Interstitial trypsinogen release and its relevance to the transformation of mild into necrotizing pancreatitis in rats

Background & Aims: Intracellular activation of trypsinogen is currently bel ieved to initiate pancreatitis. Factors responsible for the progression of mild to necrotizing pancreatitis are poorly understood. This study evaluate d the significance of interstitial protease release and activation in this process. Methods: in rats with cerulein-induced pancreatitis, concentration s of trypsinogen and its activation peptide TAP were measured in lymph and blood, and pancreatic injury was determined. Activation of extracellular tr ypsinogen was induced by intravenous infusion of enterokinase, which does n ot enter the acinar cell. Gabexate mesilate (acinar cell permeable) or soyb ean trypsin inhibitor (acinar cell nonpermeable) was administered to distin guish the effects of intracellular or extracellular protease activation. Re sults: In cerulein pancreatitis, trypsinogen levels increased prominently a nd were highest in lymph and portal vein blood, whereas TAP increments were modest. Combined cerulein/enterokinase infusions resulted in marked TAP in creases in lymph and brood and in severe necrohemorrhagic pancreatitis, Gab exate mesilate as well as soybean trypsin inhibitor significantly decreased IAP levels in both lymph and blood and reduced pancreatic injury, with no significant differences between groups. Conclusions: In secretagogue-induce d pancreatitis, large amounts of trypsinogen are present in the interstitiu m and drain via the portal and lymphatic circulation. Activation of this ex tracellular trypsinogen induces hemorrhagic necrosis in a setting of mild e dematous pancreatitis. This phenomenon may be the central event in the prog ression to fulminant necrotizing pancreatitis.