Université Paris Cité, Institut National de la Santé et de la Recherche Médicale, UMR1152, FHU APOLLO, Labex INFLAMEX, Faculté de médecine Xavier Bichat, Paris, France.
Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, United States.
Am J Physiol Lung Cell Mol Physiol. 2024 Dec 1;327(6):L818-L830. doi: 10.1152/ajplung.00184.2023. Epub 2024 Oct 1.
Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with limited therapeutic options. Fibroblast growth factor receptor-4 (FGFR4) is a known receptor for several paracrine fibroblast growth factors (FGFs). FGFR4 is also the main receptor for FGF19, an endocrine FGF that was demonstrated by our group to have antifibrotic properties in the lung. We aimed to determine whether FGFR4 could modulate pulmonary fibrogenesis. We assessed FGFR4 mRNA and protein levels in IPF and control lungs. In vitro, we determined the effect of transforming growth factor-β (TGF-β), endothelin-1, and platelet-derived growth factor (PDGF) on FGFR4 expression in human lung fibroblasts. We determined the effect of FGFR4 inhibition, using a specific pharmacological inhibitor (FGF401), or genetic deletion in murine embryonic fibroblasts (MEFs) on TGF-β-induced myofibroblastic differentiation. In vivo, we evaluated the development of bleomycin-induced lung fibrosis in -deficient () mice compared with wild-type littermates (WT) and after FGF401 treatment in WT mice compared with a control group receiving the solvent only. FGFR4 was decreased in IPF lungs, as compared with control lungs, at mRNA and protein levels. In vitro, FGFR4 was downregulated after treatment with TGF-β, endothelin-1, and PDGF. In vitro, FGFR4 inhibition by FGF401 prevented TGF-β1-induced collagen and ACTA2 increase in lung fibroblasts. Similar results were observed in MEFs. In vivo, FGFR4 genetic deficiency or FGFR4 pharmacological inhibition did not modulate bleomycin-induced pulmonary fibrosis. Our data suggest that FGFR4 exerts profibrotic properties by enhancing TGF-β signaling in vitro. However, the inhibition of FGFR4 is not sufficient to prevent the development of pulmonary fibrosis in vivo. FGFR4 has been reported to have antifibrotic effects in the liver. We aimed to determine the involvement of FGFR4 during IPF. Our data suggest that FGFR4 exerts profibrotic properties by enhancing TGF-β signaling in vitro. However, the inhibition of FGFR4 is not sufficient to prevent the development of pulmonary fibrosis in vivo. To our knowledge, this is the first study to assess the profibrotic action of FGFR4 during pulmonary fibrosis.
特发性肺纤维化（IPF）是一种具有有限治疗选择的破坏性肺部疾病。成纤维细胞生长因子受体 4（FGFR4）是几种旁分泌成纤维细胞生长因子（FGF）的已知受体。FGFR4 也是内分泌 FGF19 的主要受体，我们的研究小组已经证明 FGF19 在肺部具有抗纤维化特性。我们旨在确定 FGFR4 是否可以调节肺纤维化。我们评估了 IPF 和对照肺中的 FGFR4 mRNA 和蛋白水平。在体外，我们确定了转化生长因子-β（TGF-β）、内皮素-1 和血小板衍生生长因子（PDGF）对人肺成纤维细胞中 FGFR4 表达的影响。我们确定了使用特定的药理学抑制剂（FGF401）或在鼠胚胎成纤维细胞（MEF）中基因缺失对 FGFR4 抑制对 TGF-β诱导的肌成纤维细胞分化的影响。在体内，我们评估了与野生型同窝仔（WT）相比，缺乏（）小鼠中博来霉素诱导的肺纤维化的发展，以及在 WT 小鼠中与仅接受溶剂的对照组相比，FGF401 治疗后的发展。与对照肺相比，IPF 肺中的 FGFR4 在 mRNA 和蛋白水平上均降低。在体外，用 TGF-β、内皮素-1 和 PDGF 处理后，FGFR4 下调。在体外，FGF401 通过 FGFR4 抑制可防止 TGF-β1 诱导的肺成纤维细胞中胶原和 ACTA2 的增加。在 MEF 中也观察到类似的结果。在体内，FGFR4 遗传缺失或 FGFR4 药理学抑制均不能调节博来霉素诱导的肺纤维化。我们的数据表明，FGFR4 通过增强 TGF-β 信号在体外发挥促纤维化作用。然而，FGFR4 的抑制不足以防止体内肺纤维化的发展。FGFR4 已被报道在肝脏中具有抗纤维化作用。我们旨在确定 FGFR4 在 IPF 中的参与情况。我们的数据表明，FGFR4 通过增强 TGF-β 信号在体外发挥促纤维化作用。然而，FGFR4 的抑制不足以防止体内肺纤维化的发展。据我们所知，这是第一项评估 FGFR4 在肺纤维化过程中促纤维化作用的研究。
