TRANSGENIC EXPRESSION OF INTRACELLULAR ACTIVE TRYPSIN DOES NOT CAUSE ACUTE PANCREATITIS

Abstract

Background: It is widely believed that premature intracellular activation of trypsinogen (TRY) is the initiating event in pancreatitis. However, its biological consequences have not yet been directly tested. Therefore, the aim was to develop a transgenic mouse model expressing intracellular active TRY. Methods: Mutant TRY, which can be activated by the endogenous protease PACE, was utilized to achieve intracellular expression and activation of trypsinogen. Using a Cre-loxP approach, mutant floxed pace-TRY mice were interbred with tamoxifen regulated Cre mice. Upon activation with tamoxifen, full-length Elastase promoter driven Cre was specifically expressed in nearly all pancreatic acinar cells. Pace-TRY expression was documented by western blot in double transgenic mice. Acinar cell morphology was monitored by light and electron microscopy. Levels of apoptosis and inflammation were examined. Results: Pace-TRY was expressed and activated in acinar cells and was correctly localized to the secretory pathway. After induction by tamoxifen, the active TRY mutant caused extensive loss of zymogen granules reaching more than 80% loss after 7d. However, despite the obvious effects on acinar cell morphology, no edema or obvious inflammation was observed and only few cells underwent apoptosis. Conclusion: These results indicate that intracellular trypsinogen activation alone does not cause acute pancreatitis. Other co-factors may be necessary to precipitate the disease. This study provides important new insights into the role of trypsin activity for the initiation of pancreatitis.