TY - JOUR A1 - Gredic, Marija A1 - Karnati, Srikanth A1 - Ruppert, Clemens A1 - Guenther, Andreas A1 - Avdeev, Sergey N. A1 - Kosanovic, Djuro T1 - Combined pulmonary fibrosis and emphysema: when Scylla and Charybdis ally JF - Cells N2 - 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. KW - CPFE KW - lung fibrosis KW - emphysema KW - animal models Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313571 SN - 2073-4409 VL - 12 IS - 9 ER - TY - JOUR A1 - Stojanović, Stevan D. A1 - Fuchs, Maximilian A1 - Fiedler, Jan A1 - Xiao, Ke A1 - Meinecke, Anna A1 - Just, Annette A1 - Pich, Andreas A1 - Thum, Thomas A1 - Kunz, Meik T1 - Comprehensive bioinformatics identifies key microRNA players in ATG7-deficient lung fibroblasts JF - International Journal of Molecular Sciences N2 - Background: Deficient autophagy has been recently implicated as a driver of pulmonary fibrosis, yet bioinformatics approaches to study this cellular process are lacking. Autophagy-related 5 and 7 (ATG5/ATG7) are critical elements of macro-autophagy. However, an alternative ATG5/ATG7-independent macro-autophagy pathway was recently discovered, its regulation being unknown. Using a bioinformatics proteome profiling analysis of ATG7-deficient human fibroblasts, we aimed to identify key microRNA (miR) regulators in autophagy. Method: We have generated ATG7-knockout MRC-5 fibroblasts and performed mass spectrometry to generate a large-scale proteomics dataset. We further quantified the interactions between various proteins combining bioinformatics molecular network reconstruction and functional enrichment analysis. The predicted key regulatory miRs were validated via quantitative polymerase chain reaction. Results: The functional enrichment analysis of the 26 deregulated proteins showed decreased cellular trafficking, increased mitophagy and senescence as the major overarching processes in ATG7-deficient lung fibroblasts. The 26 proteins reconstitute a protein interactome of 46 nodes and miR-regulated interactome of 834 nodes. The miR network shows three functional cluster modules around miR-16-5p, miR-17-5p and let-7a-5p related to multiple deregulated proteins. Confirming these results in a biological setting, serially passaged wild-type and autophagy-deficient fibroblasts displayed senescence-dependent expression profiles of miR-16-5p and miR-17-5p. Conclusions: We have developed a bioinformatics proteome profiling approach that successfully identifies biologically relevant miR regulators from a proteomics dataset of the ATG-7-deficient milieu in lung fibroblasts, and thus may be used to elucidate key molecular players in complex fibrotic pathological processes. The approach is not limited to a specific cell-type and disease, thus highlighting its high relevance in proteome and non-coding RNA research. KW - bioinformatics KW - miR KW - proteomics KW - functional network analysis KW - senescence KW - lung fibrosis KW - autophagy Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285181 SN - 1422-0067 VL - 21 IS - 11 ER - TY - JOUR A1 - Rapp, Christina K. A1 - Van Dijck, Ine A1 - Laugwitz, Lucia A1 - Boon, Mieke A1 - Briassoulis, George A1 - Ilia, Stavroula A1 - Kammer, Birgit A1 - Reu, Simone A1 - Hornung, Stefanie A1 - Buchert, Rebecca A1 - Sofan, Linda A1 - Froukh, Tawfiq A1 - Witters, Peter A1 - Rymen, Daisy A1 - Haack, Tobias B. A1 - Proesmans, Marijke A1 - Griese, Matthias T1 - Expanding the phenotypic spectrum of FINCA (fibrosis, neurodegeneration, and cerebral angiomatosis) syndrome beyond infancy JF - Clinical Genetics N2 - Fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA, MIM#618278) is a rare clinical condition caused by bi‐allelic variants in NHL repeat containing protein 2 (NHLRC2, MIM*618277). Pulmonary disease may be the presenting sign and the few patients reported so far, all deceased in early infancy. Exome sequencing was performed on patients with childhood interstitial lung disease (chILD) and additional neurological features. The chILD‐EU register database and an in‐house database were searched for patients with NHLRC2 variants and clinical features overlapping FINCA syndrome. Six patients from three families were identified with bi‐allelic variants in NHLRC2. Two of these children died before the age of two while four others survived until childhood. Interstitial lung disease was pronounced in almost all patients during infancy and stabilized over the course of the disease with neurodevelopmental delay (NDD) evolving as the key clinical finding. We expand the phenotype of FINCA syndrome to a multisystem disorder with variable severity. FINCA syndrome should also be considered in patients beyond infancy with NDD and a history of distinct interstitial lung disease. Managing patients in registers for rare diseases helps identifying new diagnostic entities and advancing care for these patients. KW - cerebropulmonary disease KW - childhood interstitial lung disease KW - cholesterol pneumonia KW - FINCA KW - lung fibrosis KW - lipoid pneumonitis KW - multi‐organ disease KW - NHLRC2 Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262732 VL - 100 IS - 4 SP - 453 EP - 461 ER -