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Role of cathepsin B in intracellular trypsinogen activation and the onset of acute pancreatitis
Walter Halangk, … , Christoph Peters, Jan Deussing
Walter Halangk, … , Christoph Peters, Jan Deussing
Published September 15, 2000
Citation Information: J Clin Invest. 2000;106(6):773-781. https://doi.org/10.1172/JCI9411.
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Article

Role of cathepsin B in intracellular trypsinogen activation and the onset of acute pancreatitis

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Abstract

Autodigestion of the pancreas by its own prematurely activated digestive proteases is thought to be an important event in the onset of acute pancreatitis. The mechanism responsible for the intrapancreatic activation of digestive zymogens is unknown, but a recent hypothesis predicts that a redistribution of lysosomal cathepsin B (CTSB) into a zymogen-containing subcellular compartment triggers this event. To test this hypothesis, we used CTSB-deficient mice in which the ctsb gene had been deleted by targeted disruption. After induction of experimental secretagogue–induced pancreatitis, the trypsin activity in the pancreas of ctsb–/– animals was more than 80% lower than in ctsb+/+ animals. Pancreatic damage as indicated by serum activities of amylase and lipase, or by the extent of acinar tissue necrosis, was 50% lower in ctsb–/– animals. These experiments provide the first conclusive evidence to our knowledge that cathepsin B plays a role in intrapancreatic trypsinogen activation and the onset of acute pancreatitis.

Authors

Walter Halangk, Markus M. Lerch, Barbara Brandt-Nedelev, Wera Roth, Manuel Ruthenbuerger, Thomas Reinheckel, Wolfram Domschke, Hans Lippert, Christoph Peters, Jan Deussing

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Figure 2

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Trypsinogen activation during experimental pancreatitis. In the experime...
Trypsinogen activation during experimental pancreatitis. In the experiment shown in a, dispersed acini were generated from the pancreas of CTSB-deficient and wild-type animals as described in Methods and incubated in different concentrations of caerulein. Amylase secretion over the course of 30 minutes was expressed in percent of total amylase content. In b–d, the pancreatitis time course is shown over a 24-hour period for (b) pancreatic trypsinogen content, (c) free trypsin activity in the pancreas, and (d) trypsinogen activation peptide (TAP) in the pancreas. Data points represent the means of four or more pancreatitis animals (n ≥ 3 for controls) at each interval ± SEM. ASignificant differences (P < 0.05) between the CTSB+/+ and the CTSB–/– mice.

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