FXR调控EMT和肺成纤维细胞活化参与肺纤维化的机制研究

Pulmonary fibrosis refers to a group of progressive and lethal lung diseases with various etiologies, which is characterized by excessive accumulation of extracellular matrix (ECM) proteins. Epithelial-to-mesenchymal transition (EMT) and lung fibroblast activation are the two key events in the pathogenesis of pulmonary fibrosis. However, the underlying mechanisms of alveolar EMT and lung fibroblast activation remain unclear. Emerging evidence suggests that farnesoid X receptor (FXR) is expressed in non-classical bile acids target tissues where it exerts novel functions beyond their traditional roles. However, to date, the potential role of FXR in pulmonary fibrosis remains largely unclear. Our previous study has demonstrated that FXR was upregulated in hyperplastic type II alveolar epithelial cells and interstitial fibroblasts of lungs from patients with idiopathic pulmonary fibrosis. We hypothesize that FXR activation may contribute to the development and progression of pulmonary fibrosis by regulating EMT and lung fibroblast activation. In this study, multiple cell lines, as well as rodent models of experimental lung fibrosis, are used to explore the effect of FXR on alveolar EMT and fibroblast activation, as well as the underlying molecular mechanisms in vitro and in vivo. On the basis of this, the role of FXR in the pathogenesis and progression of pulmonary fibrosis will be further elucidated. Successful completion of this study not only provides a new insight into the pathogenesis of pulmonary fibrosis, but also leads to a better clinical prevent and treatment of pulmonary fibrosis.

肺纤维化是一组多种病因引起的进展性和致死性肺部疾病，以细胞外基质蛋白过度沉积为特征。上皮-间充质转化(EMT) 和肺成纤维细胞活化是肺纤维化发病机制中的两大关键环节，但其分子调控机制不明。近年研究发现，法尼酯X受体 (FXR) 在“非经典”胆汁酸靶器官上表达，发挥新的功能，但在肺纤维化中的作用知之甚少。我们前期研究发现，FXR在特发性肺纤维化肺组织中的Ⅱ型肺泡上皮细胞和间质成纤维细胞灶中表达上调，而且FXR的激活能够影响肺泡上皮细胞EMT和肺成纤维细胞的活化。因此我们推测FXR通过调控肺泡上皮细胞EMT和肺成纤维细胞的活化，参与肺纤维化的发生发展。本课题从“肺泡上皮细胞EMT”和“肺成纤维细胞活化”入手，在体内体外进一步明确FXR在肺纤维化发生发展中的作用，并深入剖析FXR调控肺纤维化发病的分子生物学机制。本研究将从新的视角阐释肺纤维化的发病机制，为肺纤维化的有效防治提供新的思路。

近年研究发现法尼酯X受体(FXR)在“非经典”胆汁酸靶器官上发挥新的功能，但对其在肺纤维化中的作用研究甚少。本课题组前期研究发现，FXR在特发性肺纤维化患者Ⅱ型肺泡上皮细胞和间质成纤维细胞灶中表达上调，而且FXR的激活能够影响肺泡上皮细胞EMT和肺成纤维细胞的活化，提示FXR可能肺纤维化发病的关键作用分子，其调控作用和机制需要深入阐明。本项目从“EMT”和“肺成纤维细胞活化”这两个肺纤维化发病机制的关键环节入手，在体内体外水平进一步探讨FXR参与肺纤维化发病的作用及其分子调控机制。利用IPF组织标本和肺纤维化动物模型研究发现，纤维化肺组织中FXR表达水平明显升高。肺泡上皮细胞及肺成纤维细胞表达的FXR可被纤维化因子TGF-β1激活，提示FXR的功能性表达参与了肺纤维化的进程。在肺泡上皮细胞及肺成纤维细胞模型中，证实了FXR是参与肺泡上皮细胞EMT和肺成纤维细胞活化的关键因子。功能研究显示，FXR通过调控TGF-β受体表达及其下游经典Smad通路和非经典通路的活化，介导了TGF-β1诱导的EMT和肺成纤维细胞活化效应。进一步在FXR基因敲除小鼠模型和FXR抑制剂FXR抑制剂干预的肺纤维化小鼠模型中，从体内水平证实了抑制FXR的激活或表达能够抑制肺泡上皮EMT和肺成纤维细胞活化，减轻肺纤维化。本项目研究结果为深入阐明肺纤维化的发病机制，寻找防治肺纤维化的有效策略，提供了新的思路。