title: Glutathione S-transferase M1 modulates allergen-induced NF-κB activation in asthmatic airway epithelium.
abstract: BACKGROUND
  Glutathione S-transferase M1 (GSTM1) is a phase II enzyme and regulator of inflammatory signaling in airway epithelial cells. We have found upregulation of neutrophilic airway inflammation in atopic asthmatics expressing GSTM1 gene (GSTM1+) compared to GSTM1null asthmatics. We hypothesized that GSTM1 modulates NF-κB activation in bronchial epithelium in atopic asthmatics. We determined regulation of allergen-induced NF-κB activation in bronchial epithelium by GSTM1 in human atopic asthmatics in vivo.
  
  
  METHODS
  Endobronchial biopsies and bronchoalveolar lavage fluid samples were collected from 13 GSTM1+ and 12 GSTM1null human atopic asthmatics at baseline and 24 h after segmental allergen challenge. A quantitative analysis of NF-κB activation in airway epithelium was accomplished using a polyclonal antibody against the phosphorylated p65 component of NF-κB. Elastase-positive neutrophils in the bronchial wall were quantified.
  
  
  RESULTS
  Postallergen neutrophilia in airway subepithelium and epithelial lining fluid was greater in GSTM1+ compared to GSTM1null asthmatics. Airway eosinophilia was similar in GSTM1+ and GSTM1null asthmatics. Allergen-provoked NF-κB induction in bronchial epithelium was significantly greater in GSTM1+ compared to GSTM1null asthmatics. Activation of NF-κB activation in airway epithelial cells correlated with interleukin-8 concentrations and absolute neutrophil numbers in bronchoalveolar lavage fluid in GSTM1+ but not GSTM1null asthmatics.
  
  
  CONCLUSIONS
  Allergen-induced neutrophilic airway inflammation in GSTM1+ asthmatics is associated with NF-κB activation in airway epithelial cells in vivo. These novel data provide a potential mechanism of the genomic link between GSTM1 polymorphism and airway neutrophilia in atopic asthma.
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: V V
authors.initials: VV
authors.lastname: Polosukhin
authors.forename: I V
authors.initials: IV
authors.lastname: Polosukhin
authors.forename: A
authors.initials: A
authors.lastname: Hoskins
authors.forename: W
authors.initials: W
authors.lastname: Han
authors.forename: R
authors.initials: R
authors.lastname: Abdolrasulnia
authors.forename: T S
authors.initials: TS
authors.lastname: Blackwell
authors.forename: R
authors.initials: R
authors.lastname: Dworski
mesh_terms: D000328:Adult; D000485:Allergens / Q000276:immunology*; D000818:Animals; D001249:Asthma / Q000175:diagnosis / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation; D004804:Eosinophils / Q000276:immunology / Q000473:pathology; D005260:Female; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D020545:Respiratory Mucosa / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D055815:Young Adult
chemical_list: D000485:Allergens; D016207:Cytokines; D005982:Glutathione Transferase; D016328:NF-kappa B
keywords: GSTM1 polymorphism; NF-κB; airway epithelium; atopic asthma; neutrophilic airway inflammation