Chronic microaspiration of bile acids induces lung fibrosis through multiple mechanisms in rats.
Gastroesophageal reflux (GER) and microaspiration of duodenogastric refluxate have been recognized as a risk factor for pulmonary fibrosis. Recent evidence suggests that bile acid microaspiration may contribute to the development of lung fibrosis. However, the molecular evidence is scarce and the underlying mechanisms remain to be elucidated. We have recently demonstrated that bile acids induce activation of alveolar epithelial cells (AECs) and lung fibroblastsin vitroIn the present study, a rat model of bile acid microaspiration was established by weekly intratracheal instillation of three major bile acids including chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), and lithocholic acid (LCA). Repeated microaspiration of CDCA, DCA, and LCA caused fibrotic changes, including alveolar wall thickening and extensive collagen deposition, in rat lungs. Bile acid microaspiration also induced alveolar epithelial-mesenchymal transition (EMT), as indicated by up-regulation of mesenchymal markers α-smooth muscle actin (α-SMA) and vimentin, as well as down-regulaton of epithelial markers E-cadherin and cytokeratin in alveolar epithelium of rat lungs. The expression of fibrogenic mediators, including transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and periostin, was significantly elevated in rat lungs exposed to microaspiration of bile acids. Furthermore, microaspiration of bile acids also induced p-Smad3 and farnesoid X receptor (FXR) expression in rat lungs. Our findings suggest that microaspiration of bile acids could promote the development of pulmonary fibrosisin vivo, possibly via stimulating fibrogenic mediator expression and activating TGF-β1/Smad3 signaling and FXR.
Department of Respiratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.|Department of Respiratory Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, China.
Bi
B
Chen
Department of Respiratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
Wen Jie
WJ
You
Department of Respiratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
Xue Qing
XQ
Liu
Department of Respiratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
Shan
S
Xue
Department of Respiratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
Hui
H
Qin
Department of Respiratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China jianghd@163.com.
Han Dong
HD
Jiang
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002908:Chronic Disease; D003094:Collagen / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005764:Gastroesophageal Reflux / Q000150:complications*; D006801:Humans; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000503:physiopathology; D011658:Pulmonary Fibrosis / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D001647:Bile Acids and Salts; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D055513:Connective Tissue Growth Factor; D003094:Collagen
bile acids; farnesoid X receptor; gastroesophageal reflux; idiopathic pulmonary fibrosis; microaspiration