Asthmatic airway neutrophilia after allergen challenge is associated with the glutathione S-transferase M1 genotype

Abstract

Rationale: Asthma is a heterogeneous lung disorder characterized by airway inflammation and airway dysfunction, manifesting as hyperresponsiveness and obstruction. Glutathione S-transferase M1 (GSTM1) is a multifunctional phase II enzyme and regulator of stress-activated cellular signaling relevant to asthma pathobiology. A common homozygous deletion polymorphism of the GSTM1 gene eliminates enzyme activity. Objectives: To determine the effect of GSTM1 on airway inflammation and reactivity in adults with established atopic asthma in vivo. Methods: Nineteen GSTM1 wild-type and eighteen GSTM1-null individuals with mild atopic asthma underwent methacholine and inhaled allergen challenges, and endobronchial allergen provocations through a bronchoscope. Measurements and Main Results: The influx of inflammatory cells, panels of cytokines and chemokines linked to asthmatic inflammation, F2-isoprostanes (markers of oxidative stress), and IgE were measured in bronchoalveolar lavage fluid at baseline and 24 hours after allergen instillation. Individuals with asthma with the GSTM1 wild-type genotype had greater baseline and allergen-provoked airway neutrophilia and concentrations of myeloperoxidase than GSTM1-null patients. In contrast, the eosinophilic inflammation was unaffected by GSTM1. The allergen-stimulated generation of acute-stress and proneutrophilic mediators, tumor necrosis factor-α, CXCL-8, IL-1β, and IL-6, was also greater in the GSTM1 wild-type patients. Moreover, post-allergen airway concentrations of IgE and neutrophilgenerated mediators, matrix metalloproteinase-9, B-cell activating factor, transforming growth factor-β1, and elastase were higher in GSTM1 wild-type individuals with asthma. Total airway IgE correlated with B-cell activating factor concentrations. In contrast, levels of F 2-isoprostane were comparable in both groups. Finally, GSTM1 wild-type individuals with asthma required lower threshold concentrations of allergen to produce bronchoconstriction. Conclusions: The functional GSTM1 genotype promotes neutrophilic airway inflammation in humans with atopic asthma in vivo. Copyright © 2013 by the American Thoracic Society.