Limited anti-inflammatory efficacy of cyclo-oxygenase-2 inhibition in carrageenan-airpouch inflammation
Version of Record online: 29 JAN 2009
1999 Nature Publishing Group
British Journal of Pharmacology
Volume 126, Issue 5, pages 1200–1204, March 1999
How to Cite
Wallace, J. L., Chapman, K. and McKnight, W. (1999), Limited anti-inflammatory efficacy of cyclo-oxygenase-2 inhibition in carrageenan-airpouch inflammation. British Journal of Pharmacology, 126: 1200–1204. doi: 10.1038/sj.bjp.0702420
- Issue online: 29 JAN 2009
- Version of Record online: 29 JAN 2009
- (Received October 7, 1998, Revised November 23, 1998, Accepted December 15, 1998)
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.
Indomethacin (0.3 mg kg−1), nimesulide (3 mg kg−1) and the selective COX-2 inhibitor, SC-58125 (0.3 mg kg−1), significantly suppressed the production of prostaglandin E2 at the site of inflammation. At higher doses, indomethacin (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).
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.
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 PGE2 levels without significant effects on leukocyte infiltration.
These results indicate that selective inhibition of COX-2 results in profound suppression of PGE2 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.
British Journal of Pharmacology (1999) 126, 1200–1204; doi:10.1038/sj.bjp.0702420