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

Wan Namkung, Wonsun Han, Xiang Luo, Shmuel Muallem, Kyung Hee Cho, Kyung Hwan Kim, Min Goo Lee

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1844-1859
Number of pages16
JournalGastroenterology
Volume126
Issue number7
DOIs
StatePublished - Jun 2004

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PAR-2 Receptor
Pancreatitis
Trypsin
Acinar Cells
Ceruletide
Taurocholic Acid
Interleukin-8
Bile
Pancreas
Nitric Oxide
Phosphotransferases

ASJC Scopus subject areas

  • Gastroenterology

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Protease-activated receptor 2 exerts local protection and mediates some systemic complications in acute pancreatitis. / Namkung, Wan; Han, Wonsun; Luo, Xiang; Muallem, Shmuel; Cho, Kyung Hee; Kim, Kyung Hwan; Lee, Min Goo.

In: Gastroenterology, Vol. 126, No. 7, 06.2004, p. 1844-1859.

Research output: Contribution to journalArticle

Namkung, Wan ; Han, Wonsun ; Luo, Xiang ; Muallem, Shmuel ; Cho, Kyung Hee ; Kim, Kyung Hwan ; Lee, Min Goo. / Protease-activated receptor 2 exerts local protection and mediates some systemic complications in acute pancreatitis. In: Gastroenterology. 2004 ; Vol. 126, No. 7. pp. 1844-1859.
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abstract = "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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