BACKGROUND: Chromosome 17q21 contains a cluster of genes that may either individually, or in combination, be responsible for its strong genetic linkage to asthma. In this study, we focused on GSDMB as its biological function in asthma is unknown.
METHODS: GSDMB expression was evaluated in human lung sections from asthmatic patients and normal individuals. As the SNP linking chromosome 17q21 to asthma is associated with increased GSDMB expression, we generated transgenic mice expressing increased levels of the human GSDMB transgene (hGSDMBZp3-Cre). The levels of Th2 cytokines, remodeling genes and chemokines were assessed by qPCR, immunohistochemistry and ELISA.
RESULTS: We identified that GSDMB is highly expressed in lung bronchial epithelium in human asthma. Overexpression of GSDMB in primary human bronchial epithelium increased the expression of genes important to both airway remodeling (TGF-β1, 5-LO) and airway-hyperresponsiveness (AHR) (5-LO). Interestingly, unchallenged hGSDMBZp3-Cre mice showed a significant spontaneous increase in airway remodeling, with increased smooth muscle mass and increased fibrosis as early as 8 weeks of age, which persisted until 24 weeks of age. In addition, hGSDMBZp3-Cre mice also showed a significant spontaneous increase in AHR in the absence of airway inflammation, with increases in the same remodeling and AHR mediators (TGF-β1, 5-LO) observed in vitro in GSDMB-overexpressing epithelial cells.