Disulfiram alleviates airway remodeling in ozone-induced chronic obstructive pulmonary disease mouse models via inhibiting Gasdermin D-mediated pyroptosis

<bold>Background:</bold> Pyroptosis is an inflammatory form of programed cell death. Disulfiram, a FDA-approved anti-alcoholism drug, has been reported as an effective inhibitor of pore formation by the pyroptosis executioner gasdermin D (GSDMD). The functional relevance and effects of pyroptosis on chronic obstructive pulmonary disease (COPD) airway remodeling remain nearly unknown. <bold>Methods:</bold> We analyzed the expression levels of pyroptosis-associated molecules based on GEO database and ozone-induced mouse models of COPD. Additionally, we investigated the effects of disulfiram on COPD airway remodeling. <bold>Results:</bold> Our study found that the expression level of GSDMD and other molecules involved in pyroptosis signaling pathway was significantly up-regulated in small airway brushing samples from COPD patients compared with healthy control group. We established ozone-induced oxidative stress mouse models which showed characteristics of COPD including airway remodeling. In this model, GSDMD was mainly expressed in lung epithelial cells and macrophages. GSDMD mediated pyroptosis was activated in lung tissues. Additionally, we demonstrated that disulfiram inhibited GSDMD mediated pyroptosis, decreased the expression levels of proinflammatory cytokines IL-1β and IL-18, thereby alleviating airway remodeling in COPD mouse model. <bold>Conclusion:</bold> Collectively, these findings revealed the role of GSDMD-mediated pyroptosis in airway remodeling of COPD and the potential application of disulfiram in the treatment of COPD.