Protease-activated receptor 2 exerts local protection and mediates some systemic complications in acute pancreatitis
Wan Namkung * 1, Wonsun Han * 1, Xiang Luo ++, Shmuel Muallem ++, Kyung Hee Cho *, Kyung Hwan Kim *, Min Goo Lee * *
*Department of Pharmacology and Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea South Korea
++Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
Supported by grant R01-2001-000-00208-0 from the Korea Science & Engineering Foundation (to K.H.K.), grant 03-PJ10-PG13-GD01-0002 from the Korea Health 21 R&D Project, Ministry of Health & Welfare, Korea (to M.G.L.), and National Institutes of Health grant DK38938 (to S.M.).
* Address requests for reprints to: Min Goo Lee, M.D., Department of Pharmacology, Yonsei University College of Medicine, 134 Sinchon-Dong, Seoul 120-752, Korea South Korea. fax: (82) 2-313-1894
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 (Ca2+ 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.