Montelukast reduces inhaled chlorine triggered airway hyperresponsiveness and airway inflammation in the mouse.

Abstract

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, a CysLT1 receptor antagonist, on parameters of irritant-induced asthma induced by inhalation of chlorine in the mouse.

EXPERIMENTAL APPROACH:

BALB/c mice were exposed to chlorine in air (100 ppm, for 5 min). Montelukast (3 mg·kg-1 ) or the vehicle (1% methylcellulose) was administered 24 and 1 h prior to chlorine exposure and 1 h prior to outcome measurements. Twenty-four hours after exposure, responses to inhaled aerosolized methacholine, cell composition and an array of cytokines/chemokines in bronchoalveolar lavage (BAL) fluid were measured. Neutralizing antibodies against IL-6 and VEGF were administered prior to exposures.

KEY RESULTS:

Montelukast reduced chlorine -induced airway hyperresponsiveness (AHR) to methacholine in the peripheral lung compartment as estimated from dynamic elastance, but not in large conducting airways. Montelukast treatment attenuated chlorine-induced macrophage influx, neutrophilia and eosinophilia in BAL fluid. Chlorine exposure increased VEGF, IL-6, the chemokines KC and CCL3 in BAL fluid. Montelukast treatment prevented chlorine-induced increases in VEGF and IL-6. Anti-IL-6 antibody inhibited chlorine-induced neutrophilia and reduced AHR.

CONCLUSIONS AND IMPLICATIONS:

Pre-treatment with montelukast attenuated chlorine-induced neutrophilia and AHR in mice. These effects are mediated, in part, via IL-6.

• Authors: Yoichiro Hamamoto, Satoshi Ano, Benoit Allard, Michael O'Sullivan, Toby K McGovern, James G Martin
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 174 Issue 19 Pg. 3346-3358 (Oct 2017) ISSN: 1476-5381 [Electronic] England
• PMID: 28718891 (Publication Type: Journal Article)
• Copyright: © 2017 The British Pharmacological Society.

Chemical References

• Acetates
• Anti-Inflammatory Agents
• Antibodies, Monoclonal
• Cyclopropanes
• Cytokines
• Irritants
• Leukotriene Antagonists
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• Quinolines
• Receptors, Interleukin-6
• Sulfides
• Chlorine
• montelukast

Topics

• Acetates (pharmacology, therapeutic use)
• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Antibodies, Monoclonal (pharmacology)
• Bronchoalveolar Lavage Fluid (immunology)
• Cell Line
• Chlorine (toxicity)
• Cyclopropanes
• Cytokines (immunology)
• Irritants (toxicity)
• Leukotriene Antagonists (pharmacology, therapeutic use)
• Lung (drug effects, metabolism)
• Male
• Mice, Inbred BALB C
• NF-E2-Related Factor 2 (metabolism)
• Quinolines (pharmacology, therapeutic use)
• Receptors, Interleukin-6 (immunology)
• Respiratory Hypersensitivity (chemically induced, drug therapy)
• Sulfides