Proinflammatory role of trypsin and protease-activated receptor-2 in a rat model of acute pancreatitis.
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.
Maeda
Keisuke
K
Department of Gastroenterological Surgery, Postgraduate School of Medicine, Kumamoto University, Kumamoto-city, Kumamoto, Japan.
Hirota
Masahiko
M
Kimura
Yu
Y
Ichihara
Atsushi
A
Ohmuraya
Masaki
M
Sugita
Hiroki
H
Ogawa
Michio
M
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*
D016207:Cytokines; D044464:Receptor, PAR-2; D008049:Lipase; D000681:Amylases; D014357:Trypsin; D002118:Calcium