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Trypsin activity governs increased susceptibility to pancreatitis in mice expressing human PRSS1R122H
Fu Gui, … , Yan Bi, Baoan Ji
Fu Gui, … , Yan Bi, Baoan Ji
Published September 24, 2019
Citation Information: J Clin Invest. 2020;130(1):189-202. https://doi.org/10.1172/JCI130172.
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Research Article Gastroenterology

Trypsin activity governs increased susceptibility to pancreatitis in mice expressing human PRSS1R122H

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Abstract

Currently, an effective targeted therapy for pancreatitis is lacking. Hereditary pancreatitis (HP) is a heritable, autosomal-dominant disorder with recurrent acute pancreatitis (AP) progressing to chronic pancreatitis (CP) and a markedly increased risk of pancreatic cancer. In 1996, mutations in PRSS1 were linked to the development of HP. Here, we developed a mouse model by inserting a full-length human PRSS1R122H gene, the most commonly mutated gene in human HP, into mice. Expression of PRSS1R122H protein in the pancreas markedly increased stress signaling pathways and exacerbated AP. After the attack of AP, all PRSS1R122H mice had disease progression to CP, with similar histologic features as those observed in human HP. By comparing PRSS1R122H mice with PRSS1WT mice, as well as enzymatically inactivated Dead-PRSS1R122H mice, we unraveled that increased trypsin activity is the mechanism for R122H mutation to sensitize mice to the development of pancreatitis. We further discovered that trypsin inhibition, in combination with anticoagulation therapy, synergistically prevented progression to CP in PRSS1R122H mice. These animal models help us better understand the complex nature of this disease and provide powerful tools for developing and testing novel therapeutics for human pancreatitis.

Authors

Fu Gui, Yuebo Zhang, Jianhua Wan, Xianbao Zhan, Yao Yao, Yinghua Li, Ashley N. Haddock, Ji Shi, Jia Guo, Jiaxiang Chen, Xiaohui Zhu, Brandy H. Edenfield, Lu Zhuang, Cheng Hu, Ying Wang, Debabrata Mukhopadhyay, Evette S. Radisky, Lizhi Zhang, Aurelia Lugea, Stephen J. Pandol, Yan Bi, Baoan Ji

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Figure 4

CP developed in transgenic PRSS1R122H mice.

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CP developed in transgenic PRSS1R122H mice.
(A) Schema of cerulein admin...
(A) Schema of cerulein administration protocol. (B) After cerulein induction, the body weight changes of the mice were monitored. Mean ± SEM (n = 5–10). (C) Representative pancreas images on day 70 from transgenic PRSS1R122H mice and WT C57BL/6J mice (n = 5–10). (D) Pancreas weight was compared 70 days after cerulein induction. Mean ± SEM (n = 5–10). ***P < 0.001; 2-tailed unpaired Student’s t test. (E) CP with fat replacement, fibrosis, and pancreatic intraepithelial neoplasia (PanIN) lesions developed in PRSS1R122H mice. These features were similarly observed in the pancreata of human patients with hereditary pancreatitis. (F) Overall histology score of CP. Mean ± SEM (n = 5–10). ***P < 0.001; 2-tailed unpaired Student’s t test.
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