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 (LTB(4) receptor) antagonist, 2-[2-propyl-3-¿3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxy-phenoxy]-propo xy¿phenoxy]benzoic acid sodium salt (LY293111Na), on leukotriene B(4)-induced leukocyte infiltration and interleukin-1-accelerated collagen-induced arthritis in mice were studied. Neutrophil infiltration induced into an air pouch by leukotriene B(4) was dose-dependently inhibited by LY293111Na and strongly so by another LTB(4) receptor antagonist, 4-[5-¿4-(aminoiminomethyl)phenoxy¿pentoxy]-3-methoxy-N, N-bis(1-methylethyl) (Z)-2butenedioate (1:1) (CGS25019C). Both compounds significantly inhibited the increase of the arthritis index and the ankle bone destruction in interleukin-1-accelerated collagen-induced arthritis. Phenidone, a 5-lipoxygenase inhibitor, also inhibited interleukin-1-accelerated collagen-induced arthritis, while indomethacin and tenidap, cyclooxygenase inhibitors, had slight inhibitory effects. Injection of interleukin-1 elicited a marked increase of the leukotriene B(4) level in arthritic paws, while the prostaglandin E(2) level was slightly increased. These findings indicate clearly that leukotriene B(4) is an important mediator of interleukin-1-accelerated collagen-induced arthritis in mice. If this can be extrapolated to man, LTB(4) receptor antagonists might be useful for treatment of the acute progressive phase of human arthritis.