ACS DIVISION OF BIOLOGICAL CHEMISTRY

July 30th, 2014 by Sah, R. P., Garg, S. K., Dixit, A. K., Dudeja, V., Dawra, R. K., Saluja, A. K.

The pathogenesis of chronic pancreatitis (CP) is poorly understood. Endoplasmic Reticulum (ER) stress has now been recognized as a pathogenic event in many chronic diseases. However, ER stress has not been studied in CP although pancreatic acinar cells seem to be especially vulnerable to ER dysfunction owing to their dependence on high ER volume and functionality. Here, we aim to investigate ER stress in CP, study its pathogenesis in relation to trypsinogen activation (widely regarded as the key event of pancreatitis) and explore its course during pancreatic injury. CP was induced in mice by repeated episodes of acute pancreatitis (AP) based on caerulein hyperstimulation. ER stress leads to activation of unfolded protein response (UPR) components which were measured in CP and AP. We show sustained upregulation of UPR components ATF4, CHOP, GRP78 and XBP1 in CP. Overexpression of GRP78 was seen in human CP compared to healthy donor pancreas confirming sustained ER stress in CP. We used novel trypsinogen-7 knockout mice (T-/-) which lack intra-acinar trypsinogen activation to clarify relationship of ER stress to intra-acinar trypsinogen activation in pancreatic injury. Comparable activation of ER stress was seen in wild type and T-/- mice. Induction of ER stress occurred very early in the course of pancreatic injury. Our results establish that ER stress is chronically activated in CP, is an early event in pancreatic injury and is induced independent of trypsinogen activation. ER stress may be an important pathogenic mechanism in pancreatitis which needs to be explored in future studies.