Background: Asthma is characterized by airflow obstruction, inflammatory cell infiltration, and the synthesis of mediators, such as T_H2 cytokines and leukotrienes, in the airways. Cysteinyl leukotriene (cysLT) receptor antagonists have recently been associated with clinical improvement of asthma and reduced airway inflammation. Whether the beneficial effects of cysLT antagonists are mediated through the modulation of cytokine expression has not been determined. Objective: The aim of the study was to determine the presence of eosinophils and IL-5 messenger (m)RNA⁺ cells within the lungs of antigen-challenged Brown Norway rats after treatment with the cysLT₁ receptor antagonist montelukast (MK). Methods: Ovalbumin-sensitized Brown Norway rats were treated with either MK or saline before ovalbumin challenge. Pulmonary mechanics were monitored for 8 hours. Subsequently, immunocytochemistry and in situ hybridization were used to examine bronchoalveolar lavage (BAL) fluid and lung tissue for cells expressing major basic protein (eosinophils) and IL-5 mRNA, respectively. Simultaneous in situ hybridization and immunocytochemistry was used to phenotype the cells expressing mRNA encoding IL-5. Results: Animals treated with MK had significantly lower lung resistance and fewer eosinophils and IL-5 mRNA⁺ cells within BAL fluid and lung tissue compared with that found in saline-treated animals. Colocalizaton studies revealed that the majority of IL-5 mRNA⁺ cells were T cells and that the number of IL-5 mRNA⁺/CD3⁺ or IL-5 mRNA⁺/major basic protein⁺ cells were significantly less within BAL from animals treated with MK than from those treated with saline. Conclusions: These results indicate that the cysLT₁ receptor antagonist MK can diminish the pulmonary response to antigen, tissue eosinophilia, and the number of cells expressing IL-5 mRNA, suggesting that leukotrienes may also regulate the allergic response through the modulation of inflammation and cytokine synthesis. (J Allergy Clin Immunol 1999;1147-54.)