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

Jinxiang Wu,Jintao Zhang,Jiping Zhao,Tao Zhou,Jianwei Xu,Shihong Chen

doi:10.3389/fcell.2021.780142

Abstract

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 pancreatic 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 a Food and Drug Administration (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, 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 the treatment of SAP.

Highlights

Acute pancreatitis (AP) is an inflammatory disorder featured by the destruction of acinar cells
Increases of gasdermin D (GSDMD), IL-1β, and IL-18 were observed in lung tissues in WT-severe acute pancreatitis (SAP) mouse models, while Gsdmd knockout decreased the levels of IL-1β and IL-18 in lung tissues (Figure 2)
SAP is an inflammatory disease featured by the activation of trypsinogen, infiltration of inflammatory cells, and destruction of acinar cells

Summary

Introduction

Acute pancreatitis (AP) is an inflammatory disorder featured by the destruction of acinar cells. Approximately over 20% of all patients with AP will develop to be a severe condition with multiorgan dysfunction, such as the lungs, kidneys, heart, and gut (Leppäniemi et al, 2019; Nassar and Qunibi, 2019), which results in a mortality of 15% (van Santvoort et al, 2011). Acute lung injury (ALI) is the most common distant organ dysfunction secondary to severe AP (SAP) with an incidence of 27.7% (Lei et al, 2013; Barreto et al, 2021), which accounts for up to 60% SAP-associated deaths (Elder et al, 2012). One goal of AP treatment is reducing the incidence of mild AP developing to SAP and the mortality of SAP. Understanding the mechanisms of SAP-associated ALI is helpful to effective treatment of this severe disease

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Conclusion