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

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 E _{2 (}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 (cPLA ₂) and cyclooxygenase-2 (COX-2) messenger RNA expression, PGE ₂ 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 mitogen-activated protein kinase, cPLA₂, COX-2, PGE₂ and JP, which may contribute to the pathogenesis of BA-associated lung injury. BA-related lung inflammation is seldom discussed. This study shows that BA may contribute to an increase in alveolar epithelial permeability in a dose-dependent manner. This process involves upregulation of MAPK, cPLA₂, COX-2 and PGE₂ generation, and decay of occludin, ZO-1 and E-cadherin.