CYCLOOXYGENASE-1 CONTRIBUTES TO INFLAMMATORY RESPONSES IN RATS AND MICE - IMPLICATIONS FOR GASTROINTESTINAL TOXICITY

Background & Aims: Selective inhibitors of cyclooxygenase (COX)-2 are being developed as gastrointestinal-sparing anti-inflammatory drugs ba sed on the premise that this isoform is solely responsible for prostag landin synthesis at sites of inflammation, whereas COX-1 produces pros taglandins important for maintenance of mucosal integrity. We investig ated the relationship between suppression of inflammation by COX-2 inh ibitors (NS-398, nimesulide, DuP697, and etodolac) and their effects o n gastric prostaglandin synthesis. Methods: Effects of pretreatment of rats with drugs with a range of in vitro selectivity for COX-2 vs. CO X-1 on carrageenan-induced paw inflammation were assessed, along with extent of suppression of COX-1 and COX-2. The role of COX-1 in inflamm ation was also assessed in COX-2-deficient mice. Results: Significant anti-inflammatory effects were only observed at doses of the drugs tha t inhibited COX-1. At these doses, the drugs also significantly suppre ssed gastric prostaglandin synthesis and elicited gastric mucosal eros ions. The degree of suppression of prostaglandin synthesis at the site of inflammation correlated significantly with inhibition of COX-1 but not COX-2. Conclusions: COX-1 makes an important contribution to infl ammatory responses. To achieve desirable anti-inflammatory effects, CO X-2 inhibitors needed to be given at doses in which selectivity was lo st, leading to suppression of gastric prostaglandin synthesis and to m ucosal injury.