Involvement of LTD(4)in allergic pulmonary inflammation in mice: modulation by cysLT(1)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 microg) 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.v.) in a dose-dependent manner. Maximal inhibition was 95% with 5 mg kg(-1)dexamethasone and 90% with 100 mg kg(-1)MK-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 EC(50)values for carbachol were of 22.39+/-1.12 microg 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 microg kg(-1)in animals treated with 1, 10 and 100 mg kg(-1)MK-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(-1)MK-571. All these inhibitory effects of MK-571 suggest a role for leukotriene D(4)in this animal model of allergic asthma.
Faculté de Médecine, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Canada.
J F
JF
Blain
P
P
Sirois
D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy / Q000503:physiopathology; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002199:Capillary Permeability / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D020024:Leukotriene Antagonists; D017998:Leukotriene D4 / Q000037:antagonists & inhibitors* / Q000502:physiology; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D011422:Propionates / Q000494:pharmacology* / Q000627:therapeutic use; D011657:Pulmonary Eosinophilia / Q000188:drug therapy; D011804:Quinolines / Q000494:pharmacology* / Q000627:therapeutic use; D018077:Receptors, Leukotriene
D020024:Leukotriene Antagonists; D008565:Membrane Proteins; D011422:Propionates; D011804:Quinolines; D018077:Receptors, Leukotriene; C059141:verlukast; D017998:Leukotriene D4; D003907:Dexamethasone; D010047:Ovalbumin; C412375:cysteinyl leukotriene receptor 2; C083169:leukotriene D4 receptor