Disulfiram alleviates epithelial barrier disruption in ozone-induced chronic obstructive pulmonary disease mouse models via inhibiting Gasdermin D-mediated pyroptosis

Background: Gasdermin D (GSDMD)-mediated Pyroptosis drives inflammatory cytokine release in response to environmental triggers. Disulfiram (DSF), an FDA-approved anti-alcoholism drug, has been demonstrated to inhibit GSDMD pore formation. Although airway epithelial barrier dysfunction contributes to chronic obstructive pulmonary disease (COPD) progression, the role of GSDMD-dependent Pyroptosis in ozone-induced pathogenesis, and the potential of DSF to inhibit this process, remain unexplored.

Methods: We analyzed the expression levels of pyroptosis-related molecules in airway epithelial cells from COPD patients' samples obtained from the Gene Expression Omnibus (GEO) database and evaluated the potential therapeutic effects of DSF in a mouse model of COPD induced by chronic ozone exposure.

Results: GSDMD was significantly upregulated in the airway epithelial cells of COPD patients. Chronic ozone exposure in mice elevated the cleaved form of GSDMD and reduced the expression of epithelial junctional proteins. DSF treatment effectively inhibited GSDMD-mediated Pyroptosis and attenuated epithelial barrier disruption, leading to significant improvements in airway inflammation and lung function in both large and small airways. Furthermore, Gsdmd expression was negatively correlated with the tight junction protein Occludin and pulmonary function indices, including the ratio of FEV₂₅ to FVC and MMEF.

Conclusion: Collectively, these findings revealed the role of GSDMD-mediated Pyroptosis in epithelial barrier disruption of COPD and the potential application of DSF in the treatment of COPD.

COPD; Disulfiram; Epithelial barrier; GSDMD; Pyroptosis.