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Articles in PresS, published online ahead of print April 10, 2002
Am J Physiol Gastrointest Liver Physiol, 10.1152/ajpgi.00363.2001
Submitted on August 15, 2001
Accepted on April 1, 2002
1 Department of Surgery, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: msteer{at}caregroup.harvard.edu.
Intrapancreatic activation of trypsinogen is believed to play a critical role in the initiation of acute pancreatitis, but mechanisms responsible for intrapancreatic trypsinogen activation during pancreatitis have not been clearly defined. In previous in-vitro studies, we have shown that intra-acinar cell activation of trypsinogen and acinar cell injury in response to supramaximal secretagogue stimulation could be prevented by the cell permeant cathepsin B inhibitor E64d (Saluja A et al, Gastroenterology 113:304-10, 1997). The present studies evaluated the role of intrapancreatic trypsinogen activation, this time under in-vivo conditions, in two models of pancreatitis using another highly soluble cell permeant cathepsin B inhibitor, CA-074me. Intravenous administration of CA-074me (10 mg/kg) prior to induction of either secretagogue-elicited pancreatitis in mice or duct infusion-elicited pancreatitis in rats markedly reduced the extent of intrapancreatic trypsinogen activation and substantially reduced the severity of both pancreatitis models. These observations support the hypothesis that, during the early stages of pancreatitis, trypsinogen activation in the pancreas is mediated by the lysosomal enzyme cathepsin B. Our findings also suggest that pharmacological interventions which inhibit cathepsin B may prove useful in preventing acute pancreatitis or reducing its severity.
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