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Phosphatidylinositol 3-kinase-dependent activation of trypsinogen modulates the severity of acute pancreatitis
Vijay P. Singh, … , Lewis C. Cantley, Michael L. Steer
Vijay P. Singh, … , Lewis C. Cantley, Michael L. Steer
Published November 1, 2001
Citation Information: J Clin Invest. 2001;108(9):1387-1395. https://doi.org/10.1172/JCI12874.
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Article

Phosphatidylinositol 3-kinase-dependent activation of trypsinogen modulates the severity of acute pancreatitis

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Abstract

Intra-acinar cell activation of digestive enzyme zymogens including trypsinogen is generally believed to be an early and critical event in acute pancreatitis. We have found that the phosphatidylinositol 3-kinase inhibitor wortmannin can reduce the intrapancreatic activation of trypsinogen that occurs during two dissimilar experimental models of rodent acute pancreatitis, secretagogue- and duct injection-induced pancreatitis. The severity of both models was also reduced by wortmannin administration. In contrast, the NF-κB activation that occurs during the early stages of secretagogue-induced pancreatitis is not altered by administration of wortmannin. Ex vivo, caerulein-induced trypsinogen activation is inhibited by wortmannin and LY294002. However, the cytoskeletal changes induced by caerulein were not affected by wortmannin. Concentrations of caerulein that induced ex vivo trypsinogen activation do not significantly increase phosphatidylinositol-3,4-bisphosphate or phosphatidylinositol 3,4,5-trisphosphate levels or induce phosphorylation of Akt/PKB, suggesting that class I phosphatidylinositol 3-kinases are not involved. The concentration of wortmannin that inhibits trypsinogen activation causes a 75% decrease in phosphatidylinositol 3-phosphate, which is implicated in vesicle trafficking and fusion. We conclude that a wortmannin-inhibitable phosphatidylinositol 3-kinase is necessary for intrapancreatic activation of trypsinogen and regulating the severity of acute pancreatitis. Our observations suggest that phosphatidylinositol 3-kinase inhibition might be of benefit in preventing acute pancreatitis.

Authors

Vijay P. Singh, Ashok K. Saluja, Lakshmi Bhagat, Gijs J.D. van Acker, Albert M. Song, Stephen P. Soltoff, Lewis C. Cantley, Michael L. Steer

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Figure 6

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Trypsinogen activation in duct-injection pancreatitis. Rats underwent re...
Trypsinogen activation in duct-injection pancreatitis. Rats underwent retrograde duct injection with sodium taurocholate (TAURO) as described in the text and were sacrificed 20 hours later. When given, wortmannin (1.4 mg/kg) was delivered by intraperitoneal injection 4 hours before and 12 hours after duct infusion. Trypsin activity in homogenates of pancreas was expressed relative to that noted for duct-infused animals not given wortmannin. *P < 0.05 when wortmannin groups were compared with duct-infusion group not given wortmannin.

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