Involvement of LTD4 in allergic pulmonary inflammation in mice:: modulation by cysLT1 antagonist MK-571

Cysteinyl leukotrienes are potent inflammatory molecules playing a major role in asthma. The involvement of these mediators in hypersensitivity in mice is not well known. This study aimed at elucidating their implication by using MK-571, a cysLT(1) receptor antagonist. Mice were sensitized with a suspension of ovalbumin (8 mu g) adsorbed to alum (2 mg) and were challenged with an aerosolized ovalbumin solution (0.5 %). Inflammatory cell infiltration in the bronchoalveolar lavage (mostly eosinophils) following antigen challenge was inhibited by dexamethasone (0.1,1 and 5 mg kg(-1)s.c.) and MK-571 (1,10,100 mg kg(-1) i.v3 in a dose-dependent manner. Maximal inhibition was 95% with 5 mg kg(-1) dexamethasone and 90% with 100 mg kg(-1) MLK-571. When injected together they showed an additive inhibitory effect on eosinophil infiltration. Bronchial hyperreactivity, measured by the increased pulmonary insufflation pressure to carbachol injections, was also inhibited dose-dependently by MK-571. The EC50 values for carbachol were of 22.39 +/- 1.12 mu g kg(-1) in sensitized and challenged animals that did not receive MK-571 and increased to 43.65 +/- 1.10, 50.12 +/- 1.15 and 83.18 +/- 1.16 mu g kg(-1) in animals treated with 1,10 and 100 mg kg(-1) MK-571 respectively. Lung microvascular leakage las measured by Evans blue extravasation) induced by antigen bronchoprovocation was reduced by 22% after treatment with 10 mg kg(-1) MK-571. All these inhibitory effects of MK-571 suggest a role for leukotriene D-4 in this animal model of allergic asthma. (C) 2000 Harcourt Publishers Ltd.