BI-L-239, A 5-LIPOXYGENASE INHIBITOR, BLOCKS INHALED ANTIGEN-INDUCED AIRWAY HYPERRESPONSIVENESS IN CONSCIOUS GUINEA-PIGS

Male Hartley guinea pigs were actively sensitized to ovalbumin (OA). Respiratory system resistance (Rrs) was measured by forced oscillations superimposed on tidal breathing. Airway responsiveness (inhaled methacholine PC100) was determined three days prior and three days after (day 10) three alternate day inhalations of OA. Airway cell composition was assessed on day 10 by lung lavage. Three groups (n = 5-6) were studied: A) vehicle challenged, B) OA challenged/placebo treated, C) OA challenged/BI-L-239 (2,6-dimethyl-4-[2-4-fluorophenyl)ethenyl]phenol) treated (10 x 0.75 mg/actuation, 10 minutes prior to each OA challenge). Animals were treated with pyrilamine and indomethacin (10 mg/kg i.p.) 30 minutes prior to each OA challenge. OA induced acute increases in Rrs of 143 +/- 29%, 238 +/- 73% and 102 +/- 43% in placebo and 86 +/- 34%, 45 +/- 35% (p, 0.05 vs. placebo) and 102 +/- 31% in BI-L-239 treated. OA induced a significant (p < 0.05) increase in airway leukocytes in placebo (487 +/- 36 to 1615 +/- 421 x 10(3)/ml) but not BI-L-239 treated (to 881 +/- 155 x 10(3)/ml) and decrease in methacholine PC100 in placebo (1.487 +/- 0.49 to 0.39 +/- 0.18 mg/ml) but not BI-L-239 treated (0.99 +/- 34 to 1.04 +/- 0.39 mg/ml). We conclude that BI-L-239 attenuates the airway constriction, inflammation and hyperresponsiveness induced by repeated antigen inhalations in conscious guinea pigs.