Pulmonary fibrosis requires cell-autonomous mesenchymal fibroblast growth factor (FGF) signaling
Pulmonary fibrosis requires cell-autonomous mesenchymal fibroblast growth factor (FGF) signaling
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DOI：
10.1074/jbc.m117.791764
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发表时间：
2017-06-23
影响因子：
4.8
通讯作者：
Ornitz, David M.
中科院分区：
文献类型：
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作者：
Guzy, Robert D.;Li, Ling;Ornitz, David M.
特发性肺纤维化（IPF）的特征是进行性肺瘢痕形成，肺功能下降，通常在诊断后3-5年内导致死亡。成纤维细胞生长因子（FGF）信号通路与IPF的发病机制有关；然而，FGF信号传导促进肺纤维化的机制尚不清楚。我们假设成纤维细胞中的FGF受体（FGFR）信号是对博来霉素的纤维化反应所必需的。为了验证这一点，对间充质特异性他莫昔芬诱导FGF受体1、2和3失活的小鼠（Col12-CreER； TCKO小鼠）进行谱系标记并气管内给予博来霉素。收集肺进行组织学分析，全肺RNA和蛋白，并分离进行流式细胞术和流式细胞术。Bleomycin-treated Col12-CreER;与对照组相比，TCKO小鼠肺纤维化减少，胶原蛋白生成减少，平滑肌肌动蛋白阳性（SMA+）肌成纤维细胞减少。新鲜分离的Col12-CreER；与野生型间充质细胞相比，博莱霉素处理小鼠的TCKO间充质细胞胶原表达降低。此外，谱系标记的fgfr缺陷成纤维细胞在纤维化区域的富集减少，增殖减少。这些数据确定了在肺纤维化发展过程中间充质FGFR信号的细胞自主需求，以及在博来霉素暴露后纤维化组织中Col12- creer阳性（Col12+）间充质谱系的富集。我们得出结论，间充质FGF信号是肺纤维化发展所必需的，直接针对间充质FGF信号的治疗策略可能有益于IPF的治疗。
Idiopathic pulmonary fibrosis (IPF) is characterized by progressive pulmonary scarring, decline in lung function, and often results in death within 3-5 five years after diagnosis. Fibroblast growth factor (FGF) signaling has been implicated in the pathogenesis of IPF; however, the mechanism through which FGF signaling contributes to pulmonary fibrosis remains unclear. We hypothesized that FGF receptor (FGFR) signaling in fibroblasts is required for the fibrotic response to bleomycin. To test this, mice with mesenchyme-specific tamoxifen-inducible inactivation of FGF receptors 1, 2, and 3 (Col12-CreER; TCKO mice) were lineage labeled and administered intratracheal bleomycin. Lungs were collected for histologic analysis, whole lung RNA and protein, and dissociated for flow cytometry and FACS. Bleomycin-treated Col12-CreER; TCKO mice have decreased pulmonary fibrosis, collagen production, and fewer -smooth muscle actin-positive (SMA+) myofibroblasts compared with controls. Freshly isolated Col12-CreER; TCKO mesenchymal cells from bleomycin-treated mice have decreased collagen expression compared with wild type mesenchymal cells. Furthermore, lineage labeled FGFR-deficient fibroblasts have decreased enrichment in fibrotic areas and decreased proliferation. These data identify a cell autonomous requirement for mesenchymal FGFR signaling in the development of pulmonary fibrosis, and for the enrichment of the Col12-CreER-positive (Col12+) mesenchymal lineage in fibrotic tissue following bleomycin exposure. We conclude that mesenchymal FGF signaling is required for the development of pulmonary fibrosis, and that therapeutic strategies aimed directly at mesenchymal FGF signaling could be beneficial in the treatment of IPF.