Total Parenteral Nutrition Attenuates Cerulein-Induced Pancreatitis in Rats

Acute pancreatitis is a common clinical problem, with 250,000 inpatient admissions occurring each year in the United States alone,1 resulting in direct health care costs of 2.2 billion dollars.2 Most episodes of acute pancreatitis are mild-moderate and self-limiting, requiring only a period of fasting and supportive care until the pancreatic inflammation subsides. However, up to 20% of episodes of acute pancreatitis result in pancreatic necrosis,3 leading to increased rates of multisystem organ failure, infection, and mortality.4 The transition from mild-moderate acute pancreatitis to severe acute pancreatitis and pancreatic necrosis is not completely understood, and there are currently no therapies available to prevent this transition. However, there is a growing body of literature showing that the course of severe acute pancreas, once established, can be improved with nutritional interventions such as enteral feeding5 and supplementation with inflammatory and immune modulators.6 One of the initial events in pancreatitis is the premature activation of trypsin, which according to one theory, is due to aberrant colocalization of zymogen granules with lysosomal vacuoles containing cathepsin B. Cathepsin B is a hydrolase that activates trypsinogen, and the activated trypsin enzyme is released into the cytosol where it has the ability to activate itself and other intracellular digestive enzymes in a cascade that results in autodigestion and pancreatic injury.7 This colocalization theory is supported by a study showing that cathepsin B inhibition prevents intracellular zymogen activation without affecting the colocalization of zymogens and lysosomal hydrolases in response to cerulein stimulation.8 Given that pancreatitis is difficult to attenuate once it has occurred, prevention of pancreatitis by blocking the activation of trypsinogen is an obvious therapeutic goal. Heat shock protein 70 (Hsp70) is an inducible cytosolic protein that acts as a molecular chaperone and is involved in protein folding, degradation, membrane transport, and prevention of aggregation.9 Experimental Hsp70 induction has been accomplished using hyperthermic stress10 or warm-water immersion,11 catecholamine injection12 and ischemia,13 and sodium arsenite injection.14 Several authors have shown that Hsp70 induction with hyperthermia before infusion with the secretagogue cerulein, a cholecystokinin (CCK) analogue, can prevent the onset of pancreatitis in rats10,15 and that inhibition of Hsp70 expression with antisense oligonucleotides abolishes this protective effect of hyperthermic stress.16Hsp70 seems to prevent cerulein-induced acinar injury by preventing intrapancreatic trypsinogen activation,16 a critical initial step in pancreatitis. Furthermore, selective ablation of the Hsp70 gene in mice significantly enhances basal trypsin activity in the gland.17Hsp70 induction also results in reduced levels of downstream mediators of inflammation such as tumor necrosis factor α, intercellular adhesion molecule 1, and nuclear factor κB.18 We have shown previously that a 7-day course of total parenteral nutrition (TPN) and a lack of luminal nutrients induce pancreatic atrophy and Hsp70 expression in rats.19 The purpose of this study was to determine if TPN-induced pancreatic Hsp70 expression attenuates cerulein-induced pancreatic injury in the rat.