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Involvement of the Cysteinyl–Leukotrienes in Allergen-Induced Airway Eosinophilia and Hyperresponsiveness in the Mouse

Meakins-Christie Laboratories and Respiratory Division, Department of Medicine, McGill University, Montreal, Quebec, Canada

Address correspondence to: Dr. James G. Martin, Meakins-Christie Laboratories, McGill University, 3626, Rue St-Urbain, Montreal, QC, Canada H2X 2P2. E-mail: jmartin{at}meakins.lan.mcgill.ca

The leukotriene modifiers are a novel generation of therapeutic agents in the treatment of allergic asthma. However, the mechanisms by which the cysteinyl (cys) leukotrienes (LTs) participate in allergen-induced airway eosinophilia and airway hyperresponsiveness (AHR) are still unclear. In the present study, we have investigated the role of cys-LTs in ovalbumin (OVA)-induced airway responses in a murine model of asthma. Montelukast (3 or 10 mg/kg), a selective cys-LT1 receptor antagonist, reduced airway eosinophilia and AHR after OVA challenge. The levels of interleukin (IL)-5 and eotaxin in the bronchoalveolar lavage fluid (BALF) from montelukast-treated (3 mg/kg) mice were unaffected, although a decrease in IL-5 was observed with a dose of 10 mg/kg. LTD₄ (50 ng) instilled intranasally to immunized mice augmented macrophages in the BALF, but in conjunction with OVA challenge it caused BALF eosinophilia and neutrophilia when given before challenge and BALF neutrophilia but not eosinophilia when given 2 h after challenge. However, there were no increases of IL-5 or eotaxin in BALF following LTD₄ treatment. Repeated instillations of LTD₄ to immunized mice, mimicking allergen challenge, did not induce AHR but in conjunction with OVA challenge LTD₄ enhanced AHR. These results indicate that allergen-induced eosinophilia and AHR are in part mediated by the cys-LT1 receptor, and that, although LTD₄ alone has no effect on airway eosinophilia, in conjunction with antigenic stimulation it potentiates the degree of airway inflammation and AHR.

Abbreviations: airway hyperresponsiveness, AHR • bronchoalveolar lavage, BAL • BAL fluid, BALF • cysteinyl, cys • enzyme-linked immunosorbent assay, ELISA • interleukin, IL • leukotrienes, LTs • methacholine, Mch • ovalbumin, OVA • respiratory system resistance, R_rs • regulated on activation, normal T cells expressed and secreted, RANTES

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