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Objective and design: To investigate the role of leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) in the development and progression of antigen-induced arthritis (AIA) in guinea pigs and rats.¶ Methods: Arthritis was induced by injecting cationic amidated bovine serum albumin (aBSA) into the knee joint of immunized guinea pigs or rats. The effect of a potent and selective LTB4 receptor antagonist, LY293111Na (2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]-propoxy]-phenoxy]benzoic acid sodium salt) was compared with those of indomethacin and dexamethasone. The effect of LY293111Na on adjuvant arthritis in rats was also examined.¶ Results: LY293111Na (5 to 50 mg/kg b.i.d.) significantly inhibited knee joint swelling and histopathological changes of AIA in guinea pigs, but not in rats. Especially its protective effect against bone and cartilage destruction was substantial. In contrast, the cyclooxygenase inhibitor indomethacin significantly inhibited AIA in rats, but slightly inhibited in guinea pigs, while dexamethasone markedly inhibited AIA in both guinea pigs and rats. Increases of LTB4 and myeloperoxidase (MPO) activity were observed in the knee joint tissue of AIA guinea pigs, and LY293111Na dose-dependently inhibited the increase of MPO activity. Moreover, in adjuvant arthritic rats, LY293111Na showed slight inhibitory effect, while indomethacin showed marked inhibition.¶ Conclusions: LTB4 but not PGE2 appeared to play important roles as an effective mediator in joint, particularly in cartilage and bone destruction of AIA in guinea pigs probably by inducing polymorphonuclear leukocytes (PMNs) chemotaxis to the joint tissue. In contrast, PGE2 but not LTB4 is an important mediator of arthritis in rats. [ABSTRACT FROM AUTHOR]

Objective and Design: LY293111Na, 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy] propoxy] - phenoxy]-benzoic acid sodium salt, is a novel leukotriene B4 (LTB4) receptor antagonist. Its effects on guinea pig models of asthma were compared with those of dexamethasone.¶ Methods: Effects of LY293111Na were tested in antigen (ovalbumin, OA)-induced bronchial hyperresponsiveness (BHR) and leukocyte accumulation in actively sensitized guinea pigs. Its effects on antigen-induced acute bronchoconstriction in passively sensitized guinea pigs were also studied.¶ Results: LY293111Na (10 to 30 mg/kg p.o., 1 h before and 6 h after OA challenge) inhibited BHR to acetylcholine. LY293111Na (3 mg/kg p.o.) significantly inhibited accumulation of neutrophils in bronchoalveolar lavage (BAL) fluid 24 h after antigen challenge but it did not inhibit accumulation of eosinophils and macrophages at any doses used. In contrast, dexamethasone (30 mg/kg p.o., 4 h before OA challenge) not only inhibited BHR but also reduced the infiltration of all three types of leukocytes. A significant increase of LTB4 levels in BAL fluid was noted at 3 and 15 min after the antigen challenge. LY293111Na did not inhibit antigen-induced acute bronchoconstriction in passively sensitized guinea pigs.¶ Conclusion: These results indicate that LTB4 may participate in antigen-induced BHR but not in eosinophil infiltration and acute bronchoconstriction in guinea pigs.¶ [ABSTRACT FROM AUTHOR]