Chymotrypsin Reduces the Severity of Secretagogue-Induced Pancreatitis in Mice

Intrapancreatic activation of the digestive proteases trypsin and chymotrypsin is an early event in the development of pancreatitis. Human genetic studies indicate that chymotrypsin controls trypsin activity via degradation, but there is no evidence of this from animal models. We used CRISPR-Cas9 to...

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Published inGastroenterology (New York, N.Y. 1943) Vol. 155; no. 4; pp. 1017 - 1021
Main Authors Jancsó, Zsanett, Hegyi, Eszter, Sahin-Tóth, Miklós
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 01.10.2018
Subjects
Inflammation
Mouse Model
Pancreas
Proteolysis
T7
Proteolysis
CTRB1
Inflammation
Pancreas
CTRC
Mouse Model
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Summary:Intrapancreatic activation of the digestive proteases trypsin and chymotrypsin is an early event in the development of pancreatitis. Human genetic studies indicate that chymotrypsin controls trypsin activity via degradation, but there is no evidence of this from animal models. We used CRISPR-Cas9 to disrupt the chymotrypsinogen B1 gene (Ctrb1) in C57BL/6N mice and induced pancreatitis in CTRB1-deficient and C57BL/6N (control) mice by administration of cerulein. CTRB1-deficient mice given cerulein had significant increases in intrapancreatic trypsin activity and developed more severe pancreatitis compared with control mice. CTRB1 therefore protects against secretagogue-induced pancreatitis by reducing trypsin activity. Protease inhibitors developed for treatment of pancreatitis should be designed to target trypsin but not chymotrypsin. [Display omitted]
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Author contributions: MST conceived and directed the study. ZJ, EH and MST designed the experiments; ZJ performed the animal experiments and EH performed the trypsinogen degradation experiments. ZJ, EH and MST analyzed the data; MST wrote the manuscript with significant input from ZJ and EH. All authors read and approved the manuscript.
ISSN:0016-5085
1528-0012
DOI:10.1053/j.gastro.2018.06.041