Duodenal reflux induces cyclooxygenase-2 in the esophageal mucosa of rats:Evidence for involvement of bile acids

Background & Aims: Reflux of duodenal contents including bile acids is beli eved to contribute to esophageal injury and Barrett's esophagus. Cyclooxyge nase (COX)-2, an inducible form of COX, has been implicated in both inflamm ation and carcinogenesis. In this study, we investigated the effects of bil e acids and duodenal reflux on COX-2 expression in cultured esophageal cell s and tissue, respectively. Methods: Immunoblotting and Northern blotting w ere used to assess the effects of bile acids on COX-2 expression in esophag eal cell lines. Immunoblotting and immunohistochemistry were performed to e valuate the effects of duodenal reflux on COX-2 expression and cell prolife ration in esophageal tissue. Results: Unconjugated bile acids were about fi vefold more potent inducers of COX-2 messenger RNA, COX-2 protein, and pros taglandin synthesis than conjugated bile acids. Acidifying the culture medi um sensitized esophageal cells to bile acid-mediated induction of COX-2. Th e induction of COX-2 by bile acids was mediated by phosphatidylinositol-3 k inase and extracellular signal-regulated kinase 1/2 mitogen-activated prote in kinases. In experimental animals, duodenoesophageal reflux led to esopha gitis, marked thickening of the esophageal mucosa, and enhanced expression of COX-2. Increased immunoreactivity for Ki-67 and cyclin D1 indicated that enhanced cell proliferation contributed to mucosal thickening. Conclusions : Reflux of duodenal contents into the esophagus led to increased COX-2 exp ression and mucosal thickening. Bile acids are likely to contribute to thes e effects.