Potential adverse effects of cyclooxygenase-2 inhibition: Evidence from animal models of inflammation

Cyclooxygenase (COX; prostaglandin H synthase, prostaglandin endoperoxidase ) is the key enzyme in the synthesis of the prostaglandin and thromboxane f amilies of eicosanoid mediators, and is the target for the nonsteroidal ant i inflammatory drugs (NSAIDs). The identification of an inducible COX isofo rm, COX-2, and the demonstration of its specific expression at sites of inf lammation suggested that it may provide a useful therapeutic target for nov el anti-inflammatory drugs. Inhibition of an enzyme that is not expressed i n most healthy tissues would potentially avoid most of the adverse effects associated with NSAIDs, which target a constitutively expressed isoform, CO X-1. The development of novel 'super aspirins' with high selectivity toward s the inhibition of COX-2 showed that this hypothesis was well-founded and that high levels of these drugs could be tolerated without these serious ad verse effects. The first two of these new generation NSAIDs, celecoxib and rofecoxib, are now in clinical use. More recently, however, concern has been expressed that COX-2 inhibition ma y in fact have a number of potential, previously hidden, pitfalls. These ha ve arisen from the demonstration that COX-2 induction is not exclusively as sociated with the onset of an inflammatory reaction, with expression limite d to inflammatory sites. In fact, COX-2 is expressed more chronically, and is also seen during the resolution of inflammation and in areas of wound-he aling. The application of COX-2-selective inhibitors during these periods h as been shown to be deleterious in that resolution of inflammation is delay ed, gastric ulcer healing is delayed and, in some patients, ulcers have bee n shown to progress further to perforation. The suggestion has now been mad e that, in these situations, COX-2 may help resolve the pathology, perhaps by generating alternative series of prostaglandins such as the cyclopenteno ne prostaglandins. The finding that, these prostaglandins can affect protei ns by direct chemical modifications as well as having their own receptor fa milies has rekindled debate on the deleterious and beneficial effects of pr ostanoids, and the implications of inhibiting the production of these media tors, in the body Therefore, in this review we discuss the role of COX-2 in inflammation and the potential adverse effects of its inhibition.