@article{LanghauserHeilerGrudzenskietal.2012, author = {Langhauser, Friederike L. and Heiler, Patrick M. and Grudzenski, Saskia and Lemke, Andreas and Alonso, Angelika and Schad, Lothar R. and Hennerici, Michael G. and Meairs, Stephen and Fata, Marc}, title = {Thromboembolic stroke in C57BL/6 mice monitored by 9.4 T MRI using a 1H cryo probe}, series = {Experimental and Translational Stroke Medicine}, volume = {4}, journal = {Experimental and Translational Stroke Medicine}, number = {18}, doi = {10.1186/2040-7378-4-18}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124218}, year = {2012}, abstract = {Background A new thromboembolic animal model showed beneficial effects of t-PA with an infarct volume reduction of 36.8\% in swiss mice. Because knock-out animal experiments for stroke frequently used C57BL76 mice we evaluated t-PA effects in this mouse strain and measured infarct volume and vascular recanalisation in-vivo by using high-field 9.4 T MRI and a 1H surface cryo coil. Methods Clot formation was triggered by microinjection of murine thrombin into the right middle cerebral artery (MCA). Animals (n = 28) were treated with 10 mg/kg, 5 mg/kg or no tissue plasminogen activator (t-PA) 40 min after MCA occlusion. For MR-imaging a Bruker 9.4 T animal system with a 1H surface cryo probe was used and a T2-weighted RARE sequence, a diffusion weighted multishot EPI sequence and a 3D flow-compensated gradient echo TOF angiography were performed. Results The infarct volume in animals treated with t-PA was significantly reduced (0.67 ± 1.38 mm3 for 10 mg/kg and 10.9 ± 8.79 mm3 for 5 mg/kg vs. 19.76 ± 2.72 mm3 ; p < 0.001) compared to untreated mice. An additional group was reperfused with t-PA inside the MRI. Already ten minutes after beginning of t-PA treatment, reperfusion flow was re-established in the right MCA. However, signal intensity was lower than in the contralateral MCA. This reduction in cerebral blood flow was attenuated during the first 60 minutes after reperfusion. 24 h after MCA occlusion and reperfusion, no difference in signal intensity of the contralateral and ipsilateral MCAs was observed. Conclusions We confirm a t-Pa effect using this stroke model in the C57BL76 mouse strain and demonstrate a chronological sequence MRI imaging after t-PA using a 1H surface cryo coil in a 9.4 T MRI. This setting will allow testing of new thrombolytic strategies for stroke treatment in-vivo in C57BL76 knock-out mice.}, language = {en} } @article{NiemannHuberWagneretal.2014, author = {Niemann, Axel and Huber, Nina and Wagner, Konstanze M. and Somandin, Christian and Horn, Michael and Lebrun-Julien, Fr{\´e}d{\´e}ric and Angst, Brigitte and Pereira, Jorge A. and Halfter, Hartmut and Welzl, Hans and Feltri, M. Laura and Wrabetz, Lawrence and Young, Peter and Wessig, Carsten and Toyka, Klaus V. and Suter, Ueli}, title = {The Gdap1 knockout mouse mechanistically links redox control to Charcot-Marie-Tooth disease}, series = {Brain}, volume = {137}, journal = {Brain}, number = {3}, doi = {10.1093/brain/awt371}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120731}, pages = {668-82}, year = {2014}, abstract = {The ganglioside-induced differentiation-associated protein 1 (GDAP1) is a mitochondrial fission factor and mutations in GDAP1 cause Charcot-Marie-Tooth disease. We found that Gdap1 knockout mice (\(Gdap1^{-/-}\)), mimicking genetic alterations of patients suffering from severe forms of Charcot-Marie-Tooth disease, develop an age-related, hypomyelinating peripheral neuropathy. Ablation of Gdap1 expression in Schwann cells recapitulates this phenotype. Additionally, intra-axonal mitochondria of peripheral neurons are larger in \(Gdap1^{-/-}\) mice and mitochondrial transport is impaired in cultured sensory neurons of \(Gdap1^{-/-}\) mice compared with controls. These changes in mitochondrial morphology and dynamics also influence mitochondrial biogenesis. We demonstrate that mitochondrial DNA biogenesis and content is increased in the peripheral nervous system but not in the central nervous system of \(Gdap1^{-/-}\) mice compared with control littermates. In search for a molecular mechanism we turned to the paralogue of GDAP1, GDAP1L1, which is mainly expressed in the unaffected central nervous system. GDAP1L1 responds to elevated levels of oxidized glutathione by translocating from the cytosol to mitochondria, where it inserts into the mitochondrial outer membrane. This translocation is necessary to substitute for loss of GDAP1 expression. Accordingly, more GDAP1L1 was associated with mitochondria in the spinal cord of aged \(Gdap1^{-/-}\) mice compared with controls. Our findings demonstrate that Charcot-Marie-Tooth disease caused by mutations in GDAP1 leads to mild, persistent oxidative stress in the peripheral nervous system, which can be compensated by GDAP1L1 in the unaffected central nervous system. We conclude that members of the GDAP1 family are responsive and protective against stress associated with increased levels of oxidized glutathione.}, language = {en} } @article{LiuHanBlairetal.2021, author = {Liu, Fengming and Han, Kun and Blair, Robert and Kenst, Kornelia and Qin, Zhongnan and Upcin, Berin and W{\"o}rsd{\"o}rfer, Philipp and Midkiff, Cecily C. and Mudd, Joseph and Belyaeva, Elizaveta and Milligan, Nicholas S. and Rorison, Tyler D. and Wagner, Nicole and Bodem, Jochen and D{\"o}lken, Lars and Aktas, Bertal H. and Vander Heide, Richard S. and Yin, Xiao-Ming and Kolls, Jay K. and Roy, Chad J. and Rappaport, Jay and Erg{\"u}n, S{\"u}leyman and Qin, Xuebin}, title = {SARS-CoV-2 Infects Endothelial Cells In Vivo and In Vitro}, series = {Frontiers in Cellular and Infection Microbiology}, volume = {11}, journal = {Frontiers in Cellular and Infection Microbiology}, issn = {2235-2988}, doi = {10.3389/fcimb.2021.701278}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-241948}, year = {2021}, abstract = {SARS-CoV-2 infection can cause fatal inflammatory lung pathology, including thrombosis and increased pulmonary vascular permeability leading to edema and hemorrhage. In addition to the lung, cytokine storm-induced inflammatory cascade also affects other organs. SARS-CoV-2 infection-related vascular inflammation is characterized by endotheliopathy in the lung and other organs. Whether SARS-CoV-2 causes endotheliopathy by directly infecting endothelial cells is not known and is the focus of the present study. We observed 1) the co-localization of SARS-CoV-2 with the endothelial cell marker CD31 in the lungs of SARS-CoV-2-infected mice expressing hACE2 in the lung by intranasal delivery of adenovirus 5-hACE2 (Ad5-hACE2 mice) and non-human primates at both the protein and RNA levels, and 2) SARS-CoV-2 proteins in endothelial cells by immunogold labeling and electron microscopic analysis. We also detected the co-localization of SARS-CoV-2 with CD31 in autopsied lung tissue obtained from patients who died from severe COVID-19. Comparative analysis of RNA sequencing data of the lungs of infected Ad5-hACE2 and Ad5-empty (control) mice revealed upregulated KRAS signaling pathway, a well-known pathway for cellular activation and dysfunction. Further, we showed that SARS-CoV-2 directly infects mature mouse aortic endothelial cells (AoECs) that were activated by performing an aortic sprouting assay prior to exposure to SARS-CoV-2. This was demonstrated by co-localization of SARS-CoV-2 and CD34 by immunostaining and detection of viral particles in electron microscopic studies. Moreover, the activated AoECs became positive for ACE-2 but not quiescent AoECs. Together, our results indicate that in addition to pneumocytes, SARS-CoV-2 also directly infects mature vascular endothelial cells in vivo and ex vivo, which may contribute to cardiovascular complications in SARS-CoV-2 infection, including multipleorgan failure.}, language = {en} } @article{GrotemeyerMcFlederWuetal.2022, author = {Grotemeyer, Alexander and McFleder, Rhonda Leah and Wu, Jingjing and Wischhusen, J{\"o}rg and Ip, Chi Wang}, title = {Neuroinflammation in Parkinson's disease - putative pathomechanisms and targets for disease-modification}, series = {Frontiers in Immunology}, volume = {13}, journal = {Frontiers in Immunology}, issn = {1664-3224}, doi = {10.3389/fimmu.2022.878771}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-274665}, year = {2022}, abstract = {Parkinson's disease (PD) is a progressive and debilitating chronic disease that affects more than six million people worldwide, with rising prevalence. The hallmarks of PD are motor deficits, the spreading of pathological α-synuclein clusters in the central nervous system, and neuroinflammatory processes. PD is treated symptomatically, as no causally-acting drug or procedure has been successfully established for clinical use. Various pathways contributing to dopaminergic neuron loss in PD have been investigated and described to interact with the innate and adaptive immune system. We discuss the possible contribution of interconnected pathways related to the immune response, focusing on the pathophysiology and neurodegeneration of PD. In addition, we provide an overview of clinical trials targeting neuroinflammation in PD.}, language = {en} } @article{HackerHofEmoedyetal.1986, author = {Hacker, J{\"o}rg and Hof, H. and Em{\"o}dy, L. and Goebel, W.}, title = {Influence of cloned Escherichia coli hemolysin genes, S fimbriae and serum resistance on pathogenicity in different animal models}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-59423}, year = {1986}, abstract = {The virulence of the uropathogenic E. coli strain 536 (06: K 1 5: H31) which produces the S-fimbrial adhesin (Sfa•), is serum-resistant (Sre+) and hemolytic (Hiy+) and its derivatives were assessed in five different animal models. Cloned hemolysin (h/y) determinants from the Chromosomes of 06,018 and 075 E. colistrains and from the plasmid pHiy152 were introduced into the spontaneaus Sfa-, Sre-, Hly- mutant 536-21 and its Sfa+, Sre+, Hly- variant 536-31. As already demonstrated for the 536-21 strains {lnfect. Immun. 42: 57-63) the 018-hly determinant but not the plasmid-encoded hly determinant of pHiy 1 52 transformed into 536-31 contribute to lethality in a mouse peritonitis modal. Similar results were obtained with both Hlyhost strains and their Hly+ transformants in a chicken embryo test and in a mouse nephropathogenicity assay in which the renal bacterial counts were measured 1 5 min to 8 hours after i.v. infection. S-fimbriae and serum resistance had only a marginal influence in these three in vivo systems. ln centrast all three factors, S-fimbriae, serum resistance and hemolysin, were necessary for full virulence in a respiratory mouse infection assay. ln a subcutaneously-induced sepsis model in the mouse restoration of S-fimbriae and serum resistance and separately chromosomally-encoded hemolysis increased virulence to a Ievel comparable to that of the parental 536 strain.}, subject = {Infektionsbiologie}, language = {en} } @article{BeckStegnerLorochetal.2021, author = {Beck, Sarah and Stegner, David and Loroch, Stefan and Baig, Ayesha A. and G{\"o}b, Vanessa and Schumbutzki, Cornelia and Eilers, Eva and Sickmann, Albert and May, Frauke and Nolte, Marc W. and Panousis, Con and Nieswandt, Bernhard}, title = {Generation of a humanized FXII knock-in mouse-A powerful model system to test novel anti-thrombotic agents}, series = {Journal of Thrombosis and Haemostasis}, volume = {19}, journal = {Journal of Thrombosis and Haemostasis}, number = {11}, doi = {10.1111/jth.15488}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259567}, pages = {2835-2840}, year = {2021}, abstract = {Background Effective inhibition of thrombosis without generating bleeding risks is a major challenge in medicine. Accumulating evidence suggests that this can be achieved by inhibition of coagulation factor XII (FXII), as either its knock-out or inhibition in animal models efficiently reduced thrombosis without affecting normal hemostasis. Based on these findings, highly specific inhibitors for human FXII(a) are under development. However, currently, in vivo studies on their efficacy and safety are impeded by the lack of an optimized animal model expressing the specific target, that is, human FXII. Objective The primary objective of this study is to develop and functionally characterize a humanized FXII mouse model. Methods A humanized FXII mouse model was generated by replacing the murine with the human F12 gene (genetic knock-in) and tested it in in vitro coagulation assays and in in vivo thrombosis models. Results These hF12\(^{KI}\) mice were indistinguishable from wild-type mice in all tested assays of coagulation and platelet function in vitro and in vivo, except for reduced expression levels of hFXII compared to human plasma. Targeting FXII by the anti-human FXIIa antibody 3F7 increased activated partial thromboplastin time dose-dependently and protected hF12\(^{KI}\) mice in an arterial thrombosis model without affecting bleeding times. Conclusion These data establish the newly generated hF12\(^{KI}\) mouse as a powerful and unique model system for in vivo studies on anti-FXII(a) biologics, supporting the development of efficient and safe human FXII(a) inhibitors.}, language = {en} } @article{GredicKarnatiRuppertetal.2023, author = {Gredic, Marija and Karnati, Srikanth and Ruppert, Clemens and Guenther, Andreas and Avdeev, Sergey N. and Kosanovic, Djuro}, title = {Combined pulmonary fibrosis and emphysema: when Scylla and Charybdis ally}, series = {Cells}, volume = {12}, journal = {Cells}, number = {9}, issn = {2073-4409}, doi = {10.3390/cells12091278}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-313571}, year = {2023}, abstract = {Combined pulmonary fibrosis and emphysema (CPFE) is a recently recognized syndrome that, as its name indicates, involves the existence of both interstitial lung fibrosis and emphysema in one individual, and is often accompanied by pulmonary hypertension. This debilitating, progressive condition is most often encountered in males with an extensive smoking history, and is presented by dyspnea, preserved lung volumes, and contrastingly impaired gas exchange capacity. The diagnosis of the disease is based on computed tomography imaging, demonstrating the coexistence of emphysema and interstitial fibrosis in the lungs, which might be of various types and extents, in different areas of the lung and several relative positions to each other. CPFE bears high mortality and to date, specific and efficient treatment options do not exist. In this review, we will summarize current knowledge about the clinical attributes and manifestations of CPFE. Moreover, we will focus on pathophysiological and pathohistological lung phenomena and suspected etiological factors of this disease. Finally, since there is a paucity of preclinical research performed for this particular lung pathology, we will review existing animal studies and provide suggestions for the development of additional in vivo models of CPFE syndrome.}, language = {en} } @article{PalamidesJodeleitFoehlingeretal.2016, author = {Palamides, Pia and Jodeleit, Henrika and F{\"o}hlinger, Michael and Beigel, Florian and Herbach, Nadja and Mueller, Thomas and Wolf, Eckhard and Siebeck, Matthias and Gropp, Roswitha}, title = {A mouse model for ulcerative colitis based on NOD-scid IL2R gamma(null) mice reconstituted with peripheral blood mononuclear cells from affected individuals}, series = {Disease Models \& Mechanisms}, volume = {9}, journal = {Disease Models \& Mechanisms}, doi = {10.1242/dmm.025452}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-164946}, pages = {985-997}, year = {2016}, abstract = {Animal models reflective of ulcerative colitis (UC) remain a major challenge, and yet are crucial to understand mechanisms underlying the onset of disease and inflammatory characteristics of relapses and remission. Mouse models in which colitis-like symptoms are induced through challenge with toxins such as oxazolone, dextran sodium sulfate (DSS) or 2,4,6-trinitrobenzenesulfonic acid (TNBS) have been instrumental in understanding the inflammatory processes of UC. However, these neither reflect the heterogeneous symptoms observed in the UC-affected population nor can they be used to test the efficacy of inhibitors developed against human targets where high sequence and structural similarity of the respective ligands is lacking. In an attempt to overcome these problems, we have developed a mouse model that relies on NOD-scid IL2R γnull mice reconstituted with peripheral blood mononuclear cells derived from UC-affected individuals. Upon challenge with ethanol, mice developed colitis-like symptoms and changes in the colon architecture, characterized by influx of inflammatory cells, edema, crypt loss, crypt abscesses and epithelial hyperplasia, as previously observed in immune-competent mice. TARC, TGFβ1 and HGF expression increased in distal parts of the colon. Analysis of human leucocytes isolated from mouse spleen revealed an increase in frequencies of CD1a+, CD64+, CD163+ and TSLPR+ CD14+ monocytes, and antigen-experienced CD44+ CD4+ and CD8+ T-cells in response to ethanol. Analysis of human leucocytes from the colon of challenged mice identified CD14+ monocytes and CD11b+ monocytes as the predominant populations. Quantitative real-time PCR (RT-PCR) analysis from distal parts of the colon indicated that IFNγ might be one of the cytokines driving inflammation. Treatment with infliximab ameliorated symptoms and pathological manifestations, whereas pitrakinra had no therapeutic benefit. Thus, this model is partially reflective of the human disease and might help to increase the translation of animal and clinical studies.}, language = {en} }