Cyclooxygenase 2 - implications on maintenance of gastric mucosal integrity and ulcer healing: controversial issues and perspectives

Cyclooxygenase (COX), the key enzyme for synthesis of prostaglandins, exist s in two isoforms (COX-1 and COX-2). COX-1 is constitutively expressed in t he gastrointestinal tract in large quantities and has been suggested to mai ntain mucosal integrity through continuous generation of prostaglandins. CO X-2 is induced predominantly during inflammation. On this premise selective COX-2 inhibitors not affecting COX-1 in the gastrointestinal tract mucosa have been developed as gastrointestinal sparing anti-inflammatory drugs. Th ey appear to be well tolerated by experimental animals and humans following acute and chronic (three or more months) administration. However, there is increasing evidence that COX-2 has a greater physiological role than merel y mediating pain and inflammation. Thus gastric and intestinal lesions do n ot develop when COX-1 is inhibited but only when the activity of both COX-1 and COX-2 is suppressed. Selective COX-2 inhibitors delay the healing of e xperimental gastric ulcers to the same extent as non-COX-2 specific non-ste roidal anti-inflammatory drugs (NSAIDs). Moreover, when given chronically t o experimental animals, they can activate experimental colitis and cause in testinal perforation. The direct involvement of COX-2 in ulcer healing has been supported by observations that expression of COX-2 mRNA and protein is upregulated at the ulcer margin in a temporal and spatial relation to enha nced epithelial cell proliferation and increased expression of growth facto rs. Moreover, there is increasing evidence that upregulation of COX-2 mRNA and protein occurs during exposure of the gastric mucosa to noxious agents or to ischaemia-reperfusion. These observations support the concept that CO X-2 represents (in addition to COX-1) a further line of defence for the gas trointestinal mucosa necessary for maintenance of mucosal integrity and ulc er healing.