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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 8

Anticoagulation and trypsin inhibition synergistically improved pancreatitis in PRSS1R122H mice.

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Anticoagulation and trypsin inhibition synergistically improved pancreat...
(A) Immunohistochemical analysis showed intrapancreatic fibrin deposition, an indicator of increased coagulation, in the pancreata of PRSS1R122H mice 24 hours after cerulein induction (n = 5). Scale bars: 200 μm. (B) Western blot showed that active thrombin significantly increased in the pancreata of PRSS1R122H mice compared with those from C57BL/6J mice. Representative blots from 3 independent experiments are shown. (C) Schema of pancreatitis induction and drug treatment with the anticoagulation specific agent (apixaban), trypsin specific inhibitor (camostat), or in combination. Starting 5 hours after pancreatitis induction, drugs were given twice daily by oral gavage over 7 days. (D) Combination of anticoagulation therapy with factor Xa inhibitor apixaban (100 mg/kg) and trypsin inhibitor camostat (200 mg/kg) greatly protected the pancreas, as manifested by preservation of pancreas mass. Mean ± SEM (n = 15 per group). ***P < 0.001; 1-way ANOVA with Tukey’s multiple comparisons test. (E) Representative histologic images of H&E staining from untreated, apixaban alone, camostat alone, and combination therapy–treated mice (n = 15 per group). Scale bars: 200 μm. (F) Overall histology score evaluation of the mice. Mean ± SEM. Representative results from 6 mice per group are shown. ***P < 0.001; 1-way ANOVA with Tukey’s multiple comparisons test.
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