title: Asthmatic airway neutrophilia after allergen challenge is associated with the glutathione S-transferase M1 genotype.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN 37232-2650, USA.
authors.forename: Aimee
authors.initials: A
authors.lastname: Hoskins
authors.forename: Sara
authors.initials: S
authors.lastname: Reiss
authors.forename: Pingsheng
authors.initials: P
authors.lastname: Wu
authors.forename: Ning
authors.initials: N
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.forename: Rui-hong
authors.initials: RH
authors.lastname: Do
authors.forename: Rasul
authors.initials: R
authors.lastname: Abdolrasulnia
authors.forename: Ryszard
authors.initials: R
authors.lastname: Dworski
mesh_terms: D000328:Adult; D001249:Asthma / Q000235:genetics*; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction / Q000276:immunology; D005260:Female; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008297:Male; D009504:Neutrophils / Q000378:metabolism*; D055815:Young Adult
chemical_list: D005982:Glutathione Transferase