Limited anti-inflammatory efficacy of cyclo-oxygenase-2 inhibition in carrageenan-airpouch inflammation

1 Cyclo-oxygenase-2 (COX-2) is expressed at sites of inflammation and is believed to be the major source of inflammation-associated prostaglandin synthesis. Selective inhibition of COX-2 has been suggested to produce anti-inflammatory effects with reduced toxicity in the gastrointestinal tract. We examined the extent to which suppression of COX-2 led to inhibition of various components of inflammation in the carrageenan-airpouch model in the rat. 2 Indomethacin (greater than or equal to 0.3 mg kg(-1)), nimesulide (greater than or equal to 3 mg kg(-1)) and the selective COX-2 inhibitor, SC-58125 (greater than or equal to 0.3 mg kg(-1)), significantly suppressed the production of prostaglandin E2 at the site of inflammation. At higher doses, indomethacin (greater than or equal to 1 mg kg(-1)) and nimesulide (30 mg kg(-1)), but not SC-58125 (up to 10 mg kg(-1)), significantly inhibited COX-1 activity (as measured by whole blood thromboxane synthesis). 3 All three test drugs significantly reduced the volume of exudate in the airpouch, but only at doses greater than those required for substantial (>90%) suppression of COX-2 activity. Similarly, reduction of leukocyte infiltration was only observed with the doses of indomethacin and nimesulide that caused significant suppression of COX-1 activity. 4 SC-58125 did not significantly affect leukocyte infiltration into the airpouch at any dose tested (up to 10 mg kg(-1)). A second selective COX-2 inhibitor, Dup-697, was also found to suppress exudate PGE(2) levels without significant effects on leukocyte infiltration. 5 These results indicate that selective inhibition of COX-2 results in profound suppression of PGE(2) synthesis in the carrageenan-airpouch, but does not affect leukocyte infiltration. Exudate volume was only reduced with the highly selective COX-2 inhibitor when a dose far above that necessary for suppression of COX-2 activity was used. Inhibition of leukocyte infiltration was observed with indomethacin and nimesulide, but only at doses that inhibited both COX-1 and COX-2.