PMID- 35710078 OWN - NLM STAT- MEDLINE DCOM- 20220630 LR - 20220705 IS - 1879-0720 (Electronic) IS - 0928-0987 (Linking) VI - 175 DP - 2022 Aug 1 TI - Fyn-kinase and caveolin-1 in the alveolar epithelial junctional adherence complex contribute to the early stages of pulmonary fibrosis. PG - 106236 LID - S0928-0987(22)00121-X [pii] LID - 10.1016/j.ejps.2022.106236 [doi] AB - Current pathophysiological findings indicate that damage to the alveolar epithelium plays a decisive role in the development of idiopathic pulmonary fibrosis (IPF). The available pharmacological interventions (i.e., oral pirfenidone and nintedanib) only slow down progression of the disease, but do not offer a cure. In order to develop new drug candidates, the pathophysiology of IPF needs to be better understood on a molecular level. It has previously been reported that a loss of caveolin-1 (Cav-1) contributes to profibrotic processes by causing reduced alveolar barrier function and fibrosis-like alterations of the lung-parenchyma. Conversely, overexpression of caveolin-1 appears to counteract the development of fibrosis by inhibiting the inflammasome NLRP3 and the associated expression of interleukin-1beta. In this study, the interaction between Fyn-kinase and caveolin-1 in the alveolar epithelium of various bleomycin (BLM)/TGF-beta damage models using precision-cut lung slices (PCLS), wildtype (WT) and caveolin-1 knockout (KO) mice as well as the human NCI-H441 cell line, were investigated. In WT mouse lung tissues, strong signals for Fyn-kinase were detected in alveolar epithelial type I cells, whereas in caveolin-1 KO animals, expression shifted to alveolar epithelial type II cells. Caveolin-1 and Fyn-kinase were found to be co-localized in isolated lipid rafts of NCI-H441 cell membrane fractions. These findings were corroborated by co-immunoprecipitation studies in which a co-localization of Cav-1 and Fyn-kinase was detected in the cell membrane of the alveolar epithelium. After TGF-beta and BLM-induced damage to the alveolar epithelium both in PCLS and cell culture experiments, a decrease in caveolin-1 and Fyn-kinase was found. Furthermore, TEER (transepithelial electrical resistance) measurements indicated that TGF-beta and BLM have a damaging effect on cell-cell contacts and thus impair the barrier function in NCI-H441 cell monolayers. This effect was attenuated after co-incubation with the Fyn-kinase inhibitor, PP-2. Our data suggest an involvement of Fyn-kinase and caveolin-1 in TGF-beta/bleomycin-induced impairment of alveolar barrier function and thus a possible role in the early stages of pulmonary fibrosis. Fyn-kinase and/or its complex with caveolin-1 might, therefore, be novel therapeutic targets in IPF. CI - Copyright (c) 2022 The Author(s). Published by Elsevier B.V. All rights reserved. FAU - Menzel, Viktoria AU - Menzel V AD - Institute of Anatomy, Medical Faculty "Carl Gustav Carus", Technische Universitat Dresden, Fetscherstr. 74, Dresden 01307, Germany. FAU - Ziegler, Matthias AU - Ziegler M AD - Institute of Anatomy, Medical Faculty "Carl Gustav Carus", Technische Universitat Dresden, Fetscherstr. 74, Dresden 01307, Germany. FAU - Hante, Nadhim AU - Hante N AD - School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; Faculty of Pharmacy, University of Kufa, Al-Najaf, Iraq. FAU - Sake, Johannes A AU - Sake JA AD - School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland. FAU - Santos-Martinez, Maria Jose AU - Santos-Martinez MJ AD - School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; School of Medicine, Trinity College Dublin, Dublin 2, Ireland. FAU - Ehrhardt, Carsten AU - Ehrhardt C AD - School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland. Electronic address: ehrhardc@tcd.ie. FAU - Kasper, Michael AU - Kasper M AD - Institute of Anatomy, Medical Faculty "Carl Gustav Carus", Technische Universitat Dresden, Fetscherstr. 74, Dresden 01307, Germany. FAU - Barth, Kathrin AU - Barth K AD - Institute of Anatomy, Medical Faculty "Carl Gustav Carus", Technische Universitat Dresden, Fetscherstr. 74, Dresden 01307, Germany. Electronic address: kathrin.barth@tudresden.de. LA - eng PT - Journal Article DEP - 20220613 PL - Netherlands TA - Eur J Pharm Sci JT - European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences JID - 9317982 RN - 0 (Caveolin 1) RN - 0 (Transforming Growth Factor beta) RN - 11056-06-7 (Bleomycin) RN - EC 2.7.10.2 (Fyn protein, mouse) RN - EC 2.7.10.2 (Proto-Oncogene Proteins c-fyn) SB - IM MH - *Alveolar Epithelial Cells/metabolism/pathology MH - Animals MH - Bleomycin/pharmacology MH - *Caveolin 1/metabolism MH - Fibrosis MH - *Idiopathic Pulmonary Fibrosis/chemically induced/drug therapy/metabolism/pathology MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - *Proto-Oncogene Proteins c-fyn/metabolism MH - Transforming Growth Factor beta/metabolism OTO - NOTNLM OT - Alveolar epithelial barrier function OT - Bleomycin-induced lung injury OT - Caveolin-1 OT - Cellular junctions OT - Fyn-kinase OT - TGF-beta-induced lung injury EDAT- 2022/06/17 06:00 MHDA- 2022/07/01 06:00 CRDT- 2022/06/16 19:35 PHST- 2022/01/26 00:00 [received] PHST- 2022/06/03 00:00 [revised] PHST- 2022/06/11 00:00 [accepted] PHST- 2022/06/17 06:00 [pubmed] PHST- 2022/07/01 06:00 [medline] PHST- 2022/06/16 19:35 [entrez] AID - S0928-0987(22)00121-X [pii] AID - 10.1016/j.ejps.2022.106236 [doi] PST - ppublish SO - Eur J Pharm Sci. 2022 Aug 1;175:106236. doi: 10.1016/j.ejps.2022.106236. Epub 2022 Jun 13.