Heat shock protein 70 prevents secretagogue-induced cell injury in the pancreas by preventing intracellular trypsinogen activation

Rodents given a supramaximally stimulating dose of cholecystokinin or its a nalogue cerulein develop acute pancreatitis with acinar cell injury, pancre atic inflammation, and intrapancreatic digestive enzyme (i.e., trypsinogen) activation. Prior thermal stress is associated with heat shock protein 70 (HSP70) expression and protection against cerulein-induced pancreatitis. Ho wever, thermal stress can also induce expression of other HSPs. The current studies were performed using an in vitro system to determine whether HSP70 can actually mediate protection against pancreatitis and, if so, to define the mechanism underlying that protection. We show that in vitro exposure o f freshly prepared rat pancreas fragments to a supramaximally stimulating d ose of cerulein results in changes similar to those noted in cerulein-induc ed pancreatitis, i.e., intra-acinar cell trypsinogen activation and acinar cell injury. Short-term culture of the fragments results in HSP70 expressio n and loss of the pancreatitis-like changes noted after addition of cerulei n. The culture-induced enhanced HSP70 expression can be prevented by additi on of either the flavonoid antioxidant quercetin or an antisense oligonucle otide to HSP70. Under these latter conditions, addition of a supramaximally stimulating concentration of cerulein results in trypsinogen activation an d acinar cell injury. These findings indicate that the protection against c erulein-induced pancreatitis that follows culture-induced (and possibly the rmal) stress is mediated by HSP70. They suggest that the HSP acts by preven ting trypsinogen activation within acinar cells.