MK reduces inhaled chlorine triggered AHR and airway inflammation in the mouse.

Br J Pharmacol. 2017 Jul 18. doi: 10.1111/bph.13953. [Epub ahead of print]

Hamamoto Y1, Ano S1, Allard B1, O'Sullivan M1, McGovern TK1, Martin JG1.

BACKGROUND AND PURPOSE: 

Cysteinyl leukotrienes (CysLTs) are pro-inflammatory lipid mediators that exacerbate disease state in several asthma phenotypes including asthma induced by allergen, virus and exercise. However, the role of CysLTs in irritant-induced airway disease is not well characterized. The purpose of the current study was to investigate the effect of montelukast (MK), a CysLT1Rantagonist, on parameters of irritant-induced asthma (IIA) induced by inhalation of chlorine (Cl2 ) in the mouse.

EXPERIMENTAL APPROACH: 

BALB/c mice were exposed to Cl2 (100ppm, for 5 minutes). MK (3mg/kg) or the vehicle 1% methylcellulose (MC) was administered 24 hours and 1 hour prior to Cl2 exposure and 1 hour prior to outcome measurements. Twenty-four hours after exposure, responses to inhaled aerosolized methacholine (MCh), cell composition and an array of cytokines/chemokines in bronchoalveolar lavage (BAL) fluid were measured. Neutralizing antibodies against interleukin (IL)-6 and vascular endothelial growth factor (VEGF) were administered prior to exposures.

KEY RESULTS: 

MK reduced Cl2 -induced airway hyperresponsiveness (AHR) to MCh in the peripheral lung compartment as estimated from dynamic elastance but not in large conducting airways. MK treatment attenuated Cl2 -induced macrophage influx, neutrophilia and eosinophilia in BAL fluid. Cl2 exposure increased vascular endothelial growth factor (VEGF), IL-6, keratinocyte cytokine and macrophage inflammatory protein-1α in BAL fluid. MK treatment prevented Cl2 -induced increases in VEGF and IL-6. Anti-IL-6 inhibited Cl2 -induced neutrophilia and reduced AHR.

CONCLUSION AND IMPLICATIONS: 

Findings in the present study demonstrate that MK treatment attenuates Cl2 -induced neutrophilia and AHR. These effects are mediated, in part, via IL-6.

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PMID:

28718891