Effects of combination therapy with montelukast and carbocysteine in allergen-induced airway hyperresponsiveness and airway inflammation

Abstract

Background and purpose: Montelukast and S-carbocysteine have been used in asthmatic patients as an anti-inflammatory or mucolytic agent respectively. S-carbocysteine also exhibits anti-inflammatory properties. Experimental approach: Ovalbumin (OVA) sensitized BALB/c mice were challenged with OVA for 3 days followed by single OVA re-challenge (secondary challenge) 2 weeks later. Forty-eight hours after secondary challenge, mice were assessed for airway hyperresponsiveness (AHR) and cell composition in bronchoalveolar lavage (BAL) fluid. Suboptimal doses of 10 mg·kg-1 of S-carbocysteine by intraperitoneal injection (ip), 20 mg·kg-1 of montelukast by gavage, the combination of S-carbocysteine and montelukast or 3 mg·kg-1 of dexamethasone as a control were administered from 1 day before the secondary challenge to the last experimental day. Isolated lung cells were cultured with OVA and montelukast to determine the effects on cytokine production. Key results: Treatment with S-carbocysteine or montelukast reduced both AHR and the numbers of eosinophils in BAL fluid. Neutralizing IFN-γ abolished the effects of S-carbocysteine on these airway responses. Combination of the two drugs showed further decreases in both AHR and eosinophils in the BAL fluid. Goblet cell metaplasia and Th2-type cytokines, interleukin (IL)-4, IL-5 and IL-13, in BAL fluid were decreased with montelukast treatment. Conversely, S-carbocysteine increased Th1-type cytokines, IFN-γ and IL-12 in BAL fluid. Conclusions and inplications: The combination of two agents, montelukast and S-carbocysteine, demonstrated additive effects on AHR and airway inflammation in a secondary allergen model most likely through independent mechanisms of action. © 2010 The British Pharmacological Society.