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Am J Physiol Gastrointest Liver Physiol (September 21, 2001). doi:10.1152/ajpgi.00315.2001
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Articles in PresS, published online ahead of print September 21, 2001
Am J Physiol Gastrointest Liver Physiol, 10.1152/ajpgi.00315.2001
Submitted on July 18, 2001
Accepted on September 5, 2001

Trypsin activity is not involved in premature, intrapancreatic trypsinogen activation

Walter Halangk1, Burkhard Kruger2, Manuel Ruthenburger3, Jorg Sturzebecher4, Elke Albrecht2, Hans Lippert1, and Markus M Lerch3*

1 Surgery, Otto-von Guericke-Universitaet, Magdeburg, Germany
2 Pathology, Universitat Rostock, Rostock, Germany
3 Medicine B, Westfaelische Wilhelms-Universitaet, Muenster, Germany
4 Vascular Biology and Medicine, Erfurt, Friedrich-Schiller-Universitaet Jena, Erfurt, Germany

* To whom correspondence should be addressed. E-mail: markus.lerch{at}uni-muenster.de.

A premature and intracellular activation of digestive zymogens is thought to be responsible for the onset of pancreatitis. Because trypsin has a critical role in initiating the activation cascade of digestive enzymes in the gut, it has been assumed that trypsin also initiates intracellular zymogen activation in the pancreas. We have tested this hypothesis in isolated acini and lobules from rat pancreas. Intracellular trypsinogen activation was induced by supramaximal secretagogue stimulation and measured using either specific trypsin substrates or immunoreactivity of the trypsinogen activation peptide (TAP). To prevent a trypsin-induced trypsinogen activation we used the cell permeant, highly specific and reversible inhibitor S124, and to prevent cathepsin-induced trypsinogen activation the cysteine protease inhibitor E-64d. Incubation of acini or lobules in the presence of S124 completely prevented the generation of trypsin activity in response to supramaximal caerulein, but had no effect whatsoever on the generation of TAP. Conversely, when trypsin activity was recovered at the end of the experiment by either wash-out of S124 from acini, or extensive dilution of lobule homogenates, it was up to 400% higher than after caerulein alone - and corresponded, in molar terms, to the generation of TAP. Both, trypsin activity and TAP release were inhibited in parallel by E-64d. We conclude that caerulein-induced trypsinogen activation in the pancreas is caused by an E-64d-inhibitable mechanism such as cathepsin-induced trypsinogen activation, and neither involves nor requires intracellular trypsin activity. Specific trypsin inhibition, on the other hand, prevents 80% of trypsin inactivation or autodegradation in the pancreas.




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