Disulfiram Protects Against Multiorgan Injuries and Cell Pyroptosis via Inhibiting GSDMD in Severe Acute Pancreatitis Mice

Abstract

Severe acute pancreatitis (SAP) is distinguished by an uncontrolled systemic pro-inflammatory response caused by the activation of trypsin within the pancreatic tissue, leading to the occurrence of multiple organ failure (MOF). Gasdermin D (GSDMD)-induced pyroptosis represents a form of programmed cell death characterised by robust inflammatory responses. This indicates that directing efforts towards pyroptosis could potentially offer a remedy for SAP and its related MOF. Our objective was to examine the impact of disulfiram (DSF), a potent inhibitor of pyroptosis, and its potential therapeutic mechanism in SAP. The biochemical and histological assessments provided clear evidence that DSF effectively hindered necrosis, infiltration, oedema and cellular demise within pancreatic tissues. As a result, DSF effectively suppressed acute pancreatitis. Significantly, DSF hindered the process of GSDMD-mediated pyroptosis in pancreatic cells within the context of SAP. This is evident through the observed decrease in the number of SYTOX-positive cells, the prevention of LDH release and the restriction of expression of full-length GSDMD, N-terminal GSDMD and p-NF-ĸB p65. Subsequently, we assessed the mRNA levels of the pro-inflammatory cytokines Il-18, Il-1β, Il-6, Tnf-α, Hmgb1 and Ccl2. Our findings revealed a significant rise in the levels of these pro-inflammatory cytokines in SAP mice, whereas DSF remarkably inhibited the release of them. It is noteworthy that DSF also mitigated the resultant damage to remote vital organs (lungs, liver, and kidneys). Thus, GSDMD-mediated pyroptosis has been significantly involved in the pathogenesis of SAP, and DSF could potentially serve as an alternative therapeutic agent for SAP and its associated MOF.