Influence of the anti-inflammatory compound flosulide on granulocyte function

Abstract

Polymorphonuclear leukocytes (PMN) are involved in inflammatory reactions. It is thought that oxygen-derived free radicals released from activated PMN may participate in tissue damage during inflammation. We have shown that flosulide (6-(2,4-difluorophenoxy)-5-methylsulfonylamino-1-indanone ), a novel highly potent anti-inflammatory compound, inhibits superoxide production induced by N-formyl-Met-Leu-Phe (FMLP), C5a and PMA without impairing bacterial killing or chemotaxis. Flosulide (10(-5)-10(-7) M) was more potent in inhibiting the FMLP-induced respiratory burst of PMN than the structurally related compound nimesulide. FMLP-induced superoxide generation was also inhibited by two human flosulide metabolites. A good correlation between this in vitro effect and in vivo anti-inflammatory potency in rat adjuvant arthritis was found for flosulide and its metabolites. Indomethacin, piroxicam and ibuprofen did not inhibit the respiratory burst at 10(-5) M. FMLP receptor number was decreased by 36% in the presence of 10(-5) M flosulide. However, a 250-fold molar excess of flosulide could not displace labeled FMLP from the receptor. Inhibition of degranulation of primary and secondary granules was a common effect of all anti-inflammatory compounds tested. At a concentration of 10(-5) M, all drugs inhibited degranulation to about the same degree, independent of their in vivo anti-inflammatory activity.