Overexpression of farnesoid X receptor in small airways contributes to epithelial to mesenchymal transition and COX-2 expression in chronic obstructive pulmonary disease
Overexpression of farnesoid X receptor in small airways contributes to epithelial to mesenchymal transition and COX-2 expression in chronic obstructive pulmonary disease
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小气道中法尼醇 X 受体的过度表达有助于慢性阻塞性肺疾病的上皮间质转化和 COX-2 表达
DOI：
10.21037/jtd.2016.11.08
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发表时间：
2016-11-01
影响因子：
2.5
通讯作者：
Jiang, Han-Dong
中科院分区：
文献类型：
--
作者：
Chen, Bi;You, Wen-Jie;Jiang, Han-Dong
背景资料：上皮-间质转化（EMT）和环氧合酶-2（考克斯-2）促进慢性阻塞性肺病（COPD）的气道重塑和炎症。最近的数据表明，法尼醇X受体（FXR），一种核受体，传统上被认为是胆汁酸激活受体，也表达在非经典的胆汁酸靶组织与新的功能以外的调节胆汁酸稳态。本研究旨在探讨FXR在COPD发生发展中的潜在作用，以及影响FXR表达的因素。方法：采用免疫组织化学方法检测非吸烟者、吸烟者和吸烟者COPD肺组织中FXR、EMT生物标志物和考克斯-2的表达。体外研究了FXR在TGF-β 1诱导的人支气管上皮细胞EMT和考克斯-2表达中的作用。结果：COPD患者小气道上皮细胞FXR、EMT标记物和考克斯-2的表达明显高于对照组。吸烟者小气道上皮FXR染色积分与FEV1%预测值呈负相关。FXR激动剂GW 4064显著增强TGF-β 1处理的HBE细胞EMT变化，FXR拮抗剂Z-Guggulsterone显著抑制TGF-β 1处理的HBE细胞EMT变化。鹅去氧胆酸（CDCA）和GW 4064均能增加HBE细胞中考克斯-2的表达，而Z-古古固甾酮显著抑制CDCA诱导的考克斯-2表达。结论：COPD大鼠小气道FXR过度表达可能通过调节EMT和考克斯-2的表达而参与气道重塑和炎症反应。
Background: Epithelial-mesenchymal transition (EMT) and cyclooxygenase-2 (COX-2) contribute to airway remodelling and inflammation in chronic obstructive pulmonary disease (COPD). Recent data suggest that the farnesoid X receptor (FXR), a nuclear receptor traditionally considered as bile acid-activated receptor, is also expressed in non-classical bile acids target tissues with novel functions beyond regulating bile acid homeostasis. This study aimed to investigate the potential role of FXR in the development of COPD, as well as factors that affect FXR expression.Methods: Expression of FXR, EMT biomarkers and COX-2 was examined by immunohistochemistry in lung tissues from non-smokers, smokers, and smokers with COPD. The role of FXR in TGF-beta 1-induced EMT and COX-2 expression in human bronchial epithelial (HBE) cells was evaluated in vitro. Factors regulating FXR expression were assessed in cultured HBE cells and a cigarette smoke-induced rat model of COPD.Results: Expression of FXR, EMT markers and COX-2 was significantly elevated in small airway epithelium of COPD patients compared with controls. The staining scores of FXR in small airway epithelium were negatively related with FEV1% of predicted of smokers without and with COPD. FXR agonist GW4064 remarkably enhanced and FXR antagonist Z-Guggulsterone significantly inhibited EMT changes in TGF-beta 1-treated HBE cells. Both chenodeoxycholic acid (CDCA) and GW4064 increased COX-2 expression in HBE cells, whereas Z-Guggulsterone dramatically restrained CDCA-induced COX-2 expression. Finally, FXR expression is induced by IL-4 and IL-13 in HBE cells, as well as by cigarette smoke exposure in a rat model of COPD.Conclusions: Overexpression of FXR in small airway may contribute to airway remodelling and inflammation in COPD by regulating EMT and COX-2 expression.