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P53 Activated by ER Stress Suppresses Caerulein-Induced Acute Pancreatitis Progression in Humanized PRSS1 Transgenic Mice by Inducing Acinar Cell Apoptosis

38 Pages Posted: 28 Mar 2019

See all articles by Lei Zhou

Lei Zhou

Southern Medical University - Department of Hepatobiliary Surgery

Jie-hui Tan

Southern Medical University - Department of Hepatobiliary Surgery

Wan-yan Zhou

Southern Medical University - Department of Hepatobiliary Surgery

Jia Xu

Southern Medical University - Department of Pathophysiology

He-ping Kan

Southern Medical University - Department of Hepatobiliary Surgery

Shi-jing Ren

Southern Medical University - Department of Hepatobiliary Surgery

Zhen-yu Lin

Southern Medical University - Department of Hepatobiliary Surgery

Xue-mei Chen

Southern Medical University - School of Public Health

Guo-wei Zhang

Southern Medical University - Department of Hepatobiliary Surgery

More...

Abstract

Background: Acute pancreatitis is a severe pancreatic disorder that remains associated with high mortality due to a lack of effective drugs and management strategies. This study aimed to investigate the molecular pathogenic mechanisms of acute pancreatitis involving p53 and endoplasmic reticulum (ER) stress pathways.

Methods: Expression of PRSS1 and p53 in human acute pancreatitis tissues was detected by immunohistochemistry and western blotting. Acute pancreatitis was induced with caerulein in humanized PRSS1 transgenic mice, and its severity was verified by histological imaging, evaluation of edema, and serum amylase and trypsin activity assays. A transferase mediated d-UTP nick end-labeling assay was performed to evaluate acinar cell apoptosis associated with acute pancreatitis. The expression of ER stress genes was assessed by quantitative RT-PCR (qRT-PCR) and western blotting.

Results: PRSS1 and p53 were highly expressed in human acute pancreatitis tissues. Expression of human PRSS1 in caerulein-treated mice induced significant acinar cell apoptosis and acute pancreatitis progression. p53 knockout significantly aggravated acute pancreatitis progression in humanized PRSS1 transgenic mice. The ER stress pathway was activated by PRSS1 and mediated the progression of acute pancreatitis in mouse pancreatic tissues. Application of a p53 inhibitor promoted caerulein-induced acute pancreatitis in PRSS1 transgenic mice, while a p53 activator ameliorated the progression of acute pancreatitis.

Conclusion: P53, which was activated by the ER stress pathway, suppresses the progression of acute pancreatitis in mice expressing PRSS1 by inducing acinar cell apoptosis.

Funding: The article is supported by Scientific Research Startup Program of Southern Medical University by High-level University Construction Funding of Guangdong Provincial Department of Education (CX2018N012) & Clinical Research Program of Nanfang Hospital, Southern Medical University (2018CR046) & Clinical Research Startup Program of Southern Medical University by High-level University Construction Funding of Guangdong Provincial Department of Education (LC2016PY011).

Declaration of Interest: The authors declare no conflict of interest.

Ethical Approval: All experimental procedures performed with mice were approved by the Institutional Animal Care and Use Committee of Southern Medical University.

Keywords: P53; PRSS1; Acute pancreatitis; ER stress; Apoptosis

Suggested Citation

Zhou, Lei and Tan, Jie-hui and Zhou, Wan-yan and Xu, Jia and Kan, He-ping and Ren, Shi-jing and Lin, Zhen-yu and Chen, Xue-mei and Zhang, Guo-wei, P53 Activated by ER Stress Suppresses Caerulein-Induced Acute Pancreatitis Progression in Humanized PRSS1 Transgenic Mice by Inducing Acinar Cell Apoptosis (March 26, 2019). Available at SSRN: https://ssrn.com/abstract=3360103

Lei Zhou

Southern Medical University - Department of Hepatobiliary Surgery

Guangzhou
China

Jie-hui Tan

Southern Medical University - Department of Hepatobiliary Surgery

Guangzhou
China

Wan-yan Zhou

Southern Medical University - Department of Hepatobiliary Surgery

Guangzhou
China

Jia Xu

Southern Medical University - Department of Pathophysiology

Guangzhou
China

He-ping Kan

Southern Medical University - Department of Hepatobiliary Surgery

Guangzhou
China

Shi-jing Ren

Southern Medical University - Department of Hepatobiliary Surgery

Guangzhou
China

Zhen-yu Lin

Southern Medical University - Department of Hepatobiliary Surgery

Guangzhou
China

Xue-mei Chen

Southern Medical University - School of Public Health

Guangzhou, 510515
China

Guo-wei Zhang (Contact Author)

Southern Medical University - Department of Hepatobiliary Surgery ( email )

Guangzhou
China

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