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Involvement of LTD4in allergic pulmonary inflammation in mice: modulation by cysLT1antagonist MK-571

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Abstract

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 cysLT1receptor antagonist. Mice were sensitized with a suspension of ovalbumin (8 μg) 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−1s.c.) and MK-571 (1, 10, 100 mg kg−1i.v.) in a dose-dependent manner. Maximal inhibition was 95% with 5 mg kg−1dexamethasone and 90% with 100 mg kg−1MK-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 EC50values for carbachol were of 22.39±1.12 μg kg−1in 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 μg kg−1in animals treated with 1, 10 and 100 mg kg−1MK-571 respectively. Lung microvascular leakage (as measured by Evans blue extravasation) induced by antigen bronchoprovocation was reduced by 22% after treatment with 10 mg kg−1MK-571. All these inhibitory effects of MK-571 suggest a role for leukotriene D4in this animal model of allergic asthma.

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    Correspondence to: Dr Pierre Sirois, Institut de Pharmacologie de Sherbrooke, Faculté de Médecine, Université de Sherbrooke, Sherbrooke (Qc) J1H 5N4, Canada. Tel.: +1 819 564 5239; Fax: +1 819 564 5400; E-mail: [email protected]

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