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, F 2 -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-a, CXCL-8, IL-1b, 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-b1, 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.Keywords: atopic asthma; GSTM1 polymorphism; inflammatory asthma phenotypes; neutrophilic airway inflammation Asthma is a heterogeneous airway disorder characterized by inflammation, hyperresponsiveness, and obstruction. There is considerable interest in classifying asthma phenotypes. It has been suggested that the type of airway inflammation might define asthma phenotypes. One proposed classification uses eosinophilic, neutrophilic, and paucigranulocytic cellular inflammation to define three subtypes of asthma (1). The neutrophilic inflammation has recently drawn more attention because of its association with severe asthma and poor response to corticosteroids (2). The relationship between various asthmatic phenotypes and genotypes in humans is poorly understood.Glutathione S-transferase M1 (GSTM1) is a phase II cytoprotective protein from the family of cytosolic GSTs (3). The GSTM1 gene is located on chromosome 1p13.3 and ha...

MD2 Facilitates Pollen and Cat Dander-Induced Innate and Allergic Airway Inflammation

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