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Background & Aims: Intracellular activation of trypsinogen is currently believed to initiate pancreatitis. Factors responsible for the progression of mild to necrotizing pancreatitis are poorly understood. This study evaluated the significance of interstitial protease release and activation in this process., Methods: In rats with cerulein-induced pancreatitis, concentrations of trypsinogen and its activation peptide TAP were measured in lymph and blood, and pancreatic injury was determined. Activation of extracellular trypsinogen was induced by intravenous infusion of enterokinase, which does not enter the acinar cell. Gabexate mesilate (acinar cell permeable) or soybean trypsin inhibitor (acinar cell nonpermeable) was administered to distinguish the effects of intracellular or extracellular protease activation., Results: In cerulein pancreatitis, trypsinogen levels increased prominently and were highest in lymph and portal vein blood, whereas TAP increments were modest. Combined cerulein/enterokinase infusions resulted in marked TAP increases in lymph and blood and in severe necrohemorrhagic pancreatitis. Gabexate mesilate as well as soybean trypsin inhibitor significantly decreased TAP levels in both lymph and blood and reduced pancreatic injury, with no significant differences between groups., Conclusions: In secretagogue-induced pancreatitis, large amounts of trypsinogen are present in the interstitium and drain via the portal and lymphatic circulation. Activation of this extracellular trypsinogen induces hemorrhagic necrosis in a setting of mild edematous pancreatitis. This phenomenon may be the central event in the progression to fulminant necrotizing pancreatitis.

Background & Aims: The mechanism by which alcohol injures the pancreas remains unknown. Alcohol-intoxicated humans have high levels of fatty acid ethyl esters (FAEEs), nonoxidative products of ethanol metabolism, in blood, pancreas, and liver. The aims of this study were to determine whether FAEEs are toxic to the pancreas in vivo and, if so, to assess whether this injury is specific to the pancreas and to compare it to the injury observed in acute pancreatitis., Methods: FAEEs were infused into Sprague-Dawley rats. Levels of FAEEs in plasma and pancreas were measured, and pancreatic injury was assessed during a 48-hour period for edema formation and ectopic trypsinogen activation and by light and electron microscopy., Results: FAEEs induced highly significant increases in pancreatic edema, pancreatic trypsinogen activation, and vacuolization of acinar cells. These findings were specific to the pancreas and were not found in liver, lung, myocardium, skeletal muscle, or subcutaneous fat., Conclusions: FAEEs at concentrations found in human plasma produce a pancreatitis-like injury in rats, providing direct evidence that FAEEs can produce organ-specific toxicity. Thus, FAEEs may contribute to acute alcohol-induced damage to the pancreas.

Background & Aims: Clinical and experimental observations have associated acute and chronic hypercalcemia with pancreatitis. The aim of this study was to determine whether acute hypercalcemia can induce acute pancreatitis and, if so, whether the pathogenesis involves premature protease activation., Methods: Rats given bolus infusions of CaCl2 (200 mg/kg; n = 76) were compared with saline-treated controls (n = 40). Serum [Ca2+], serum amylase activity, trypsinogen activation peptide (TAP) concentration in serum and pancreatic tissue, pancreatic wet/dry weight ratio, and histology were assessed for 24 hours. For dose-response analysis, CaCl2 was injected at a dose of 50-200 mg/kg, and the aforementioned indices were assayed for 1 hour (n = 5 each)., Results: There were no significant changes in the controls. Calcium infusion increased serum [Ca2+] 3-fold after 5 minutes (P < 0.001). Within 1 hour, serum amylase (2.5-fold) and tissue TAP (3-fold) levels increased along with macroscopic and microscopic edema formation and leukocytic infiltration. The extent of the changes at 1 hour correlated with the calcium dose. Amylase and tissue TAP concentrations remained elevated until 24 hours when serum TAP concentration had increased (P < 0.001) and focal acinar necrosis became evident., Conclusions: Acute experimental hypercalcemia induces dose-dependent morphological alterations characteristic of acute pancreatitis, acute hyperamylasemia, and early ectopic trypsinogen activation. This supports the pathophysiological relevance of excess calcium and offers a possible pathogenetic mechanism for its association with clinical pancreatitis.

Background/aims: Contrast-enhanced computed tomography (CECT) is used to show areas of decreased pancreatic perfusion in severe acute pancreatitis (AP). To evaluate possible adverse effects of the contrast medium (CM) on the course of AP, the impact of intravenous CM in AP of graded severity in the rat was studied., Methods: Pancreatitis of three levels of severity was induced in Sprague-Dawley rats with intravenous cerulein hyperstimulation plus time- and pressure-controlled intraductal infusion of saline or glycodeoxycholic acid. At 7 hours, control and pancreatitis animals received intravenous ionic CM, nonionic CM, or saline. The principal outcome measures were 24-hour survival, trypsinogen activation peptides (TAP) in ascites, and histological acinar necrosis score., Results: There was no measurable effect of CM on the index features in control animals or animals with mild or moderate AP. In severe AP, CM caused a significant increase in mortality, ascites TAP, and necrosis score., Conclusions: Intravenous CM increases pancreatic injury when administered early in the course of severe experimental AP. Because CM may convert borderline ischemia to irreversible necrosis, CECT performed early in pancreatitis to show poor perfusion and predict areas of necrosis may depict a self-fulfilling prophecy. Early CECT should be reconsidered and perhaps avoided.