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Protease-activated receptor 2 exerts local protection and mediates some systemic complications in acute pancreatitis

 Wan Namkung  ;  Wonsun Han  ;  Min Goo Lee  ;  Kyung Hwan Kim  ;  Kyung Hee Cho  ;  Shmuel Muallem  ;  Xiang Luo 
 GASTROENTEROLOGY, Vol.126(7) : 1844-1859, 2004 
Journal Title
Issue Date
Acute Disease ; Animals ; Blood Pressure ; Cell Survival/physiology ; Cells, Cultured ; Ceruletide ; Endopeptidases/pharmacology ; Gene Expression ; In Vitro Techniques ; Male ; Monocytes/pathology ; Pancreas/cytology ; Pancreatic Ducts/cytology ; Pancreatitis/chemically induced ; Pancreatitis/metabolism* ; Pancreatitis/pathology* ; Rats ; Rats, Sprague-Dawley ; Receptor, PAR-2/genetics* ; Receptor, PAR-2/metabolism* ; Trypsin/blood
BACKGROUND & AIMS: 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.
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1. College of Medicine (의과대학) > Dept. of Family Medicine (가정의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Kyung Hwan(김경환)
Lee, Min Goo(이민구) ORCID logo https://orcid.org/0000-0001-7436-012X
Cho, Kyung Hee(조경희)
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