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1 Division of Experimental Surgery, Department of Surgery, Otto-von-Guericke-Universität, 39120 Magdeburg; 2 Division of Medical Biology, Department of Pathology, Universität Rostock, 18057 Rostock; 3 Department of Medicine B, Westfälische Wilhelms-Universität, 48129 Münster; and 4 Center for Vascular Biology and Medicine Erfurt, Friedrich-Schiller-Universität Jena, 99089 Erfurt, Germany
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
N
-(2-naphthylsulfonyl)-3-amidinophenylalanine-carboxymethylpiperazide (S124), and to prevent cathepsin-induced trypsinogen activation, we
used 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 washout
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.
autoactivation; cathepsin B; acute pancreatitis
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