Bile acids induce activation of alveolar epithelial cells and lung fibroblasts through farnesoid X receptor-dependent and independent pathways
Bile acids induce activation of alveolar epithelial cells and lung fibroblasts through farnesoid X receptor-dependent and independent pathways
复制标题
胆汁酸通过法尼醇 X 受体依赖性和独立途径诱导肺泡上皮细胞和肺成纤维细胞的活化
DOI：
10.1111/resp.12815
复制
发表时间：
2016-08-01
期刊：
影响因子：
6.9
通讯作者：
Jiang, Han-Dong
中科院分区：
文献类型：
--
作者：
Chen, Bi;Cai, Hou-Rong;Jiang, Han-Dong
背景与目的胆汁酸微抽吸和胆汁酸激活的法尼酯X受体（FXR）在特发性肺纤维化（IPF）发病机制中的作用尚不清楚。我们假设，胆汁酸激活肺泡上皮细胞（AECs）和肺成纤维细胞，这可能是由FXR activation.MethodsHuman AECs和正常或IPF衍生的肺成纤维细胞与三种主要的胆汁酸：石胆酸（LCA），脱氧胆酸（DCA）和鹅脱氧胆酸（CDCA）孵育。观察肺动脉内皮细胞损伤指数、上皮-间质转化（EMT）和肺成纤维细胞活化情况。IPF肺FXR表达和胆汁酸诱导的profibrotic effects的FXR和FXR-独立途径的作用也investigated.ResultsLCA，DCA和CDCA降低细胞活力和增加细胞内活性氧（ROS）在A549细胞的生产。它们都诱导EMT，如增强的SMA和波形蛋白和降低的E-钙粘蛋白水平所示。LCA直接诱导肺成纤维细胞分化为肌成纤维细胞。所有三种胆汁酸促进细胞迁移，但不是肺成纤维细胞的增殖。IPF肺组织中FXR表达上调，抑制FXR可抑制胆汁酸诱导的EMT和肺成纤维细胞活化。暴露于胆汁酸刺激的A549细胞的条件培养基中的肺成纤维细胞的分化和增殖增强，其中含有增加水平的促纤维化因子。结论胆汁酸微抽吸可能通过FXR依赖和非依赖途径诱导AECs和肺成纤维细胞活化，促进肺纤维化的发生发展，探讨胆汁酸微抽吸和FXR在肺纤维化发生发展中的作用激活在特发性肺纤维化的发病机制中的作用，并证明胆汁酸可以通过FXR依赖性和非依赖性机制诱导肺泡上皮细胞和肺成纤维细胞的激活。
Background and objectiveThe roles of bile acid microaspiration and bile acid-activated farnesoid X receptor (FXR) in the pathogenesis of idiopathic pulmonary fibrosis (IPF) remain unclear. We hypothesized that bile acids activate alveolar epithelial cells (AECs) and lung fibroblasts, which may be regulated by FXR activation.MethodsHuman AECs and normal or IPF-derived lung fibroblast cells were incubated with the three major bile acids: lithocholic acid (LCA), deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA). The AECs injury indices, epithelial-mesenchymal transition (EMT) and lung fibroblast activation were evaluated. FXR expression in IPF lungs and the roles of FXR and FXR-independent pathways in bile acid-induced profibrotic effects were also investigated.ResultsLCA, DCA and CDCA reduced cell viability and increased intracellular reactive oxygen species (ROS) production in A549 cells. They all induced EMT, as shown by enhanced -SMA and vimentin and decreased E-cadherin levels. LCA directly induced differentiation of lung fibroblasts to myofibroblasts. All three bile acids promoted cellular migration but not proliferation of lung fibroblasts. FXR expression was upregulated in IPF lungs, and inhibition of FXR restrained the bile acid-induced EMT and lung fibroblast activation. Differentiation and proliferation were enhanced in lung fibroblasts exposed to conditioned medium from bile acid-stimulated A549 cells, which contained increased levels of profibrotic factors. TGF-/Smad3 signaling was also involved in the bile acid-induced EMT and lung fibroblast differentiation.ConclusionBile acid microaspiration may promote the development of pulmonary fibrosis by inducing activation of AECs and lung fibroblasts via FXR-dependent and independent pathways.This study explores the role of bile acid microaspiration and Farnesoid X receptor (FXR) activation in the pathogenesis of idiopathic pulmonary fibrosis and demonstrates that bile acids could induce activation of alveolar epithelial cells and lung fibroblasts via FXR-dependent and independent mechanisms.