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.
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 Cl2exposure 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.
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. Cl2exposure 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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