Bile acids increase alveolar epithelial permeability via mitogen‐activated protein kinase, cytosolic phospholipase A₂, cyclooxygenase‐2, prostaglandin E₂ and junctional proteins

Abstract

Background and objective: Bile acid (BA) aspiration is associated with various lung diseases. It was hypothesized that BA may induce changes in alveolar epithelium permeability and contribute to the pathogenesis of lung injury. Methods: Human alveolar epithelial cells were grown in monolayer and stimulated with a major component of BA, chenodeoxycholic acid (CDCA). Transepithelial electrical resistance (TER) and paracellular fluxes were measured to assess permeability alteration. Prostaglandin E2 (PGE2) production was measured, and its effect on TER and junctional proteins (JP) was also examined. Reverse transcription polymerase chain reaction and Western blots were used to investigate the expression of messenger RNA and JP. Results: CDCA induced significant p38 and c-Jun N-terminal kinase (JNK) phosphorylation, cytosolic phospholipase A2 (cPLA2) and cyclooxygenase-2 (COX-2) messenger RNA expression, PGE2 production, TER reduction and decay of JP (including occludin, zonula occludens-1 (ZO-1) and E-cadherin, in which ZO-1 had maximal change). CDCA also increased paracellular fluxes, which was abolished by dexamethasone. Both CDCA and PGE2 contributed to TER reduction in an identical trend and a dose-response manner. PGE2 also reduced ZO-1 expression, which was similar to that observed by CDCA stimulation. Pretreatment with inhibitors of p38 (SB203580), JNK (SP600125), cPLA2 (mepacrine) and COX-2 (NS398) as well as dexamethasone reversed the CDCA-induced PGE2 production, TER reduction and decay of ZO-1. Conclusions:The increase in alveolar permeability was associated with decay of JP. BA may induce permeability alteration through the upregulation of mitogenactivated protein kinase, cPLA2, COX-2, PGE2 and JP, which may contribute to the pathogenesis of BA-associated lung injury. made equal contributions to this study.

Overexpression of farnesoid X receptor in small airways contributes to epithelial to mesenchymal transition and COX-2 expression in chronic obstructive pulmonary disease

“…Similar to previous reports (6,7), our data also demonstrated the overexpression of COX-2 in small airways of COPD lungs. It has been reported that the bile acid CDCA promotes COX-2 expression in primary human alveolar epithelial cells (11), and FXR mediates bile acid-induced COX-2 expression in esophageal cancer cell lines (34). We further investigated whether bile acid also could induce COX-2 in airway epithelial cells and if FXR was involved in this process.…”

“…Gastroesophageal reflux disease (GERD) is recognized as a potential risk factor for exacerbation of COPD (29) and the bile acid aspiration has been reported to induce lung injury by promoting COX-2 expression in human alveolar epithelial cells (11). Therefore, we next explored whether FXR activation could regulate the bile acid-induced COX-2 expression in HBE cells.…”

“…The levels of COX-2 and PGE 2 are significantly increased in COPD lungs, and the expression of PGE2 is associated with the severity of airflow limitation (6)(7)(8). Several types of lung cells, including airway epithelial cells and lung fibroblasts, are capable of producing COX-2 in response to toxic irritators such as cigarette smoke, bile acid aspiration and bacterial infection (9)(10)(11). Moreover, inhibition of COX-2 or COX-2-induced PGE 2 was shown to attenuate airway inflammation and the development of emphysema in cigarette smoking (CS)-exposed rats (12,13), supporting a role for COX-2 in the pathobiology of COPD.…”

Hepatoprotective impact of the bile acid receptor TGR5

“…The impact of BA on paracellular permeability in pathophysiological conditions has been scarcely studied, and is generally viewed as deleterious, increasing paracellular passage in intestinal 83 and respiratory epithelial cells 84 . However the precise signal transduction mechanisms, in particular the BA receptors involved, were not investigated in these studies.…”

Bile acids induce activation of alveolar epithelial cells and lung fibroblasts through farnesoid X receptor‐dependent and independent pathways

“…Recent data suggest that elevated levels of bile acids and pepsin in bronchoalveolar lavage fluid (BALF) and sputum are effective biomarkers for diagnosis and treatment of gastropulmonary aspiration . Bile acid aspiration has been implicated in lung injury and airway fibrosis . The presence/concentration of bile acids in BALF has been correlated with the degree of lung fibrosis in patients with IPF, suggesting bile acid microaspiration may be an active player in the development and/or progression of IPF.…”