Effect of co-treatment with disulfiram and resatorvid on the pyroptosis of monocytes in sepsis

Abstract

Purpose

To evaluate the effects of co-treatment with Disulfiram and Resatorvid on sepsis.

Methods

Monocytes were isolated from the peripheral blood of sepsis patients with Staphylococcus aureus (S. aureus)-induced infective endocarditis and healthy controls. The expression of Gasdermin D (GSDMD) was analyzed using quantitative polymerase chain reaction (qRT-PCR), Western blotting, and immunofluorescence. An in vitro cellular model of sepsis was established by stimulating monocytes with heat-killed Staphylococcus aureus (HK S. aureus). Cells were pre-treated with Disulfiram and/or Resatorvid. Caspase-1, GSDMD, and interleukin-1 beta (IL-1β) expression were measured by qRT-PCR and Western blotting. A cecal ligation and puncture (CLP) mouse model was used to study in vivo sepsis. Outcomes assessed included survival rate, sickness behavior score, lung wet-to-dry weight ratio, and neutrophil count in the lung.

Results

Compared to healthy controls, GSDMD expression was elevated in monocytes from sepsis patients. Cleaved Caspase-1, N-terminal GSDMD fragments, and secreted IL-1β increased in monocytes were stimulated with HK S. aureus over time. Disulfiram pre-treatment reduced the secretion of IL-1β in HK S. aureus-stimulated monocytes. Resatorvid pre-treatment decreased levels of cleaved Caspase-1, N-terminal GSDMD fragments, and secreted IL-1β. Co-treatment with Disulfiram and Resatorvid resulted in greater reductions in cleaved Caspase-1, N-terminal GSDMD fragments, and IL-1β, and improved outcomes in the CLP mouse model, including higher survival rates, lower sickness behavior scores, reduced lung wet-to-dry weight ratios, and fewer neutrophils in the lung.

Conclusion

These findings indicated that pyroptosis of monocytes was activated in sepsis. Disulfiram and Resatorvid pre-treatment effectively suppressed the pyroptosis of monocytes through the Caspase-1/GSDMD/IL-1β signaling pathway. The combination of Disulfiram and Resatorvid showed potential as a therapeutic strategy to mitigate sepsis severity.