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

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 5

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Extrapancreatic manifestations of experimental pancreatitis. The time co...
Extrapancreatic manifestations of experimental pancreatitis. The time course over 24 hours is shown for (a) serum concentrations of IL-6, (b) MPO levels in the pancreas, (c) MPO levels in the lungs, and (d–g) morphological changes in the lungs. Data points represent the means of five or more animals at each interval ± SEM. ASignificant differences (P < 0.05) between CTSB+/+ and CTSB–/– animals. (d–g) Representative examples for the lung histology of saline-injected control (CTSB+/+, d; CTSB–/–, e) mice, and pancreatitis animals at 24 hours of the disease (CTSB+/+, f; CTSB–/–, g) are shown. Note that the thickening of the interalveolar tissue, its hyperemia, and the infiltration by leukocytes are indistinguishable between the CTSB+/+ and CTSB–/– group of animals. Calibration bar = 100 μm.