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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 7

Effective experimental therapeutics with an FDA-approved anticoagulation agent in PRSS1R122H mice.

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Effective experimental therapeutics with an FDA-approved anticoagulation...
(A) Schema of pancreatitis induction and treatment in PRSS1R122H mice. Pancreatitis was induced by cerulein, and therapeutic drugs were administered 5 hours after the first cerulein injection. (B) After 7 days of treatment, pancreata in the untreated control group became smaller. In contrast, pancreata in dabigatran-treated groups were mostly normal. Camostat only exhibited intermediate effects at higher does (300 mg/kg). Both drugs were given twice daily for 7 days. Mean ± SEM (n = 10 per group). ***P < 0.001; 1-way ANOVA with Tukey’s multiple comparisons test. (C) Histology score evaluation showed that dabigatran significantly improved CP. Mean ± SEM (n = 10 per group). ***P < 0.001; 1-way ANOVA with Tukey’s multiple comparisons test. (D) Representative images of H&E staining after drug treatments over 7 days (n = 10 per group). Scale bars: 200 μm.
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