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: Chiko Shimbori, Pierre-Simon Bellaye, Jiaji Xia, Jack Gauldie, Kjetil Ask, Carlos Ramos, Carina Becerril, Annie Pardo, Moises Selman, Martin Kolb
• Journal: The Journal of pathology (J Pathol) Vol. 240 Issue 2 Pg. 197-210 (10 2016) ISSN: 1096-9896 [Electronic] England
• PMID: 27425145 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Chemical References

• Cadherins
• Smad2 Protein
• Fibroblast Growth Factor 1
• Proteasome Endopeptidase Complex

Topics

• Animals
• Cadherins (metabolism)
• Cell Differentiation (genetics)
• Cell Proliferation (genetics)
• Epithelial Cells (metabolism, pathology)
• Female
• Fibroblast Growth Factor 1 (genetics, metabolism)
• Fibroblasts (metabolism, pathology)
• Humans
• Phosphorylation
• Proteasome Endopeptidase Complex
• Pulmonary Alveoli (metabolism, pathology)
• Pulmonary Fibrosis (genetics, metabolism, pathology)
• Rats
• Rats, Sprague-Dawley
• Smad2 Protein (metabolism)
• Up-Regulation