Glutathione S‐transferase M1 modulates allergen‐induced NF‐κB activation in asthmatic airway epithelium

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.