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 myofibroblast, 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 antifibrogenic 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 TGFβRI protein and mRNA levels in fibroblasts. In AECs, AdFGF-1 decreased TGFβRI protein by favouring TGFβRI 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 AECs 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 AECs proliferation, regulating TGF-β1 signalling by controlling TGFβRI expression and degradation, and regulating FGFR1 expression. Thus, modulating FGF-1 signalling represents a potential therapy for the treatment of pulmonary fibrosis.

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