期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：46
页码：13132-13137
DOI：10.1073/pnas.1610433113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceBecause the SNP linking chromosome 17q21 to asthma is associated with increased gasdermin B (GSDMB) expression, we generated transgenic mice expressing increased levels of the human GSDMB transgene (hGSDMBZp3-Cre), which develop an asthma phenotype characterized by a spontaneous increase in airway responsiveness and airway remodeling (increased peribronchial smooth muscle) in the absence of the development of airway inflammation. These results challenge the current paradigm in asthma that airway inflammation induces smooth muscle remodeling and airway responsiveness, as these hGSDMBZp3-Cre mice develop increased airway-hyperresponsiveness and smooth muscle in the absence of airway inflammation. Furthermore, this study adds to our understanding of gene networks in asthma that we have identified can act in sequential pathways (i.e., GSDMB induces 5-lipoxygenase to induce TGF-{beta}1). Gasdermin B (GSDMB) on chromosome 17q21 demonstrates a strong genetic linkage to asthma, but its function in asthma is unknown. Here we identified that GSDMB is highly expressed in lung bronchial epithelium in human asthma. Overexpression of GSDMB in primary human bronchial epithelium increased expression of genes important to both airway remodeling [TGF-{beta}1, 5-lipoxygenase (5-LO)] and airway-hyperresponsiveness (AHR) (5-LO). Interestingly, hGSDMBZp3-Cre mice expressing increased levels of the human GSDMB transgene showed a significant spontaneous increase in AHR and a significant spontaneous increase in airway remodeling, with increased smooth muscle mass and increased fibrosis in the absence of airway inflammation. In addition, hGSDMBZp3-Cre mice showed increases in the same remodeling and AHR mediators (TGF-{beta}1, 5-LO) observed in vitro in GSDMB-overexpressing epithelial cells. GSDMB induces TGF-{beta}1 expression via induction of 5-LO, because knockdown of 5-LO in epithelial cells overexpressing GSDMB inhibited TGF-{beta}1 expression. These studies demonstrate that GSDMB, a gene highly linked to asthma but whose function in asthma is previously unknown, regulates AHR and airway remodeling without airway inflammation through a previously unrecognized pathway in which GSDMB induces 5-LO to induce TGF-{beta}1 in bronchial epithelium.
