Effects of the second-generation leukotriene B-4 receptor antagonist, LY293111Na, on leukocyte infiltration and collagen-induced arthritis in mice

The effects of the second-generation leukotriene B-4 receptor (LTB4 recepto r) antagonist, 2-[2-propyl-3-{3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxy-pheno xy]-propoxy}phenoxy]benzoic acid sodium salt (LY293111Na), on leukotriene B -4-induced leukocyte infiltration and interleukin-1-accelerated collagen-in duced arthritis in mice were studied. Neutrophil infiltration induced into an air pouch by leukotriene B-4 was dose-dependently inhibited by LY293111N a and strongly so by another LTB4 receptor antagonist, 4-[5-{4-(aminoiminom ethyl)phenoxy}pentoxy]-3-methoxy-N,N-bis(1-methylethyl) (Z)-2butenedioate ( 1:1) (CGS25019C). Both compounds significantly inhibited the increase of th e arthritis index and the ankle bone destruction in interleukin-1-accelerat ed collagen-induced arthritis. Phenidone, a 5-lipoxygenase inhibitor, also inhibited interleukin-1-accelerated collagen-induced arthritis, while indom ethacin and tenidap, cyclooxygenase inhibitors, had slight inhibitory effec ts. Injection of interleukin-1 elicited a marked increase of the leukotrien e B-4 level in arthritic paws, while the prostaglandin E-2 level was slight ly increased. These findings indicate clearly that leukotriene B-4 is an im portant mediator of interleukin-1-accelerated collagen-induced arthritis in mice. If this can be extrapolated to man, LTB4 receptor antagonists might be useful for treatment of the acute progressive phase of human arthritis. (C) 2000 Elsevier Science B.V. All rights reserved.