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

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

Research output: Contribution to journalArticle

106 Citations (Scopus)

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-KB 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.

Original languageEnglish (US)
Pages (from-to)1387-1394
Number of pages8
JournalJournal of Clinical Investigation
Volume108
Issue number9
DOIs
StatePublished - 2001

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Phosphatidylinositol 3-Kinase
Trypsinogen
Pancreatitis
Ceruletide
Class I Phosphatidylinositol 3-Kinases
Enzyme Precursors
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Enzyme Activation
Acinar Cells
wortmannin
Rodentia
Theoretical Models
Phosphorylation
Injections

ASJC Scopus subject areas

  • Medicine(all)

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Phosphatidylinositol 3-kinase-dependent activation of trypsinogen modulates the severity of acute pancreatitis. / Singh, Vijay Prem; Saluja, Ashok K.; Bhagat, Lakshmi; Van Acker, Gijs J D; Song, Albert M.; Soltoff, Stephen P.; Cantley, Lewis C.; Steer, Michael L.

In: Journal of Clinical Investigation, Vol. 108, No. 9, 2001, p. 1387-1394.

Research output: Contribution to journalArticle

Singh, VP, Saluja, AK, Bhagat, L, Van Acker, GJD, Song, AM, Soltoff, SP, Cantley, LC & Steer, ML 2001, 'Phosphatidylinositol 3-kinase-dependent activation of trypsinogen modulates the severity of acute pancreatitis', Journal of Clinical Investigation, vol. 108, no. 9, pp. 1387-1394. https://doi.org/10.1172/JCI200112874
Singh, Vijay Prem ; Saluja, Ashok K. ; Bhagat, Lakshmi ; Van Acker, Gijs J D ; Song, Albert M. ; Soltoff, Stephen P. ; Cantley, Lewis C. ; Steer, Michael L. / Phosphatidylinositol 3-kinase-dependent activation of trypsinogen modulates the severity of acute pancreatitis. In: Journal of Clinical Investigation. 2001 ; Vol. 108, No. 9. pp. 1387-1394.
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