Role of cyclooxygenase-2 in gastric mucosal defense

Two isoenzymes of cyclooxygenase (COX), the key enzyme in prostaglandin (PG ) biosynthesis, COX-1 and COX-2, have been identified. COX-1 was proposed t o reg late physiological functions, COX-2 to mediate pathophysiological rea ctions such as inflammation. In particular, it was suggested that maintenan ce of gastric mucosal integrity relies exclusively on COX-1. Recently, it w as shown that a selective COX-I inhibitor does not damage the mucosa in the healthy rat stomach, although mucosal prostaglandin formation is near-maxi mally suppressed. However, concurrent treatment with a COX-1 and a COX-2 in hibitor induces severe gastric damage. This indicates that in normal mucosa both COX-1 and COX-2 have to be inhibited to evoke ulcerogenic effects. In the acid-challenged rat stomach inhibition of COX-1 alone is associated wi th dose-dependent injury which is aggravated by additional inhibition of CO X-2 activity or prevention of acid-induced up-regulation of COX-2 expressio n by dexamethasone. After acid exposure, COX-2 inhibitors cause substantial gastric injury when nitric oxide formation is suppressed or afferent nerve s are defunctionalized. Ischemia-reperfusion of the gastric artery increase s levels of COX-2 but not COX-1 mRNA. COX-2 inhibitors or dexamethasone agg ravate ischemia-reperfusion-induced mucosal damage up to 4-fold, an effect abolished by concurrent administration of 16,16-dimethyl-PGE(2). Furthermor e, the protective effects elicited by a mild irritant or intragastric pepto ne perfusion are antagonized by COX-2 inhibitors. Finally, COX-2 expression is increased in experimental ulcers. COX-2 inhibitors delay the healing of chronic gastric ulcers in experimental animals and decrease epithelial cel l proliferation, angiogenesis and maturation of the granulation tissue to t he same extent as non-steroidal anti-inflammatory drugs. These observations indicate that, in contrast to the initial concept, COX-2 plays an importan t role in gastric mucosal defense. (C) 2001 Elsevier Science Inc. All right s reserved.