Duodenal reflux induces cyclooxygenase-2 in the esophageal mucosa of rats: evidence for involvement of bile acids.
OBJECTIVE
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.
Zhang
F
F
Department of Cardiothoracic Surgery, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.
Altorki
N K
NK
Wu
Y C
YC
Soslow
R A
RA
Subbaramaiah
K
K
Dannenberg
A J
AJ
D000818:Animals; D001647:Bile Acids and Salts / Q000502:physiology; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D051546:Cyclooxygenase 2; D004383:Duodenogastric Reflux / Q000150:complications / Q000201:enzymology*; D004790:Enzyme Induction; D004947:Esophagus / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D005764:Gastroesophageal Reflux / Q000150:complications / Q000201:enzymology / Q000473:pathology; D005999:Glycochenodeoxycholic Acid / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D009092:Mucous Membrane / Q000187:drug effects / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011453:Prostaglandins / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D001647:Bile Acids and Salts; D007527:Isoenzymes; D011453:Prostaglandins; D002635:Chenodeoxycholic Acid; D005999:Glycochenodeoxycholic Acid; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D019869:Phosphatidylinositol 3-Kinases