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

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.

• Authors: Wan Namkung, Wonsun Han, Xiang Luo, Shmuel Muallem, Kyung Hee Cho, Kyung Hwan Kim, Min Goo Lee
• Journal: Gastroenterology (Gastroenterology) Vol. 126 Issue 7 Pg. 1844-59 (Jun 2004) ISSN: 0016-5085 [Print] United States
• PMID: 15188179 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Receptor, PAR-2
• Ceruletide
• Endopeptidases
• Trypsin

Topics

• 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, metabolism, pathology)
• Rats
• Rats, Sprague-Dawley
• Receptor, PAR-2 (genetics, metabolism)
• Trypsin (blood)