title: Proinflammatory role of trypsin and protease-activated receptor-2 in a rat model of acute pancreatitis.
abstract: OBJECTIVE
  The pathophysiology of acute pancreatitis is strongly associated with autoactivation of trypsin. The biologic activity of trypsin on cells is attributed to the activation of protease-activated receptor-2 (PAR-2). We hypothesize that trypsin may activate acinar cells or inflammatory cells through PAR-2 signals in acute pancreatitis.
  
  
  METHODS
  We immunochemically analyzed the expression of PAR-2 in the rat acinar cell line, ARIP, and the rat pancreas, using anti-rat PAR-2 cleavage site (PCS) and anti-rat PAR-2 N-terminal fragment (PNF) antibodies. Plasma levels of PNF were determined. Furthermore, the effects of the anti-rat PCS antibody and nafamostat mesylate, a potent trypsin inhibitor, on PAR-2 activation during acute pancreatitis were also analyzed.
  
  
  RESULTS
  ARIP cells expressed PAR-2, which was activated by exogenous trypsin activity. We also showed that PAR-2 is strongly expressed in pancreatic acinar and duct cells and that it is activated in rat cerulein-induced acute pancreatitis. The anti-rat PCS antibody and nafamostat mesylate reduced interleukin-6 and interferon gamma production and alleviated distant organ injury.
  
  
  CONCLUSIONS
  These results suggest that trypsin and its specific receptor, PAR-2, play an important role in cytokine production and the resultant development of distant organ injury during rat acute pancreatitis.
authors.affiliation: Department of Gastroenterological Surgery, Postgraduate School of Medicine, Kumamoto University, Kumamoto-city, Kumamoto, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Maeda
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hirota
authors.forename: Yu
authors.initials: Y
authors.lastname: Kimura
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ichihara
authors.forename: Masaki
authors.initials: M
authors.lastname: Ohmuraya
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sugita
authors.forename: Michio
authors.initials: M
authors.lastname: Ogawa
mesh_terms: D000208:Acute Disease; D000681:Amylases / Q000097:blood; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D008049:Lipase / Q000097:blood; D008297:Male; D010195:Pancreatitis / Q000209:etiology* / Q000473:pathology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D044464:Receptor, PAR-2 / Q000032:analysis / Q000276:immunology / Q000502:physiology*; D014357:Trypsin / Q000502:physiology*
chemical_list: D016207:Cytokines; D044464:Receptor, PAR-2; D008049:Lipase; D000681:Amylases; D014357:Trypsin; D002118:Calcium