Fibroblast growth factor-1 attenuates TGF-β1-induced lung fibrosis
Fibroblast growth factor-1 attenuates TGF-β1-induced lung fibrosis
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DOI：
10.1002/path.4768
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发表时间：
2016-10-01
影响因子：
7.3
通讯作者：
Kolb, Martin
中科院分区：
文献类型：
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作者：
Shimbori, Chiko;Bellaye, Pierre-Simon;Kolb, Martin
特发性肺纤维化（IPF）的特征是成纤维细胞和肌成纤维细胞的进行性增殖，以及细胞外基质（ECM）的广泛沉积。成纤维细胞生长因子-1 （FGF-1）属于FGF家族，已被证明可以抑制成纤维细胞胶原的产生和向肌成纤维细胞的分化，并通过抑制tgf - β信号通路恢复上皮-间质转化。然而，FGF-1在肺纤维化中的确切作用尚未阐明。在这项研究中，我们通过使用腺病毒载体长时间过表达FGF-1 （AdFGF-1）和tgf - β (adtgf - β)，探索FGF-1在体外和体内抗肺纤维化作用的机制。在体内，当同时或延迟给予FGF-1过表达时，通过增强肺泡上皮细胞（AECs）的增殖和增生，可显著减轻大鼠肺中tgf - β诱导的肺纤维化。AdFGF-1还能减弱tgf - β 1信号通路并诱导aec中的FGFR1表达。在体外，adtgf -1可阻止adtgf -1诱导的正常人肺成纤维细胞、原代人肺AECs和A549细胞中β - sma的增加和E-cadherin的减少。同时，adtgf -1诱导的Smad2磷酸化在两种细胞类型中均被adtgf -1显著降低。AdFGF-1还能减弱成纤维细胞中TGF β R1蛋白和mRNA水平的升高。在AECs中，AdFGF-1通过小窝蛋白-1/蛋白酶体途径促进TGF β R1降解，从而降低TGF β R1蛋白。此外，FGFR1在aec中的表达增加，而在成纤维细胞中的表达减少。在IPF患者的血清中，与对照组相比，FGF-1水平升高。有趣的是，FGF-1的表达仅限于AEC增生区域，而不是IPF肺组织中β - sma阳性区域。我们的研究结果表明，FGF-1可能通过抑制肌成纤维细胞分化、诱导AEC增殖、通过控制TGF β R1表达和降解调节TGF β 1信号传导、调节FGFR1表达，对TGF β 1驱动的肺纤维化具有预防和治疗作用。因此，调节FGF-1信号是治疗肺纤维化的一种潜在疗法。版权所有2016年英国和爱尔兰病理学会。约翰·威利父子有限公司出版。
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.