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

Fan Zhang, Nasser K. Altorki, Yu Chung Wu, Robert A. Soslow, Kotha Subbaramaiah, Andrew J. Dannenberg

Research output: Contribution to journalArticlepeer-review

137 Scopus citations


Background & Aims: Reflux of duodenal contents including bile acids is believed to contribute to esophageal injury and Barrett's esophagus. Cyclooxygenase (COX)-2, an inducible form of COX, has been implicated in both inflammation and carcinogenesis. In this study, we investigated the effects of bile acids and duodenal reflux on COX-2 expression in cultured esophageal cells and tissue, respectively. Methods: Immunoblotting and Northern blotting were used to assess the effects of bile acids on COX-2 expression in esophageal cell lines. Immunoblotting and immunohistochemistry were performed to evaluate the effects of duodenal reflux on COX-2 expression and cell proliferation in esophageal tissue. Results: Unconjugated bile acids were about fivefold more potent inducers of COX-2 messenger RNA, COX-2 protein, and prostaglandin synthesis than conjugated bile acids. Acidifying the culture medium sensitized esophageal cells to bile acid-mediated induction of COX-2. The induction of COX-2 by bile acids was mediated by phosphatidylinositol-3 kinase and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases. In experimental animals, duodenoesophageal reflux led to esophagitis, 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 expression and mucosal thickening. Bile acids are likely to contribute to these effects.

Original languageEnglish (US)
Pages (from-to)1391-1399
Number of pages9
Issue number6
StatePublished - 2001

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology


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