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

Abstract

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.

• Authors: F Zhang, N K Altorki, Y C Wu, R A Soslow, K Subbaramaiah, A J Dannenberg
• Journal: Gastroenterology (Gastroenterology) Vol. 121 Issue 6 Pg. 1391-9 (Dec 2001) ISSN: 0016-5085 [Print] United States
• PMID: 11729118 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bile Acids and Salts
• Isoenzymes
• Prostaglandins
• Chenodeoxycholic Acid
• Glycochenodeoxycholic Acid
• Cyclooxygenase 2
• Prostaglandin-Endoperoxide Synthases
• Phosphatidylinositol 3-Kinases

Topics

• Animals
• Bile Acids and Salts (physiology)
• Chenodeoxycholic Acid (pharmacology)
• Cyclooxygenase 2
• Duodenogastric Reflux (complications, enzymology)
• Enzyme Induction
• Esophagus (drug effects, enzymology, pathology)
• Gastroesophageal Reflux (complications, enzymology, pathology)
• Glycochenodeoxycholic Acid (pharmacology)
• Isoenzymes (metabolism)
• Male
• Mucous Membrane (drug effects, enzymology)
• Phosphatidylinositol 3-Kinases (physiology)
• Prostaglandin-Endoperoxide Synthases (metabolism)
• Prostaglandins (biosynthesis)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction
• Tumor Cells, Cultured