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Gastroenterology. 2019 Aug 13. pii: S0016-5085(19)41228-6. doi: 10.1053/j.gastro.2019.08.016. [Epub ahead of print]

Transgenic Expression of PRSS1R122H Sensitizes Mice to Pancreatitis.

Author information

1
Department of Cancer BiologyUniversity of Texas M.D. Anderson Cancer Center, Houston, TX; Department of Gastroenterology, Second Military Medical University, Shanghai, People's Republic of China.
2
Department of Cancer BiologyUniversity of Texas M.D. Anderson Cancer Center, Houston, TX; Department of Gastroenterology, Medical University of Bialystok, Bialystok, Poland.
3
Department of Cancer BiologyUniversity of Texas M.D. Anderson Cancer Center, Houston, TX.
4
Department of Gastroenterology, Second Military Medical University, Shanghai, People's Republic of China.
5
Department of Gastroenterology, Guangzhou Medical University, Guangzhou, China; Department of Cancer Biology.
6
Oncology, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China; Department of Cancer Biology.
7
Department of Pathology, the University of Texas M.D. Anderson Cancer Center, Houston, TX.
8
Gastroenterology, Mayo Clinic, Jacksonville, FL.
9
Department of Cancer Biology. Electronic address: ji.baoan@mayo.edu.
10
Department of Cancer BiologyUniversity of Texas M.D. Anderson Cancer Center, Houston, TX. Electronic address: clogsdon@mdanderson.org.

Abstract

BACKGROUND & AIMS:

Mutations in the trypsinogen gene (PRSS1) cause human hereditary pancreatitis. However, it is not clear how mutant forms of PRSS1 contribute to disease development. We studied the effects of expressing mutant forms of human PRSS1 in mice.

METHODS:

We expressed forms of PRSS1 with and without the mutation encoding R122H (PRSS1R122H) specifically in pancreatic acinar cells under control of a full-length pancreatic elastase gene promoter. Mice that did not express these transgenes were used as controls. Mice were given injections of caerulein to induce acute pancreatitis or injections of lipopolysaccharide (LPS) to induce chronic pancreatitis. Other groups of mice were fed ethanol or placed on a high-fat diet to induce pancreatitis. Pancreata were collected and analyzed by histology, immunoblots, real-time PCR, and immunohistochemistry. Trypsin enzymatic activity and chymotrypsin enzymatic activity were measured in pancreatic homogenates. Blood was collected and serum amylase activity was measured.

RESULTS:

Pancreata from mice expressing transgenes encoding PRSS1 or PRSS1R122H had focal areas of inflammation; these lesions were more prominent in mice that express PRSS1R122H. Pancreata from mice that express PRSS1 or PRSS1R122H had increased levels of HSP70 and NRF2 and reduced levels of chymotrypsin C (CTRC), compared with control mice. Increased expression of PRSS1 or PRSS1R122H increased focal damage in pancreatic tissues and increased the severity of acute pancreatitis after caerulein injection. Administration of LPS exacerbated inflammation in mice that express PRSS1R122H compared to mice that express PRSS1 or control mice. Mice that express PRSS1R122H developed more severe pancreatitis after ethanol feeding or a high-fat diet than mice that express PRSS1 or control mice. Pancreata from mice that express PRSS1R122H had more DNA damage, apoptosis, and collagen deposition and increased trypsin activity and infiltration by inflammatory cells than mice that express PRSS1 or control mice.

CONCLUSIONS:

Expression of a transgene encoding PRSS1R122H in mice promoted inflammation and increase the severity of pancreatitis, compared with mice that express PRSS1 or control mice. These mice might be used as a model for human hereditary pancreatitis and can be studied to determine mechanisms of induction of pancreatitis by LPS, ethanol, or a high-fat diet.

KEYWORDS:

Digestive enzyme; animal model; endotoxin; immune cells

PMID:
31419436
DOI:
10.1053/j.gastro.2019.08.016
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