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Am J Respir Crit Care Med. 2013 Jan 1;187(1):34-41. doi: 10.1164/rccm.201204-0786OC. Epub 2012 Nov 29.

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

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  • 1Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN 37232-2650, USA.

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-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 neutrophil-generated 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.

PMID:
23204253
[PubMed - indexed for MEDLINE]
PMCID:
PMC3570644
Free PMC Article
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