Pathogenesis of NSAID-induced gastric damage:Importance of cyclooxygenase inhibition and gastric hypermotility

This article reviews the pathogenic mechanism of nonsteroidal anti-inflammatory drug(NSAID)-induced gastric damage,focusing on the relation between cyclooxygenase(COX) inhibition and various functional events.NSAIDs,such as indomethacin,at a dose that inhibits prostaglandin(PG) production,enhance gastric motility,resulting in an increase in mucosal permeability,neutrophil infiltration and oxyradical production,and eventually producing gastric lesions.These lesions are prevented by pretreatment with PGE 2 and antisecretory drugs,and also via an atropine-sensitive mechanism,not related to antisecretory action.Although neither rofecoxib(a selective COX-2 inhibitor) nor SC-560(a selective COX-1 inhibitor) alone damages the stomach,the combined administration of these drugs provokes gastric lesions.SC-560,but not rofecoxib,decreases prostaglandin E 2(PGE 2) production and causes gastric hypermotility and an increase in mucosal permeability.COX-2 mRNA is expressed in the stomach after administration of indomethacin and SC-560 but not rofecoxib.The up-regulation of indomethacin-induced COX-2 expression is prevented by atropine at a dose that inhibits gastric hypermotility.In addition,selective COX-2 inhibitors have deleterious influences on the stomach when COX-2 is overexpressed under various conditions,including adrenalectomy,arthritis,and Helicobacter pylori-infection.In summary,gastric hypermotility plays a primary role in the pathogenesis of NSAID-induced gastric damage,and the response,causally related with PG deficiency due to COX-1 inhibition,occurs prior to other pathogenic events such as increased mucosal permeability;and the ulcerogenic properties of NSAIDs require the inhibition of both COX-1 and COX-2,the inhibition of COX-1 upregulates COX-2 expression in association with gastric hypermotility,and PGs produced by COX-2 counteract the deleterious effect of COX-1 inhibition.