Significance Because 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 (hGSDMB ^Zp3-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 hGSDMB ^Zp3-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-β1).