Cough, asthma, and cysteinyl-leukotrienes

Abstract

Asthma is a chronic inflammatory disease of the lower airways, involving various cells such as eosinophils, and cytokines and mediators. Cyteinyl-leukotrienes (cys-LTs) are one of the chemical mediators that play major pathophysiological roles in asthma. They are produced by eosinophils and mast cells, and induce bronchoconstriction, mucous hypersecretion, microvascular leakage, eosinophil chemotaxis and airway remodeling. Anti-leukotrienes, including leukotriene receptor antagonists (LTRAs) which block cysLT1 receptors, exert both bronchodilatory and anti-inflammatory effects and are utilized as second- to third-line controller medication of persistent asthma. Cough is a major symptom of asthma, and cough variant asthma (CVA) is an asthma phenotype that solely presents with coughing. Sputum levels of cys-LTs are increased in patients with CVA. Antitussive effects of monotherapy with LTRAs in patients with CVA have been reported. We have recently demonstrated that 4 weeks' treatment with an LTRA montelukast exerted anti-inflammatory effect as proved by a decrease of sputum eosinophils, in addition to attenuation of cough VAS and capsaicin cough sensitivity, as reported previously. Spirometry, airway responsiveness, and impulse oscillation indices (respiratory resistance and reactance) were unchanged. These results suggested that the antitussive effect of montelukast in CVA might be attributable to its anti-inflammatory ability rather than bronchodilation. The treatment did not affect sputum levels of mediators (cys-LTs, LTB4, PGD2, PGE2, PGF2α, and TXB2). Since inhaled corticosteroid does not seem to affect cough sensitivity while attenuating cough in patients with CVA, LTRAs may involve different mechanism(s) from that of corticosteroid. LTRAs must theoretically be effective against cough of asthmatic subjects through its "anti-asthma" effects, while evidence supporting direct antitussive effects of cys-LTs on "cough receptors" is scarce. An important clinical question is that whether LTRAs involve non-specific antitussive effects. While a definite answer is not available yet, this possibility seems unlikely at the moment, although some secondary anti-inflammatory properties have been reported for montelukast. This issue needs to be clarified by future research to avoid overuse of this expensive class of medication.

Keywords: Asthma; Cough; Leukotriene receptor antagonists; Mast cells; Neutrophils; Substance P.