Protease-activated receptor 2 exerts local protection and mediates some systemic complications in acute pancreatitis.
OBJECTIVE
Protease-activated receptor 2 can be stimulated by interstitially released trypsin during acute inflammation of the pancreas. In this study, we investigated the roles of pancreatic and circulatory protease-activated receptor 2 in the pathogenesis of acute pancreatitis by using in vitro and in vivo model systems.


METHODS
Physiological and pathologic effects of protease-activated receptor 2 activation were measured in isolated pancreatic cells and in rats with experimental pancreatitis. Consequences of protease-activated receptor 2 activation on the systemic and inflammatory responses were measured after treatments with trypsin or protease-activated receptor 2-activating peptide.


RESULTS
Stimulation of protease-activated receptor 2 in rat pancreatic acinar cells activated short-lasting (Ca(2+) signaling) and long-lasting (extracellular signal-related kinase) signaling pathways and protected the cells against bile-induced cell damage. More importantly, protease-activated receptor 2 activation ameliorated the pathologic effects observed in the in vivo model of cerulein-induced pancreatitis. Trypsin in the circulation of rats with taurocholate-induced severe acute pancreatitis reached levels sufficient to activate endothelial and immune cells to stimulate nitric oxide and interleukin-8 production, respectively. Most notably, activation of systemic protease-activated receptor 2 by circulating protease-activated receptor 2 agonists induced a hemodynamic response pattern similar to that observed in rats with severe acute pancreatitis. The effects of protease-activated receptor 2 agonists and acute pancreatitis were not additive.


CONCLUSIONS
These findings suggest that protease-activated receptor 2 may have a dual role in acute pancreatitis: protecting acinar and duct cells against pancreatitis-induced cell damage while mediating or aggravating the systemic complications of acute pancreatitis, which are the major cause of mortality in the early phase of necrotizing pancreatitis.
Namkung
Wan
W
Department of Pharmacology and Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, 134 Sinchon-dong, Seoul 120-752, Korea.
Han
Wonsun
W
Luo
Xiang
X
Muallem
Shmuel
S
Cho
Kyung Hee
KH
Kim
Kyung Hwan
KH
Lee
Min Goo
MG
D000208:Acute Disease; D000818:Animals; D001794:Blood Pressure; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D002108:Ceruletide; D010450:Endopeptidases / Q000494:pharmacology; D015870:Gene Expression; D066298:In Vitro Techniques; D008297:Male; D009000:Monocytes / Q000473:pathology; D010179:Pancreas / Q000166:cytology; D010183:Pancreatic Ducts / Q000166:cytology; D010195:Pancreatitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044464:Receptor, PAR-2 / Q000235:genetics* / Q000378:metabolism*; D014357:Trypsin / Q000097:blood
D044464:Receptor, PAR-2; D002108:Ceruletide; D010450:Endopeptidases; D014357:Trypsin