title: Interstitial trypsinogen release and its relevance to the transformation of mild into necrotizing pancreatitis in rats.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Surgery, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts, USA. fernandez-delcastillo.carlos@mgh.harvard.edu
authors.forename: W
authors.initials: W
authors.lastname: Hartwig
authors.forename: R E
authors.initials: RE
authors.lastname: Jimenez
authors.forename: J
authors.initials: J
authors.lastname: Werner
authors.forename: K B
authors.initials: KB
authors.lastname: Lewandrowski
authors.forename: A L
authors.initials: AL
authors.lastname: Warshaw
authors.forename: C
authors.initials: C
authors.lastname: Fernández-del Castillo
mesh_terms: D000818:Animals; D002108:Ceruletide / Q000494:pharmacology; D004765:Enteropeptidase / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D008297:Male; D009842:Oligopeptides / Q000378:metabolism; D010195:Pancreatitis / Q000473:pathology / Q000503:physiopathology*; D019283:Pancreatitis, Acute Necrotizing / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014362:Trypsinogen / Q000378:metabolism*
chemical_list: D009842:Oligopeptides; C080396:trypsinogen activation peptide; D002108:Ceruletide; D014362:Trypsinogen; D004765:Enteropeptidase