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The prostaglandin endoperoxide H synthase isoform 2, cyclooxygenase 2 (COX-2), is induced at high levels in migratory and other responding cells by pro-inflammatory stimuli. COX-2 is generally considered to be a mediator of inflammation. Its isoform, COX-1, is constitutively expressed in most tissues and is thought to mediate "housekeeping" functions. These two enzymes are therapeutic targets of the widely used nonsteroidal anti-inflammatory drugs (NSAIDs). To investigate further the different physiologic roles of these isoforms, we have used homologous recombination to disrupt the mouse gene encoding COX-2 (Ptgs2). Mice lacking COX-2 have normal inflammatory responses to treatments with tetradecanoyl phorbol acetate or with arachidonic acid. However, they develop severe nephropathy and are susceptible to peritonitis.

Cyclooxygenases 1 and 2 (COX-1 and COX-2) are key enzymes in prostaglandin biosynthesis and the target enzymes for the widely used nonsteroidal anti-inflammatory drugs. To study the physiological roles of the individual isoforms, we have disrupted the mouse Ptgs1 gene encoding COX-1. Homozygous Ptgs1 mutant mice survive well, have no gastric pathology, and show less indomethacin-induced gastric ulceration than wild-type mice, even though their gastric prostaglandin E2 levels are about 1% of wild type. The homozygous mutant mice have reduced platelet aggregation and a decreased inflammatory response to arachidonic acid, but not to tetradecanoyl phorbol acetate. Ptgs1 homozygous mutant females 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.

Prostaglandins and their precursorsSince the discovery in 1991 of a second isoform of prostaglandin endoperoxide H synthase (PGHS, or cyclooxygenase), there has been considerable interest in the question of why two isoforms of this enzyme are necessary and what roles they might play. PGHS-1-deficient (1) and PGHS-2-deficient (2, 3) mice and isoform-specific inhibitors have been developed and used to investigate the physiological functions of PGHS-1 and PGHS-2. These studies suggest that there are processes in which each isozyme is uniquely involved (e.g., platelet aggregation for PGHS-1, ovulation for PGHS-2) and others in which both isozymes function coordinately (e.g., carcinogenesis, inflammation). There are also physiological events in which one PGHS isozyme normally functions but for which the other can compensate when the first is lacking (e.g., parturition and remodeling of the ductus arteriosus). Biochemical studies indicate that each isoform can function independently; namely, that there are distinct PGHS-1 and PGHS-2 prostanoid biosynthetic pathways. Thus, the unique physiological roles for each isozyme can be rationalized by what is known about the biochemistry of the enzymes.To facilitate discussion of the physiological functions of PGHS-1 and PGHS-2 and to point out those functions for which PGHS-1 and PGHS-2 can substitute for one another, we describe the following in sequence: (a) physiological processes that depend solely or primarily on PGHS-1, (b) physiological processes that depend solely or primarily on PGHS-2, and (c) processes in which both PGHS-1 and PGHS-2 are involved and act coordinately. We then summarize the biochemical evidence for distinct PGHS-1 and PGHS-2 biosynthetic pathways.

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