PROSTAGLANDIN-SYNTHASE-1 GENE DISRUPTION IN MICE REDUCES ARACHIDONIC ACID-INDUCED INFLAMMATION AND INDOMETHACIN-INDUCED GASTRIC-ULCERATION

Cyclooxygenases 1 and 2 (COX-1 and COX-2) are key enzymes in prostagla ndin biosynthesis and the target enzymes for the widely used nonsteroi dal anti-inflammatory drugs. To study the physiological roles of the i ndividual isoforms, we have disrupted the mouse Ptgs1 gene encoding CO X-1. Homozygous Ptgs1 mutant mice survive well, have no gastric pathol ogy, and show less indomethacin-induced gastric ulceration than wild-t ype mice, even though their gastric prostaglandin E(2) levels are abou t 1% of wild type. The homozygous mutant mice have reduced platelet ag gregation and a decreased inflammatory response to arachidonic acid, b ut not to tetradecanoyl phorbol acetate. Ptgs1 homozygous mutant femal es mated to homozygous mutant males produce few live offspring. COX-1- deficient mice provide a useful model to distinguish the physiological roles of COX-1 and COX-2.