Leukotriene E₄ induces airflow obstruction and mast cell activation through the cysteinyl leukotriene type 1 receptor.

Abstract

Leukotriene (LT) E₄ is the final active metabolite among the cysteinyl leukotrienes (CysLTs). Animal studies have identified a distinct LTE₄ receptor, suggesting that current cysteinyl leukotriene type 1 (CysLT₁) receptor antagonists can provide incomplete inhibition of CysLT responses. We tested this hypothesis by assessing the influence of the CysLT₁ antagonist montelukast on responses induced by means of inhalation of LTE₄ in asthmatic patients. Fourteen patients with mild intermittent asthma and 2 patients with aspirin-exacerbated respiratory disease received 20 mg of montelukast twice daily and placebo for 5 to 7 days in a randomized, double-blind, crossover study (NCT01841164). The PD₂₀ value was determined at the end of each treatment period based on an increasing dose challenge. Measurements included lipid mediators in urine and sputum cells 4 hours after LTE₄ challenge. Montelukast completely blocked LTE₄-induced bronchoconstriction. Despite tolerating an at least 10 times higher dose of LTE₄ after montelukast, there was no difference in the percentage of eosinophils in sputum. Urinary excretion of all major lipid mediators increased after LTE₄ inhalation. Montelukast blocked release of the mast cell product prostaglandin (PG) D₂, as well as release of PGF_2α and thromboxane (Tx) A₂, but not increased excretion of PGE₂ and its metabolites or isoprostanes. LTE₄ induces airflow obstruction and mast cell activation through the CysLT₁ receptor.