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

Polosukhin VV, Polosukhin IV, Hoskins A, Han W, Abdolrasulnia R, Blackwell TS, Dworski R
Allergy. 2014 69 (12): 1666-72

PMID: 25118837 · PMCID: PMC4317365 · DOI:10.1111/all.12506

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.

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

MeSH Terms (18)

Adult Allergens Animals Asthma Bronchoalveolar Lavage Fluid Cytokines Enzyme Activation Eosinophils Female Genotype Glutathione Transferase Humans Male Middle Aged Neutrophils NF-kappa B Respiratory Mucosa Young Adult

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