Title:Fenbufen Alleviates Severe Acute Pancreatitis by Suppressing
Caspase-1/Caspase-11-mediated Pyroptosis in Mice
Volume: 17
Author(s): Shien Shen, Wenqin Xiao, Weiliang Jiang, Kai Li, Xingya Guo, Guanzhao Zong, Chuanyang Wang, Jingpiao Bao, Jiahui Chen, Zhiyuan Cheng, Jie Shen and Rong Wan*
Affiliation:
- Department of Gastroenterology, Shanghai First People’s Hospital, Shanghai Jiao Tong University School of Medicine, No.85 Wujin Road,
Shanghai 200080, China
- Department of Gastroenterology, Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University
School of Medicine, No.650 Xinsongjiang Road, Shanghai 201620, China
Keywords:
Severe acute pancreatitis, Fenbufen, Pyroptosis, Caspase-1, Caspase-11, Acinar cell.
Abstract:
Aim:
In the present study, we aimed to investigate the effects of Fenbufen treatment on the SAP model induced by caerulein and lipopolysaccharide.
Background:
Severe acute pancreatitis (SAP) is an extremely dangerous disease with high mortality, which is associated with inflammatory response and acinar
cell death. The caspase family plays an important role in cell death, such as caspase-1 and caspase-11 in pyroptosis. In recent years, caspases have
been shown to be a novel pharmacological target of Fenbufen.
Objective:
Effects of Fenbufen on pancreatic tissue damage and serum levels of lipase and amylase in SAP in mice; Effect of Fenbufen on caspase-1 pathway
in SAP in mice; Effect of Fenbufen on caspase-1/caspase-11-mediated pyroptosis of PACs in SAP in mice; Effect of Fenbufen on isolated PACs
and caspase-1/caspase-11-mediated pyroptosis in vitro.
Methods:
In vivo, eighteen female C57BL/6 mice were randomly divided into 3 groups: the NC group, the SAP group, and the Fenbufen +SAP group with 6
mice in each group. The SAP model was induced by intraperitoneal injection of caerulein and lipopolysaccharide. The pathological changes in
pancreatic and the serum levels of lipase and amylase and the relative gene and protein expressions in each group were compared. In vitro,
pancreatic acinar cells were assigned to 5 groups: medium group, SAP group, Fenbufen 100μM group, Fenbufen 200μM group, and Fenbufen
400μM group. The cell damage and the relative gene and protein expressions in each group were evaluated.
Results:
Our results showed that Fenbufen ameliorated the severity of SAP and decreased the serum levels of lipase and amylase. Meanwhile, the in vivo
and in vitro data demonstrated that Fenbufen inhibited the activation of caspase-1 and caspase-11, decreasing the levels of IL-1β, IL-18, and
GSDMD. In in vitro experiments, we found that by inhibiting the activation of caspase-1 and caspase-11, Fenbufen significantly reduced lactate
dehydrogenase (LDH) excretion by acinar cells.
Conclusion:
In general, our data showed that Fenbufen could protect the pancreatic acinar cell from injury by inhibiting pyroptosis.
