-Infektion reagieren, wurde die Anzahl der Viruspartikel vermutet, welche 1 dpi im soliden Tumor vorliegt. Eine m{\"o}gliche Korrelation zwischen initialem viralen Titer 1 dpi und sp{\"a}terer Tumorregression konnte experimentell aber nicht nachgewiesen werden. Zwei voneinander unabh{\"a}ngige Experimentreihen zeigten, dass bei identischer systemischer Applikation in den beiden soliden Tumoren kein Unterschied des viralen Titers vorlag. Weiterhin wurden die Komponenten der Tumormikroumgebung und ihr m{\"o}glicher Einfluss auf die Effizienz der Virusinfektion untersucht. Immunhistologische Studien zeigten, dass es im uninfizierten Zustand bei soliden 888-MEL Tumoren zu einer massiven Infiltration CD45-positiver Zellen kam, die bei 1936-MEL-Tumoren jedoch nicht zu finden war. Die Beobachtung steht in {\"U}bereinstimmung mit Ergebnissen einer vergleichenden Microarray-Analyse, die das Infiltrat CD45-positiver Zellen in 888-MEL Tumoren genauer charakterisierte. Es wurde mit Microarray-Analyse eine erh{\"o}hte Expression chemotaktischer Molek{\"u}le in soliden 888-MEL Tumoren nachgewiesen. Unter anderem wird CCL8 (MCP-2) erh{\"o}ht exprimiert. Als chemotaktisches Molek{\"u}l hat CCL8 eine erh{\"o}hte Monozyteninfiltration zur Folge. Weiterhin wurde eine erh{\"o}hte Expression von MIF (macrophage migration inhibitory factor) und dem entsprechendem Rezeptor CD74 in uninfizierten 888-MEL-Tumoren gemessen. MIF induziert als proinflammatorisches Zytokin die Synthese inflammatorischer Mediatoren. Dies erkl{\"a}rt die Anh{\"a}ufung CD45-positiver Zellen in der Tumormikroumgebung. Durch eine erh{\"o}hte Expression MHC II-verwandter Gene in soliden 888-MEL- Tumoren wurden die CD45-positiven Zellen als Monozyten identifiziert. Um die Funktion der Immunzellen zu analysieren, wurde durch eine intraperitoneale Applikation des Zytostatikums Cyclophosphamid eine Monozytendepletion induziert. Diese Immundepletion resultierte in soliden 888-MEL- Tumoren in einer signifikant verringerten Virusreplikation und -Ausbreitung nach Infektion mit GLV-1h68. Diese Ergebnisse implizieren, dass durch eine erh{\"o}hte Infiltration CD45-positiver Zellen in die Tumormikroumgebung die GLV-1h68-Infektion und -Replikation erleichtert wird. Nach Ausbreitung der Infektion kommt es in respondierenden Tumoren nach einem ersten Wachtumsarrest zu einer Tumorregression. Um Aufschluss {\"u}ber den beteiligten Mechanismus bei der Tumorregression zu erlangen, wurden GLV-1h68-infizierte-Tumore in der sp{\"a}ten Phase der Infektion untersucht. Drei m{\"o}gliche Mechanismen viral verursachter Onkolyse wurden beschrieben: Tumorzell-spezifische Onkolyse, Zerst{\"o}rung der Tumorvaskulatur oder anti-tumorale Immunantwort. F{\"u}r diese Experimente wurden humane Brustkarzinomzellen als Tumormodell verwendet. Mit diesem Tumormodell sollte analysiert werden, welcher der drei bislang diskutierten Mechanismen bei einer GLV-1h68-Infektion vorlag. Als erstes zeigten histologische Studien, dass Virusinfektion und -Replikation zu ausgedehnten Tumornekrosen f{\"u}hren. Dabei blieben die Blutgef{\"a}ße in uninfizierten und auch in infizierten Bereichen des Tumors intakt und funktionell aktiv. Systemische Perfusion der Vaskulatur mit Lektin zeigte, dass die Tumorvaskulatur an das periphere Blutgef{\"a}ßsystem angeschlossen war. Nachfolgende Experimente zeigten, dass Endothelzellen nicht durch die Viren infiziert wurden, wohingegen aber Endothelzell-ummantelnde, Gef{\"a}ß-stabilisierende Perizyten nur in uninfizierten, nicht aber in infizierten Bereichen des Tumors vorkamen. Perizyten wurden m{\"o}glicherweise durch Virusinfektion lysiert. Morphologische und funktionelle Analyse der Blutgef{\"a}ße im Tumor zeigte, dass GLV-1h68-Infektion Hyperpermeabilit{\"a}t, Vasodilatation und eine erh{\"o}hte Expression des Adh{\"a}sionsmolek{\"u}ls CD31 verursachte. Eine erh{\"o}hte CD31-Expression erleichtert eine Infiltration rekrutierter Immunzellen. Das konnte durch immunhistochemische F{\"a}rbung von CD45 und MHC II besonders in intratumoralen Bereichen gezeigt werden. Durch Cyclophosphamid-vermittelte Immunsuppression wurde nachgewiesen, dass diese rekrutierten Immunzellen keinen ausschlaggebenden Einfluss auf die Tumorregression haben. Nach Immundepletion in soliden GI-101A-Tumoren konnte eine verst{\"a}rkte Virusinfektion, effektivere Onkolyse und fr{\"u}hzeitigere Tumorregression nachgewiesen werden. Zusammenfassend zeigten diese Ergebnisse, dass der dominierende Mechanismus, welcher zur Tumorregression f{\"u}hrt, die Onkolyse ist.},
  subject      = {Vaccinia-Virus},
  language  = {de}
}
@phdthesis{Grimm2010,
  author    = {Grimm, Martin},
  title     = {Die Bedeutung der Expression des Tumornekrosefaktor-alpha bei Patienten mit kolorektalem Karzinom},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-52757},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2010},
  abstract  = {F{\"u}r Tumorprogression m{\"u}ssen entartete Zellen Wege finden, die immunologische Abwehr und die Apoptose zu umgehen. Tumorzellen haben daf{\"u}r verschiedene, sogenannte Tumor-Escape-Mechanismen entwickelt. Gegenstand dieser Arbeit war in diesem Zusammenhang die Untersuchung des TNF-α-TNF-R1-Systems. Eine signifikante erh{\"o}hte TNF-α Protein- und Genexpression konnte in Gewebeproben kolorektaler Karzinome nachgewiesen werden, wobei eine m{\"a}ßig starke Korrelation beider Analysemethoden ersichtlich war (т = 0.794). Sowohl die immunhistochemische Analyse als auch die Genexpression durch RT-PCR konnten mit Tumorprogression assoziiert werden. Mit erh{\"o}hter Expression des Apoptose-induzierenden Zytokins TNF-α durch Tumorzellen konnte dar{\"u}ber hinaus ein signifikant schlechteres Gesamt{\"u}berleben der Patienten mit KRK beobachtet werden. In unmittelbarer Umgebung TNF-α exprimierender Tumorzellen wurden zahlreiche TNF-R1+/CD8+ Zellen analysiert, die als Hinweis auf Apoptose in TILs angesehen werden k{\"o}nnen. Dieser Weg k{\"o}nnte als Tumor-Escape-Mechanismus verstanden werden. Die Verwendung potentieller TNF-α Biologicals (z.B. Etanercept, Infliximab) bleibt jedoch unter dem Aspekt einer geringf{\"u}gig erh{\"o}hten Lymphominzidenz gegen{\"u}ber der Normalbev{\"o}lkerung auch als kritisch zu bewerten. Der Einsatz von Anti-TNF-α-Therapien stellt jedoch eine vielversprechende Option bei Patienten mit metastasiertem KRK und Tumorrezidiv dar. Zusammenfassend liefern die Ergebnisse dieser Arbeit zus{\"a}tzlichen Einblick in die Regulationsmechanismen, die verantwortlich f{\"u}r die Immunsuppression durch kolorektale Karzinome sein k{\"o}nnen. Diese basiswissenschaftlichen Erkenntnisse stellen eine m{\"o}gliche Grundlage neuer Behandlungsm{\"o}glichkeiten kolorektaler Karzinomen dar, die weiter erforscht werden sollten.},
  subject      = {Cancer},
  language  = {de}
}
@phdthesis{Schwab2009,
  author    = {Schwab, Nicholas},
  title     = {The importance of CD8\(^+\) T cells and antigen-presenting cells in the immune reaction of primary inflammatory versus degenerative diseases},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-37330},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2009},
  abstract  = {The bidirectional influence of parenchymal cells and cells of the immune system, especially of antigen-presenting and CD8\(^+\) T cells, in situations of putative auto- immune pathogenicity and degeneration was the main topic of this thesis. In the first part, the influence of human muscle cells on antigen-presenting cells was investigated. In inflammatory myopathies prominent infiltrates of immune cells containing T cells and antigen-presenting cells like macrophages and dendritic cells are present. The hypothesis was that human myoblasts have an inhibiting influence on these antigen-presenting cells under homeostatic conditions. A dysfunction or impairment under inflammatory circumstances might contribute to the development of myopathic conditions. The surface analysis of dendritic cells cocultured with myoblasts showed that immature dendritic cells could be driven into a reversible semi- mature state with significantly elevated levels of CD80. These dendritic cells were additionally characterized by their inhibiting function on T-cell proliferation. It was also shown that the lysates of healthy myoblasts could strongly enhance the phagocytic ability of macrophages, which could help with muscle regeneration and which might be disturbed in myositis patients. The second part of this thesis was about the clonal specificity of CD8\(^+\) T cells in a mouse model with genetically induced over-expression of PLP in oligodendrocytes. Here, we could show that the cytotoxic T lymphocytes, which had previously been shown to be pathogenic, were clonally expanded in the CNS of the transgenic mice. The amino acid sequences of the corresponding receptor chains were not identical, yet showed some similarities, which could mean that these clones recognize similar antigens (or epitopes of the same antigen). The knockout of PD-1 in this setting allowed for an analysis of the importance of tissue immune regulation. It became evident that the absence of PD-1 induced a larger number of clonal expansions in the CNS, hinting towards a reduced threshold for clonal disturbance and activation in these T cells. The expansions were, however, not pathogenic by themselves. Only in the presence of tissue damage and an antigenic stimulus (in our case the overexpression of PLP), the PD-1 limitation exacerbated the immune pathogenicity. Therefore, only in the presence of a "tissue damage signal", the dyshomeostasis of T cells lacking PD-1 achieved high pathogenetic relevance. Finally, we investigated the pathogenetic role of CD8 T cells in Rasmussen encephalitis, a rare and chronic neurological disease mainly affecting children. The analysis of the T-cell receptor repertoire in Rasmussen encephalitis patients in the peripheral CD4\(^+\) and CD8\(^+\) T-cell compartments as well as the brain revealed the involvement of T cells in the pathogenicity of this disease. Many clonal expansions in the brain matched CD8\(^+\) T-cell expansions in the periphery on the sequence level. These putatively pathogenic clones could be visualized by immunohistochemistry in the brain and were found in close proximity to astrocytes and neurons. Additionally, the expanded clones could be found in the periphery of patients for at least one year.},
  subject      = {T-Lymphozyt},
  language  = {en}
}
@phdthesis{Adamek2008,
  author    = {Adamek, Anna Katharina},
  title     = {Einfluss des Immunsystems und der endothelialen NO-Synthase auf den myokardialen isch{\"a}mischen Schaden},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-35795},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2008},
  abstract  = {Die Entwicklung von therapeutischen Strategien, die den infarktbedingten Untergang des Myokardgewebes minimieren und die Gewebsheilung nach abgelaufenem Myokardinfarkt unterst{\"u}tzen, geh{\"o}rt zu dem Hauptziel in der modernen Kardiologie. Bis jedoch eine spezifische Intervention als Therapieform anerkannt wird, ist ein detailliertes Entschl{\"u}sseln der zellul{\"a}ren und molekularen Mechanismen w{\"a}hrend und nach der Myokardsch{\"a}digung notwendig. Die vorliegende Arbeit besch{\"a}ftigt sich intensiv mit den Vorg{\"a}ngen der Stickstoffmonoxid- (NO) Produktion und der Inflammation nach Okklusion von Kranzarterien. Im ersten Teil der Dissertation steht die endotheliale NO-Synthase-Expression (eNOS) im Mittelpunkt der Untersuchung. eNOS ist als wichtiger Katalysator an der Biosynthese von Stickstoffmonoxid, das als protektiver Faktor f{\"u}r die Gef{\"a}ßhom{\"o}ostase seit Jahren bekannt ist, beteiligt. Ferner besteht experimentell sehr gute Evidenz daf{\"u}r, dass der endothelialen NO-Synthase am Ausmaß des kardialen Isch{\"a}mie-/ Reperfusionsschadens eine entscheidende Rolle zukommt. Folglich wurde mittels der Substanz AVE 9488 versucht, die eNOS-Expression in M{\"a}usen zu steigern und den Effekt auf das Infarktgeschehen n{\"a}her zu betrachten. Die Behandlung mit AVE 9488 erzielte einen signifikant reduzierten Isch{\"a}mie-/Reperfusionsschaden. Bei anschließenden Isch{\"a}mie-/Reperfusionsveruchen mit eNOS defizienten M{\"a}usen war der protektive Effekt wieder aufgehoben. Der Erfolg dieser Substanz wird in der signifikanten Reduktion des oxidativen Stresses vermutet. Ein zus{\"a}tzlicher wichtiger Parameter, der w{\"a}hrend der Isch{\"a}mie/Reperfusion aktiviert wird, ist der Schl{\"u}ssel-Transkriptionsfaktor Nuclear Factor kappa B (NF-kB). Durch seine Bindung an bestimmte Enhancer und Promotoren reguliert der Faktor die Entz{\"u}ndungsprozesse, indem er die Genexpression proinflammatorischer Marker verst{\"a}rkt. Folglich wurden eine Reduktion der Inflammation sowie ein protektiver Effekt nach erfolgter isch{\"a}mischer Sch{\"a}digung durch Hemmung von NF-kB angenommen. Zur Pr{\"u}fung dieser Hypothese wurden NF-kB-Untereinheit p50 defiziente M{\"a}use (p50 KO) einer Okklusion einer Herzkranzarterie unterzogen. Durch die Hemmung der NF-kB-Aktivierung kam es zu einer signifikanten Reduzierung des Infarktareals im Vergleich zu den entsprechenden Wildtyp-M{\"a}usen. Der große Benefit konnte auf die geringere Einwanderung der neutrophilen Granulozyten in das infarzierte Gebiet zur{\"u}ckgef{\"u}hrt werden. Knochenmarktransplantationsversuche mit p50 KO- und Wildtyp-Knochenmark untermauerten die Beobachtung, dass die beeintr{\"a}chtigte Aktivierung von NF-kB in p50 defizienten Leukozyten protektive Effekte in der Isch{\"a}mie/Reperfusion vermittelt. Die Aktivierung der proinflammatorischen Proteine w{\"a}hrend des linksventrikul{\"a}ren Remodelings nach Myokardinfarkt geh{\"o}rt zum Fokus des dritten Teils dieser Arbeit. Dieser Teil besch{\"a}ftigt sich mit der Frage, inwieweit eine hochdosierte Aspirin-Therapie die linksventrikul{\"a}ren Umbauprozesse g{\"u}nstig beeinflussen kann. Daf{\"u}r wurden M{\"a}use f{\"u}r 4 Wochen mit Placebo oder Aspirin (120 mg/kg pro Tag) mittels osmotischer Mini-Pumpen, die 2 Stunden nach Ligatur der Kranzarterie implantiert wurden, behandelt. In beiden Gruppen kam es zur erwarteten linksventrikul{\"a}ren Dilatation nach Myokardinfarkt, jedoch ohne signifikanten Unterschied zwischen Placebo- und Aspirin-behandelten Tieren. Es kam allerdings zu einer erwarteten Reduktion proinflammatorischer Proteine durch die Aspirin-Therapie. So war die Expression von Tumor-Nekrose-Faktor-alpha; (TNF-alpha) und Interleukin-1ß (IL-ß) in der Aspirin-Gruppe signifikant reduziert. Zusammenfassend l{\"a}sst sich sagen, dass durch die gezielte Beeinflussung bestimmter Faktoren in der Isch{\"a}mie/Reperfusion wie z. B. die Verst{\"a}rkung der eNOS-Expression oder die Hemmung der NF-kB-Aktivierung die Isch{\"a}miesch{\"a}digung signifikant reduziert werden kann.},
  subject      = {Isch{\"a}mie},
  language  = {de}
}
@phdthesis{Wienrich2006,
  author    = {Wienrich, Bernd Gregor},
  title     = {Expression von LEEP-CAM (Lymphocyte Endothelial EPithelial-Cell Adhesion Molecule) in Haut und Hoden - funktionelle Implikationen f{\"u}r die Immunevasion epithelialer Hauttumoren und Entz{\"u}ndungen immunprivilegierter Gewebe},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-27872},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2006},
  abstract  = {Der Schutz vor der Einwanderung von Immunzellen ist einerseits unter physiologischen Bedingungen wichtig f{\"u}r die Integrit{\"a}t immunprivilegierter Organe, andererseits aber auch (mit)entscheidend f{\"u}r die Pathogenese maligner Tumoren. Vor diesem Hintergrund wurde LEEP-CAM (Lymphocyte Endothelial EPithelial-Cell Adhesion Molecule) untersucht, ein Adh{\"a}sionsmolek{\"u}l, welches in der Epidermis und den dermalen Blutgef{\"a}ßen in normaler Haut konstitutiv exprimiert wird. Durch immunhistochemische Untersuchungen wurde im ersten Teil der Arbeit gezeigt, dass LEEP-CAM in Basalzellkarzinomen, Plattenepithelkarzinomen und Keratoakanthomen der Haut deutlich vermindert oder gar nicht exprimiert wird. Die verminderte Expression war mit fehlender Infiltration von T-Lymphozyten in das Tumorgewebe assoziiert, was insbesondere durch zwei hinsichtlich ihrer LEEP-CAM-Expression unterschiedenen Populationen von Keratoakanthomen nahe gelegt wurde. Die Hypothese, dass LEEP-CAM in die epidermale Rekrutierung aktivierter T-Zellen involviert ist, wurde durch funktionelle Stamper-Woodruff-Experimente (Adh{\"a}sion aktivierter T-Lymphozyten an Gewebe-Gefrierschnitte) mit Basalzellkarzinomen und psoriatischer Haut gest{\"u}tzt. Durch metabolische Markierung mit 35(S)-Methionin und anschließende Radioimmunpr{\"a}zipitation sowie durch durchflusszytometrische Untersuchungen an kultivierten Zellen wurde gezeigt, dass LEEPCAM in transformierten Keratinozyten im Vergleich zu normalen Keratinozyten deutlich vermindert synthetisiert und exprimiert wird. In zwei komplement{\"a}ren murinen Karzinogenese-Modellen wurde die Assoziation der verminderten LEEP-CAM-Expression mit Entdifferenzierung und invasivem Wachstum der Tumorzellen untermauert. Insgesamt kann experimentelle Evidenz f{\"u}r die Hypothese, dass die Herabregulation der LEEP-CAM-Expression ein (Teil)-Mechanismus ist, durch welchen sich invasiv wachsende Tumoren den Angriffen des Immunsystems entziehen k{\"o}nnen, pr{\"a}sentiert werden. Im Weiteren wurde die Expression und Funktion von LEEPCAM im Keimepithel des Hodens (als ein Beispiel f{\"u}r ein immunprivilegiertes Gewebe) untersucht. Durch immunhistochemische Untersuchungen wurde die konstitutive Expression von LEEP-CAM in den Sertoli-Zellen des Keimepithels nachgewiesen. Mittels Immun-Elektronenmikroskopie wurde dann die Lokalisation an desmosomalen Strukturen sowie entlang der Zellmembran gezeigt. Im Hinblick auf die Funktion von LEEP-CAM wurde in modifizierten Stamper-Woodruff-Experimenten erstmals gezeigt, dass aktivierte T-Lymphozyten an das Keimepithel des Hodens binden k{\"o}nnen und dass diese Adh{\"a}sion durch LEEP-CAM-gerichtete Antik{\"o}rper inhibiert werden kann. Damit ist LEEP-CAM das erste Molek{\"u}l, f{\"u}r welches direkte experimentelle Evidenz eine m{\"o}gliche Rolle bei der testikul{\"a}ren Lymphozyten-Rekrutierung belegt. Dies k{\"o}nnte Relevanz f{\"u}r die Pathogenese von Orchitiden, den h{\"a}ufigsten Ursachen m{\"a}nnlicher Infertilit{\"a}t, haben.},
  subject      = {Zell-Adhesionsmolek{\"u}l},
  language  = {de}
}
@phdthesis{Mueller2007,
  author    = {M{\"u}ller, Verena},
  title     = {Candida albicans-induzierte Genexpression in prim{\"a}ren humanen Endothelzellen - Mechanismen der Signaltransduktion und M{\"o}glichkeiten der Intervention},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-26224},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2007},
  abstract  = {Endothelzellen sind ein aktiver Bestandteil der angeborenen Immunabwehr des Menschen gegen mikrobielle Pathogene. Unter ung{\"u}nstigen Bedingungen kann die Abwehrreaktion sogar zu einer lebensbedrohlichen Sepsis f{\"u}hren. Hier wurde die bislang wenig bekannte Endothelantwort auf den fakultativ humanpathogenen Hefepilz Candida albicans, einem der h{\"a}ufigsten Verursacher von letaler Sepsis beim Menschen, n{\"a}her untersucht. Mittels Oligonukleotid-Mikroarray-Analyse von HUVEC nach Exposition mit C. albicans konnten 56 hochregulierte Gene identifiziert werden, w{\"a}hrend 69 Gene herunterreguliert wurden. Ein bedeutender Anteil der regulierten Gene ist an Prozessen der angeborenen Immunantwort beteiligt und dient haupts{\"a}chlich der Rekrutierung von Neutrophilen. Weitere Untersuchungen ergaben eine zentrale Rolle des proinflammatorischen NF-kappaB-Weges bei der Regulation des Candida-induzierten Transkriptoms von Endothelzellen. Es konnte gezeigt werden, dass C. albicans diesen Signalweg sequenziell aktiviert. Zus{\"a}tzlich konnte durch die Expression einer dominant-negativen Mutante einer Signalkomponente des NF-kappaB-Signalwegs die Candida-vermittelte Induktion von kappaB-abh{\"a}ngigen Genen gehemmt werden. Mit einem pharmakologischen Ansatz wurde der p38 MAP Kinase-Signalweg als weiterer bedeutsamer Signalweg identifiziert, der die Expression einzelner Candida-Zielgene wie CXCL8/IL-8 moduliert. Schließlich wurde gezeigt, dass die Candida-induzierte NF-kappaB-Aktivierung im untersuchten endothelialen Zellsystem unabh{\"a}ngig von den Toll-like Rezeptoren TLR2 und TLR4 geschieht, die {\"u}blicherweise an der Erkennung mikrobieller Pathogene beteiligt sind. Durch RNA-Interferenz-Experimente konnte jedoch dargelegt werden, dass das Adaptermolek{\"u}l MyD88 und die Kinase IRAK1, die beide entscheidend an der TLR-vermittelten Signaltransduktion beteiligt sind, essentiell f{\"u}r die Weiterleitung des Signals in Endothelzellen sind. Nachfolgend konnte mit TLR3 zumindest einer der signaltransduzierenden Rezeptoren identifiziert werden. Als erste umfassende Untersuchung der endothelialen Antwort auf Candida albicans erlaubt die vorliegende Arbeit neue Einblicke in die komplexen Signalmuster von Endothelzellen, die dieser klinisch bedeutende Krankheitserreger ausl{\"o}st.},
  subject      = {Angeborene Immunit{\"a}t},
  language  = {de}
}
@phdthesis{Schopf2007,
  author    = {Schopf, Thilo},
  title     = {Wertigkeit von Entz{\"u}ndungsparametern in der postoperativen Phase nach Implantation von H{\"u}ft- und Kniegelenk-Totalendoprothesen},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-25028},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2007},
  abstract  = {Ziel dieser Arbeit ist, die Wertigkeit von Entz{\"u}ndungsparametern (CRP, BSG, Leukozyten und Temperatur) in der postoperativen Phase anhand einer retrospektiven Studie mit 531 Patienten nach Implantation von Knie- und H{\"u}ft-Totalendoprothesen zu beurteilen. Hierbei sollten zum einen die Auswirkungen von Vorerkrankungen (Asthma bronchiale, Rheumatoider Arthritis, Nikotinabusus, Gicht/Hyperurik{\"a}mie, Z. n. Thrombosen) auf den postoperativen Verlauf der Entz{\"u}ndungsparameter und zum anderen postoperative Komplikationen (Thrombosen, bronchopulmonale Infekte, Harnwegsinfekte, Wundinfekte, Protheseninfekte) anhand der Entz{\"u}ndungsparameter erfasst werden. Die Auswertung erfolgte mittels SPSS f{\"u}r Windows durch den Mann-Whitney Test als nicht parametrischen Test f{\"u}r unabh{\"a}ngige Variablen. Im Durchschnitt stieg der CRP-Wert von 0,6 mg/dl pr{\"a}operativ auf etwa 8,5 mg/dl um den 3. postoperativen Tag an und fiel dann durchschnittlich auf 1,4 mg/dl um den 14. postoperativen Tag ab. Die BSG-Werte stiegen von etwa 18 mm/h pr{\"a}operativ auf 52 mm/h um den 3. postoperativen Tag an. Der h{\"o}chste BSG-Wert (56 mm/h) wurde erst um den 7. postoperativen Tag erreicht. Danach fiel der BSG-Wert leicht ab auf durchschnittlich etwa 43 mm/h um den 14. postoperativen Tag. Die Temperaturkurve verlief {\"a}hnlich: Auch hier stieg die Temperatur rasch auf einen H{\"o}chstwert von 37,1°C um den 2. postoperativen Tag. Es folgte ein langsamer Abfall der Temperatur, bis hin zu Normwerten ab dem 10. postoperativen Tag. Die Leukozyten zeigten im Durchschnitt einen geradlinigen Verlauf mit durchschnittlichen Werten zwischen 7 und 8 G/l, allerdings bei einer großen Standartabweichung. Patienten mit Asthma bronchiale zeigten pr{\"a}operativ signifikant erh{\"o}hte BSG und Leukozytenwerte. Patienten mit Gicht/Hyperurik{\"a}mie fielen durch signifikant niedrigere Temperaturwerte am 6. und 12. postoperativen Tag sowie durch Trends zu niedrigeren Werten am 10. und 16. postoperativen Tag auf. Signifikant h{\"o}here Werte fanden sich bei der CRP-AUC-Kurve vom 7.-14. postoperativen Tag. Des Weiteren fanden sich Trends zu h{\"o}heren Werten am 14. postoperativen Tag bei der BSG und am 3. postoperativen Tag bei den Leukozyten. Bei Patienten mit Z.n. Thrombose zeigte sich der postoperative BSG-Verlauf vom 3.-14. Tag signifikant erniedrigt, ebenso waren die postoperativen Temperaturwerte vom 15. und 16. Tag signifikant niedriger. Der einzig signifikante Unterschied zwischen Rauchern und Nichtrauchern fand sich in der pr{\"a}operativen BSG, wo Raucher signifikant niedrigere Werte hatten. Des Weiteren zeigten sich Trends zu h{\"o}heren Leukozytenwerten am 3. und 7. postoperativen Tag sowie Trends zu niedrigeren Temperaturen am 1., 2., 7., 8. und 14. postoperativen Tag. Patienten mit Rheumatoider Arthritis fielen durch signifikant erh{\"o}hte pr{\"a}operative CRP- und BSG-Werte auf. Zus{\"a}tzlich traten Trends zu h{\"o}heren Werten am 14. postoperativen Tag f{\"u}r CRP, BSG und Leukozyten auf. Dem Trend zur Temperaturerh{\"o}hung am 2. postoperativen Tag folgten erneute Trends am 9. und 11. postoperativen Tag sowie signifikant h{\"o}here Temperaturen am 10. und 12. postoperativen Tag. Patienten, die einen Harnwegsinfekt erlitten, hatten signifikant erh{\"o}hte Werte am 14. postoperativen Tag f{\"u}r CRP und BSG. Auch die CRP-AUC-Kurve zeigte diesen Verlauf signifikant. Bei Patienten, die an einem bronchopulmonalem Infekt erkrankten, war der CRP-Wert des 3. postoperativen Tages signifikant erh{\"o}ht. Dies ließ sich auch in der CRP-AUC-Kurve vom 0.-3. postoperativen Tag signifikant nachweisen. Dar{\"u}ber hinaus lag ein Trend am 3.-7. postoperativen Tag zu h{\"o}heren Werten vor. Bei Patienten mit tiefer Beinvenenthrombose fiel eine signifikante Temperaturerh{\"o}hung am 7., 8. und 11. postoperativen Tag auf, sowie ein Trend am 9., 10. und 12. postoperativen Tag. Die CRP-Werte stiegen um den 14. postoperativen Tag signifikant an. Gleiches Verhalten zeigte die CRP-AUC-Kurve vom 7.-14. postoperativen Tag. Patienten mit Wundinfektionen fielen durch Trends zu niedrigeren Temperaturwerten am 4. und 5. postoperativen Tag auf. Außerdem stieg um den 7. postoperativen Tag die BSG trendwertig an. Die Leukozyten waren pr{\"a}operativ signifikant erh{\"o}ht. Dagegen war bei Patienten mit TEP-Infektion der CRP-Wert um den 14. postoperativen Tag signifikant erh{\"o}ht. Die Temperaturwerte des 8. postoperativen Tages zeigten einen Trend zu niedrigeren Zahlen. Die Ergebnisse entsprechen in etwa denen anderer Studien. Insgesamt l{\"a}sst sich eine Tendenz ablesen: BSG und Temperatur sind vor allem bei den erw{\"a}hnten Vorerkrankungen erh{\"o}ht, Leukozyten spielen kaum eine Rolle und die CRP-Bestimmung findet ihren Platz haupts{\"a}chlich in der Diagnostik von Komplikationen. Außerdem wird klar, dass kein Entz{\"u}ndungsparameter spezifisch f{\"u}r eine bestimmte Vorerkrankung oder Komplikation ist. Dar{\"u}ber hinaus sind nicht Einzelwerte, sondern viel mehr der Verlauf der Entz{\"u}ndungsparameter entscheidend.},
  subject      = {Totalendoprothese},
  language  = {de}
}
@phdthesis{Timmermann2005,
  author    = {Timmermann, Meike},
  title     = {Zellul{\"a}re Regulation und klinische Aspekte des monocyten-/macrophagenspezifischen Proteins CD163},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-16028},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2005},
  abstract  = {In der vorliegenden Arbeit wurde die zellul{\"a}re Regulation des monocyten-/ macrophagenspezifischen Oberfl{\"a}chenproteins CD163 untersucht und klinische Aspekte der l{\"o}slichen Form des CD163 (sCD163) diskutiert. sCD163 wird in vivo durch einen inflammatorischen Reiz von der Zelloberfl{\"a}che abgespalten. Bislang waren jedoch noch keine Mediatoren charakterisiert worden, die immer unter Entz{\"u}ndungsbedingungen vorhanden sind. In den eigenen Untersuchungen des Shedding von CD163 konnten f{\"u}r die Generierung des sCD163 neue endogene Aktivatoren identifiziert werden. Sowohl reaktive Sauerstoffspezies, wie Wasserstoffperoxid oder Stickstoffmonoxid, als auch das Produkt von endogenen Oxidationsreaktionen mit reaktiven Sauerstoffspezies 8-iso Prostaglandin F2a erwiesen sich als potente Aktivatoren des Shedding von CD163. Neben den bekannten physiologischen Funktionen des 8-iso Prostaglandin F2a konnte erstmals eine neue Funktion bei Entz{\"u}ndungen definiert werden. Dieser Effekt wurde spezifisch durch 8-iso Prostaglandin F2a hervorgerufen, da das isomere Prostaglandin F2a unter gleichen Bedingungen keinen Einfluss auf das Shedding von CD163 aus{\"u}bte. Das Immunsuppressivum Cyclosporin A konnte ebenfalls als Induktor des Shedding von CD163 ermittelt werden. Damit konnte zus{\"a}tzlich zur bekannten immunmodulatorischen Wirkung des Cyclosporin A eine weitere antiinflammatorische Wirkung {\"u}ber Monocyten/Macrophagen aufgezeigt werden. Durch Untersuchungen der Inhibierung des Shedding von CD163 konnten Gemeinsamkeiten bez{\"u}glich der in die sCD163-Generierung involvierten Mediatoren dargestellt werden. Obwohl die untersuchten Verbindungen wahrscheinlich {\"u}ber unterschiedliche Signalwege das Shedding von CD163 induzieren, waren die Anwesenheit von reaktiven Sauerstoffspezies und intrazellul{\"a}rem Calcium und die Beteiligung einer TIMP-3-sensitiven Metalloproteinase an diesem Prozess essentiell. Bei einem Vergleich zwischen dem Shedding von CD163 und Tumor necrosis factor-a (TNF-a) ergaben sich Gemeinsamkeiten durch die Induktion des Shedding beider Verbindungen durch 8-iso Prostaglandin F2a und in sehr viel geringerem Maße durch Wasserstoffperoxid. Im Gegensatz dazu waren deutliche Unterschiede in dem Ausmaß der induzierten Stimulation des Shedding durch Stickstoffmonoxid, Prostaglandin F2a und Cyclosporin A zu erkennen. Im Hinblick auf die entgegengesetzten Wirkungen von sCD163 als antiinflammatorisch wirkende Verbindung und TNF-a als proinflammatorisches Cytokin, konnte dargestellt werden, dass die Freisetzung durch unterschiedliche Aktivatoren erfolgt. Nach Bestimmung der Konzentrationen von sCD163 und 8-iso PGF2a in bronchoalveol{\"a}rer Lavage-Fl{\"u}ssigkeit von Patienten mit Cystischer Fibrose konnten keine abschließende Aussagen {\"u}ber die Eignung beider Parameter als biologische Marker f{\"u}r chronische Entz{\"u}ndungen der Lunge bei diesen Patienten getroffen werden. Weiterf{\"u}hrend zu der Kenntnis, dass sCD163 die antiinflammatorische Wirkung {\"u}ber eine Interaktion des Proteins mit humanen T-Lymphocyten und nachfolgender Hemmung der Proliferation dieser Zellen aus{\"u}bt, wurde diese Wechselwirkung genauer untersucht. In quantitativen Bestimmungen des sCD163 in isolierten T-Lymphocyten verschiedener Spender konnte erstmals gezeigt werden, dass sCD163 zu einem Teil konstitutiv in die T-Lymphocyten aufgenommen wird und dass diese Aufnahme durch proinflammatorische Aktivierung der T-Lymphocyten stark gesteigert werden kann. Durch fluoreszenzmikroskopische Aufnahmen unstimulierter T-Lymphocyten konnte die intrazellul{\"a}re Lokalisation des sCD163 visualisiert werden. Nach Aktivierung der Zellen mit einem proinflammatorischen Reiz fand innerhalb der Zellen eine Translokalisation des sCD163 aus dem cytoplasmatischen Bereich zur Zellmembran statt. Damit konnte erstmals gezeigt werden, dass abh{\"a}ngig vom Aktivierungsstatus der T-Lymphocyten eine Umverteilung des sCD163 innerhalb der Zellen erfolgt. Eine quantitative Bestimmung des sCD163 und seines Bindungspartners in T-Lymphocyten nichtmuskul{\"a}res Myosin Typ IIA gelang mittels eines neu entwickeltem ELISA, der spezifisch sCD163 und Myosin ausschließlich im Komplex erfasst. Damit konnte durch die in dieser Arbeit beschriebenen Untersuchungen ein grundlegender Beitrag zur Charakterisierung der Regulation der Proteinexpression und des Shedding von CD163 in humanen Monocyten sowie der Interaktion des sCD163 mit T-Lymphocyten geleistet werden.},
  subject      = {Antigen CD163},
  language  = {de}
}