Treatment of Severe Acute Pancreatitis and Related Lung Injury by Targeting Gasdermin D-Mediated Pyroptosis

The functional relevance and effects of the pyroptosis executioner gasdermin D (GSDMD) on severe acute pancreatitis (SAP) associated lung injury are unclear. We established caerulein-induced mouse models of SAP associated lung injury, which showed that GSDMD mediated pyroptosis was activated in both pancreas and lung tissues. Compared with Gsdmd wild type SAP mouse models, Gsdmd knockout (Gsdmd-/-) ameliorated SAP-induced pancreas and related lung injury. Additionally, we investigated the effects of disulfiram on the treatment of SAP. Disulfiram is an FDA-approved anti-alcoholism drug, which is reported as an effective pyroptosis inhibitor by either directly covalently modifying GSDMD or indirectly inhibiting the cleavage of GSDMD via inactivating nod-like receptor protein 3 inflammasome. We demonstrated that disulfiram inhibited the cleavage of GSDMD and alleviated caerulein-induced SAP and related lung injury and decreased the expression levels of proinflammatory cytokines (IL-1β and IL-18). Collectively, these findings disclosed the role of GSDMD mediated pyroptosis in SAP and the potential application of disulfiram in treatment of SAP.