title: Fibroblast growth factor-1 attenuates TGF-β1-induced lung fibrosis.
abstract: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive fibroblast and myofibroblast proliferation, and extensive deposition of extracellular matrix (ECM). Fibroblast growth factor-1 (FGF-1) belongs to the FGF family and has been shown to inhibit fibroblast collagen production and differentiation into myofibroblasts, and revert epithelial-mesenchymal transition by inhibiting TGF-β1 signalling pathways. However, the precise role of FGF-1 in pulmonary fibrosis has not yet been elucidated. In this study, we explore the mechanisms underlying the anti-fibrogenic effect of FGF-1 in pulmonary fibrosis in vitro and in vivo by prolonged transient overexpression of FGF-1 (AdFGF-1) and TGF-β1 (AdTGF-β1) using adenoviral vectors. In vivo, FGF-1 overexpression markedly attenuated TGF-β1-induced pulmonary fibrosis in rat lungs when given both concomitantly, or delayed, by enhancing proliferation and hyperplasia of alveolar epithelial cells (AECs). AdFGF-1 also attenuated the TGF-β1 signalling pathway and induced FGFR1 expression in AECs. In vitro, AdFGF-1 prevented the increase in α-SMA and the decrease in E-cadherin induced by AdTGF-β1 in normal human lung fibroblasts, primary human pulmonary AECs, and A549 cells. Concomitantly, AdTGF-β1-induced Smad2 phosphorylation was significantly reduced by AdFGF-1 in both cell types. AdFGF-1 also attenuated the increase in TGFβR1 protein and mRNA levels in fibroblasts. In AECs, AdFGF-1 decreased TGFβR1 protein by favouring TGFβR1 degradation through the caveolin-1/proteasome pathway. Furthermore, FGFR1 expression was increased in AECs, whereas it was decreased in fibroblasts. In serum of IPF patients, FGF-1 levels were increased compared to controls. Interestingly, FGF-1 expression was restricted to areas of AEC hyperplasia, but not α-SMA-positive areas in IPF lung tissue. Our results demonstrate that FGF-1 may have preventative and therapeutic effects on TGF-β1-driven pulmonary fibrosis via inhibiting myofibroblast differentiation, inducing AEC proliferation, regulating TGF-β1 signalling by controlling TGFβR1 expression and degradation, and regulating FGFR1 expression. Thus, modulating FGF-1 signalling represents a potential therapy for the treatment of pulmonary fibrosis. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Firestone Institute for Respiratory Health, Departments of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Chiko
authors.initials: C
authors.lastname: Shimbori
authors.affiliation: Firestone Institute for Respiratory Health, Departments of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Pierre-Simon
authors.initials: PS
authors.lastname: Bellaye
authors.affiliation: Firestone Institute for Respiratory Health, Departments of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Jiaji
authors.initials: J
authors.lastname: Xia
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Jack
authors.initials: J
authors.lastname: Gauldie
authors.affiliation: Firestone Institute for Respiratory Health, Departments of Medicine, McMaster University, Hamilton, Ontario, Canada.|Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Kjetil
authors.identifier: 0000-0002-0202-735X
authors.initials: K
authors.lastname: Ask
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias, México DF, México, Mexico.
authors.forename: Carlos
authors.initials: C
authors.lastname: Ramos
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias, México DF, México, Mexico.
authors.forename: Carina
authors.initials: C
authors.lastname: Becerril
authors.affiliation: Facultad de Ciencias, Universidad Nacional Autónoma de México, Ciudad de México, Mexico.
authors.forename: Annie
authors.initials: A
authors.lastname: Pardo
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias, México DF, México, Mexico.
authors.forename: Moises
authors.initials: M
authors.lastname: Selman
authors.affiliation: Firestone Institute for Respiratory Health, Departments of Medicine, McMaster University, Hamilton, Ontario, Canada. kolbm@mcmaster.ca.|Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada. kolbm@mcmaster.ca.
authors.forename: Martin
authors.initials: M
authors.lastname: Kolb
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D016220:Fibroblast Growth Factor 1 / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D011650:Pulmonary Alveoli / Q000378:metabolism* / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051899:Smad2 Protein / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D015820:Cadherins; D051899:Smad2 Protein; D016220:Fibroblast Growth Factor 1; D046988:Proteasome Endopeptidase Complex
keywords: FGF-1; FGFR; TGF-β1; TGFβR1; caveolin-1; pulmonary fibrosis