Role of cyclooxygenase isoforms in gastric mucosal defence

A complex system of interacting mediators exists in the gastric mucosa to s trengthen its resistance against injury. In this system prostaglandins play an important role. Prostaglandin biosynthesis is catalysed by the enzyme c yclooxygenase (COX), which exists in two isoforms, COX-1 and COX-2. Initial ly the concept was developed that COX-I functions as housekeeping enzyme, w hereas COX-2 yields prostaglandins involved in pathophysiological reactions such as inflammation. In the gastrointestinal tract, the maintenance of mu cosal integrity was attributed exclusively to COX-I without a contribution of COX-2 and ulcerogenic effects of non-steroidal anti-inflammatory drugs ( NSAIDs) were believed to be the consequence of inhibition of COX-1. Recent findings, however, indicate that both COX-1 and COX-2 either alone or in co ncert contribute to gastric mucosal defence. Thus, in normal rat gastric mu cosa specific inhibition of COX-1 does not elicit mucosal lesions despite n ear-maximal suppression of gastric prostaglandin formation. When a selectiv e COX-2 inhibitor which is not ulcerogenic when given alone is added to the COX-1 inhibitor, severe gastric damage develops. In contrast to normal gas tric mucosa. which requires simultaneous inhibition of COX-1 and COX-2 for breakdown of mucosal resistance, in the acid-challenged rat stomach inhibit ion of COX-I alone results in dose-dependent injury which is further increa sed by additional inhibition of COX-2 enzyme activity or prevention of acid -induced up-regulation of COX-2 expression by dexamethasone. COX-2 inhibito rs do not damage the normal or acid-challenged gastric mucosa when given al one. However, when nitric oxide formation is suppressed or afferent nerves are defunctionalized, specific inhibition of COX-2 induces severe gastric d amage. Ischemia-reperfusion of the gastric artery is associated with up-reg ulation of COX-2 but not COX-1 mRNA. COX-2 inhibitors or dexamethasone augm ent ischemia-reperfusion-induced gastric damage up to four-fold, an effect abolished by concurrent administration of 16,16-dimethyl-PGE(2).(.) Selecti ve inhibition of COX-1 is less effective. Furthermore, COX-2 inhibitors ant agonize the protective effect of a mild irritant or intragastric peptone pe rfusion in the rat stomach, whereas the protection induced by chronic admin istration of endotoxin is mediated by COX-1. Finally, an important function of COX-2 is the acceleration of ulcer healing. COX-2 is up-regulated in ch ronic gastric ulcers and inhibitors of COX-2 impair the healing of ulcers t o the same extent as non-selective NSAIDs. Taken together, these observatio ns show that both COX isoenzymes are essential factors in mucosal defence w ith specific contributions in various physiological and pathophysiological situations. (C) 2001 Elsevier Science Ltd. All rights reserved.