Fibroblast growth factor-1 attenuates TGF-β1-induced lung fibrosis

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-beta 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-beta (AdTGF-beta) using adenoviral vectors. In vivo, FGF-1 overexpression markedly attenuated TGF-beta-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-beta 1 signalling pathway and induced FGFR1 expression in AECs. In vitro, AdFGF-1 prevented the increase in beta-SMA and the decrease in E-cadherin induced by AdTGF-beta 1 in normal human lung fibroblasts, primary human pulmonary AECs, and A549 cells. Concomitantly, AdTGF-beta 1-induced Smad2 phosphorylation was significantly reduced by AdFGF-1 in both cell types. AdFGF-1 also attenuated the increase in TGF beta R1 protein and mRNA levels in fibroblasts. In AECs, AdFGF-1 decreased TGF beta R1 protein by favouring TGF beta R1 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 beta-SMA-positive areas in IPF lung tissue. Our results demonstrate that FGF-1 may have preventative and therapeutic effects on TGF-beta 1-driven pulmonary fibrosis via inhibiting myofibroblast differentiation, inducing AEC proliferation, regulating TGF-beta 1 signalling by controlling TGF beta R1 expression and degradation, and regulating FGFR1 expression. Thus, modulating FGF-1 signalling represents a potential therapy for the treatment of pulmonary fibrosis. Copyright (C) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.