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

被引：44
作者：
Wu, Jinxiang [1 ]
Zhang, Jintao [2 ]
Zhao, Jiping [1 ]
Chen, Shihong [3 ]
Zhou, Tao [4 ]
Xu, Jianwei [3 ]
机构：
[1] Shandong Univ, Qilu Hosp, Dept Pulm & Crit Care Med, Cheeloo Coll Med, Jinan, Peoples R China
[2] Shandong Univ, Shandong Qianfoshan Hosp, Dept Resp, Cheeloo Coll Med, Jinan, Peoples R China
[3] Shandong Univ, Qilu Hosp, Dept Pancreat Surg, Gen Surg,Cheeloo Coll Med, Jinan, Peoples R China
[4] Shandong Univ, Qilu Hosp, Dept Gastroenterol, Cheeloo Coll Med, Jinan, Peoples R China
来源：
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY | 2021年 / 9卷
基金：
中国国家自然科学基金;
关键词：
severe acute pancreatitis; acute lung injury; pyroptosis; GSDMD; disulfiram; programmed cell death; inflammation; DISULFIRAM; ACTIVATION; MICE;
D O I：
10.3389/fcell.2021.780142
中图分类号：
Q2 [细胞生物学];
学科分类号：
071009 ; 090102 ;
摘要：
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-1 beta 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.
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页数：9
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