Interstitial protease activation is the central event in progression to necrotizing pancreatitis.

ABSTRACT

BACKGROUND: Although intracellular protease activation is thought to be an early event in acute pancreatitis, factors determining progression from edematous to necrotizing pancreatitis are largely unknown. With enterokinase as a probe and an immunoassay quantifying free trypsinogen activation peptides (TAP), we sought evidence for the presence of interstitial trypsinogen in edematous pancreatitis and documented the effects of its ectopic activation. METHODS: Edematous pancreatitis in the rat was induced by supramaximal stimulation with cerulein (5 micrograms/kg/hr) and coupled with enterokinase infused into the pancreatic duct at 30 mm Hg. Blue dextran infusion at this pressure corroborated interstitial delivery. Rats with no stimulation, maximal physiologic stimulation (0.25 microgram/kg/hr of cerulein), or intraductal saline infusion served as controls. TAP levels measured by enzyme-linked immunosorbent assay, 6-hour survival, and histopathology were used as end points. RESULTS: Intraductal enterokinase infusion alone or in combination with maximal physiologic stimulation generated only slight increases in TAP level and no or minimal pancreatic injury. In contrast, enterokinase superimposed on edematous pancreatitis (supramaximal cerulein stimulation) produced fulminant pancreatitis and rapid death of all animals within 6 hours. Pancreatic histopathology showed severe intrapancreatic hemorrhage, acinar inflammation, and necrosis. TAP levels were significantly higher in plasma (p = 0.02), urine (p = 0.05), and ascites (p < 0.001) when compared with all other groups. CONCLUSIONS: In edematous pancreatitis a large pool of trypsinogen accumulates in the interstitial space. Activation of these proenzymes leads to catastrophic consequences and may underlie progression from mild to necrotizing pancreatitis.