PMID- 30219058 OWN - NLM STAT- MEDLINE DCOM- 20181211 LR - 20181211 IS - 1465-993X (Electronic) IS - 1465-9921 (Print) IS - 1465-9921 (Linking) VI - 19 IP - 1 DP - 2018 Sep 15 TI - Differential effects of Nintedanib and Pirfenidone on lung alveolar epithelial cell function in ex vivo murine and human lung tissue cultures of pulmonary fibrosis. PG - 175 LID - 10.1186/s12931-018-0876-y [doi] LID - 175 AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease. Repetitive injury and reprogramming of the lung epithelium are thought to be critical drivers of disease progression, contributing to fibroblast activation, extracellular matrix remodeling, and subsequently loss of lung architecture and function. To date, Pirfenidone and Nintedanib are the only approved drugs known to decelerate disease progression, however, if and how these drugs affect lung epithelial cell function, remains largely unexplored. METHODS: We treated murine and human 3D ex vivo lung tissue cultures (3D-LTCs; generated from precision cut lung slices (PCLS)) as well as primary murine alveolar epithelial type II (pmATII) cells with Pirfenidone or Nintedanib. Murine 3D-LTCs or pmATII cells were derived from the bleomycin model of fibrosis. Early fibrotic changes were induced in human 3D-LTCs by a mixture of profibrotic factors. Epithelial and mesenchymal cell function was determined by qPCR, Western blotting, Immunofluorescent staining, and ELISA. RESULTS: Low muM concentrations of Nintedanib (1 muM) and mM concentrations of Pirfenidone (2.5 mM) reduced fibrotic gene expression including Collagen 1a1 and Fibronectin in murine and human 3D-LTCs as well as pmATII cells. Notably, Nintedanib stabilized expression of distal lung epithelial cell markers, especially Surfactant Protein C in pmATII cells as well as in murine and human 3D-LTCs. CONCLUSIONS: Pirfenidone and Nintedanib exhibit distinct effects on murine and human epithelial cells, which might contribute to their anti-fibrotic action. Human 3D-LTCs represent a valuable tool to assess anti-fibrotic mechanisms of potential drugs for the treatment of IPF patients. FAU - Lehmann, Mareike AU - Lehmann M AD - Research Unit Lung Repair and Regeneration, Helmholtz Zentrum Munchen and University Hospital of the Ludwig Maximilians Universitat, Member of the German Center for Lung Research (DZL), Munich, Germany. FAU - Buhl, Lara AU - Buhl L AD - Research Unit Lung Repair and Regeneration, Helmholtz Zentrum Munchen and University Hospital of the Ludwig Maximilians Universitat, Member of the German Center for Lung Research (DZL), Munich, Germany. FAU - Alsafadi, Hani N AU - Alsafadi HN AD - Research Unit Lung Repair and Regeneration, Helmholtz Zentrum Munchen and University Hospital of the Ludwig Maximilians Universitat, Member of the German Center for Lung Research (DZL), Munich, Germany. FAU - Klee, Stephan AU - Klee S AD - Research Unit Lung Repair and Regeneration, Helmholtz Zentrum Munchen and University Hospital of the Ludwig Maximilians Universitat, Member of the German Center for Lung Research (DZL), Munich, Germany. FAU - Hermann, Sarah AU - Hermann S AD - Research Unit Lung Repair and Regeneration, Helmholtz Zentrum Munchen and University Hospital of the Ludwig Maximilians Universitat, Member of the German Center for Lung Research (DZL), Munich, Germany. FAU - Mutze, Kathrin AU - Mutze K AD - Research Unit Lung Repair and Regeneration, Helmholtz Zentrum Munchen and University Hospital of the Ludwig Maximilians Universitat, Member of the German Center for Lung Research (DZL), Munich, Germany. FAU - Ota, Chiharu AU - Ota C AD - Research Unit Lung Repair and Regeneration, Helmholtz Zentrum Munchen and University Hospital of the Ludwig Maximilians Universitat, Member of the German Center for Lung Research (DZL), Munich, Germany. FAU - Lindner, Michael AU - Lindner M AD - Center for Thoracic Surgery, Asklepios Biobank for Lung Diseases, Comprehensive Pneumology Center, Asklepios Clinic Munich-Gauting, Munich, Germany. FAU - Behr, Jurgen AU - Behr J AD - Center for Thoracic Surgery, Asklepios Biobank for Lung Diseases, Comprehensive Pneumology Center, Asklepios Clinic Munich-Gauting, Munich, Germany. AD - Medizinische Klinik und Poliklinik V, Klinikum der Ludwig Maximilians University, Munich, Germany. FAU - Hilgendorff, Anne AU - Hilgendorff A AD - Research Unit Lung Repair and Regeneration, Helmholtz Zentrum Munchen and University Hospital of the Ludwig Maximilians Universitat, Member of the German Center for Lung Research (DZL), Munich, Germany. FAU - Wagner, Darcy E AU - Wagner DE AD - Research Unit Lung Repair and Regeneration, Helmholtz Zentrum Munchen and University Hospital of the Ludwig Maximilians Universitat, Member of the German Center for Lung Research (DZL), Munich, Germany. AD - Department of Experimental Medical Sciences, Lung Bioengineering and Regeneration, Lund University, Lund, Sweden. AD - Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden. AD - Stem Cell Centre, Lund University, Lund, Sweden. FAU - Konigshoff, Melanie AU - Konigshoff M AUID- ORCID: 0000-0001-9414-5128 AD - Research Unit Lung Repair and Regeneration, Helmholtz Zentrum Munchen and University Hospital of the Ludwig Maximilians Universitat, Member of the German Center for Lung Research (DZL), Munich, Germany. melanie.koenigshoff@ucdenver.edu. AD - Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, AMC, Research 2, 9th Flr, 12700 East 19th Ave, Aurora, Denver, CO, 80045, USA. melanie.koenigshoff@ucdenver.edu. LA - eng PT - Journal Article DEP - 20180915 PL - England TA - Respir Res JT - Respiratory research JID - 101090633 RN - 0 (Anti-Inflammatory Agents, Non-Steroidal) RN - 0 (Antineoplastic Agents) RN - 0 (Indoles) RN - 0 (Pyridones) RN - D7NLD2JX7U (pirfenidone) RN - G6HRD2P839 (nintedanib) SB - IM MH - Alveolar Epithelial Cells/*drug effects/pathology/*physiology MH - Animals MH - Anti-Inflammatory Agents, Non-Steroidal/pharmacology/therapeutic use MH - Antineoplastic Agents/pharmacology/therapeutic use MH - Cell Culture Techniques MH - Female MH - Humans MH - Idiopathic Pulmonary Fibrosis/*drug therapy/metabolism/pathology MH - Indoles/*pharmacology/therapeutic use MH - Lung/drug effects/pathology/physiology MH - Mice MH - Mice, Inbred C57BL MH - Pyridones/*pharmacology/therapeutic use PMC - PMC6138909 OTO - NOTNLM OT - ATII OT - Epithelial cells OT - IPF OT - Lung disease OT - Nintedanib OT - PCLS OT - Pirfenidone OT - ex vivo COIS- ETHICS APPROVAL: Human tissue Human tissue has been obtained from the Comprehensive Pneumology Center cohort of the BioArchive CPC-M at the University Hospital Grosshadern of the Ludwig Maximilian University (Munich, Germany) and by the Asklepios Biobank of Lung Diseases (Gauting, Germany). Participants provided written informed consent to participate in this study, in accordance with approval by the local ethics committee of the LMU, Germany (Project 333-10, 455-12). Animal experiment All mouse experiments were performed in accordance with the guidelines of the ethics committee of the Helmholtz Zentrum Munich (Germany) and approved by the regional council of Upper Bavaria Germany (Project 55.2-1-54-2532-88-12). CONSENT FOR PUBLICATION: Not applicable COMPETING INTERESTS: The authors declare that they have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2018/09/17 06:00 MHDA- 2018/12/12 06:00 PMCR- 2018/09/15 CRDT- 2018/09/17 06:00 PHST- 2018/07/12 00:00 [received] PHST- 2018/08/29 00:00 [accepted] PHST- 2018/09/17 06:00 [entrez] PHST- 2018/09/17 06:00 [pubmed] PHST- 2018/12/12 06:00 [medline] PHST- 2018/09/15 00:00 [pmc-release] AID - 10.1186/s12931-018-0876-y [pii] AID - 876 [pii] AID - 10.1186/s12931-018-0876-y [doi] PST - epublish SO - Respir Res. 2018 Sep 15;19(1):175. doi: 10.1186/s12931-018-0876-y.