PMID- 28314802 OWN - NLM STAT- MEDLINE DCOM- 20170731 LR - 20200930 IS - 1522-1504 (Electronic) IS - 1040-0605 (Linking) VI - 312 IP - 6 DP - 2017 Jun 1 TI - An ex vivo model to induce early fibrosis-like changes in human precision-cut lung slices. PG - L896-L902 LID - 10.1152/ajplung.00084.2017 [doi] AB - Idiopathic pulmonary fibrosis (IPF) is a devastating chronic interstitial lung disease (ILD) characterized by lung tissue scarring and high morbidity. Lung epithelial injury, myofibroblast activation, and deranged repair are believed to be key processes involved in disease onset and progression, but the exact molecular mechanisms behind IPF remain unclear. Several drugs have been shown to slow disease progression, but treatments that halt or reverse IPF progression have not been identified. Ex vivo models of human lung have been proposed for drug discovery, one of which is precision-cut lung slices (PCLS). Although PCLS production from IPF explants is possible, IPF explants are rare and typically represent end-stage disease. Here we present a novel model of early fibrosis-like changes in human PCLS derived from patients without ILD/IPF using a combination of profibrotic growth factors and signaling molecules (transforming growth factor-beta, tumor necrosis factor-alpha, platelet-derived growth factor-AB, and lysophosphatidic acid). Fibrotic-like changes of PCLS were qualitatively analyzed by histology and immunofluorescence and quantitatively by water-soluble tetrazolium-1, RT-qPCR, Western blot analysis, and ELISA. PCLS remained viable after 5 days of treatment, and fibrotic gene expression (FN1, SERPINE1, COL1A1, CTGF, MMP7, and ACTA2) increased as early as 24 h of treatment, with increases in protein levels at 48 h and increased deposition of extracellular matrix. Alveolar epithelium reprogramming was evident by decreases in surfactant protein C and loss of HOPX In summary, using human-derived PCLS, we established a novel ex vivo model that displays characteristics of early fibrosis and could be used to evaluate novel therapies and study early-stage IPF pathomechanisms. CI - Copyright (c) 2017 the American Physiological Society. FAU - Alsafadi, Hani N AU - Alsafadi HN AD - Helmholtz Zentrum Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research, Munich, Germany. FAU - Staab-Weijnitz, Claudia A AU - Staab-Weijnitz CA AD - Helmholtz Zentrum Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research, Munich, Germany. FAU - Lehmann, Mareike AU - Lehmann M AD - Helmholtz Zentrum Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research, Munich, Germany. FAU - Lindner, Michael AU - Lindner M AD - Asklepios Fachkliniken Munchen-Gauting Center of Thoracic Surgery, Gauting, Germany; and. FAU - Peschel, Britta AU - Peschel B AD - Helmholtz Zentrum Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research, Munich, Germany. FAU - Konigshoff, Melanie AU - Konigshoff M AUID- ORCID: 0000-0001-9414-5128 AD - Helmholtz Zentrum Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research, Munich, Germany. AD - Division of Pulmonary Sciences and Critical Care Medicine Department of Medicine, University of Colorado Denver, Aurora, Colorado. FAU - Wagner, Darcy E AU - Wagner DE AUID- ORCID: 0000-0003-3794-1309 AD - Helmholtz Zentrum Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research, Munich, Germany; darcy.wagner@helmholtz-muenchen.de. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20170317 PL - United States TA - Am J Physiol Lung Cell Mol Physiol JT - American journal of physiology. Lung cellular and molecular physiology JID - 100901229 RN - 0 (Biomarkers) RN - 0 (Collagen Type I) RN - 0 (Inflammation Mediators) SB - IM EIN - Am J Physiol Lung Cell Mol Physiol. 2020 Apr 1;318(4):L844. PMID: 32239982 MH - Aged MH - Alveolar Epithelial Cells/metabolism/pathology MH - Biomarkers/metabolism MH - Collagen Type I/metabolism MH - Extracellular Matrix/metabolism MH - Female MH - Humans MH - Idiopathic Pulmonary Fibrosis/*pathology MH - Inflammation Mediators/metabolism MH - Lung/*pathology MH - Male MH - *Models, Biological MH - Tissue Survival MH - Up-Regulation OTO - NOTNLM OT - disease model OT - ex vivo OT - fibrosis OT - idiopathic pulmonary fibrosis OT - precision-cut lung slices EDAT- 2017/03/21 06:00 MHDA- 2017/08/02 06:00 CRDT- 2017/03/19 06:00 PHST- 2017/02/22 00:00 [received] PHST- 2017/03/09 00:00 [revised] PHST- 2017/03/10 00:00 [accepted] PHST- 2017/03/21 06:00 [pubmed] PHST- 2017/08/02 06:00 [medline] PHST- 2017/03/19 06:00 [entrez] AID - ajplung.00084.2017 [pii] AID - 10.1152/ajplung.00084.2017 [doi] PST - ppublish SO - Am J Physiol Lung Cell Mol Physiol. 2017 Jun 1;312(6):L896-L902. doi: 10.1152/ajplung.00084.2017. Epub 2017 Mar 17.