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1 Department of Surgery, Tuts-New England Medical Center and Tufts University School of Medicine, Boston, MA, USA
2 Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA
3 Drug Discovery, Johnson and Johnson Pharmaceutical Research and Development, Spring House, PA, USA
* To whom correspondence should be addressed. E-mail: gperides{at}tufts-nemc.org.
Protease-Activated Receptor-2 (PAR-2) is a widely expressed tethered ligand receptor which can be activated by trypsin and other trypsin-like serine proteases. In the exocrine pancreas, PAR-2 activation modulates acinar cell secretion of digestive enzymes and duct cell ion channel function. During acute pancreatitis digestive enzyme zymogens, including trypsinogen, are activated within the pancreas. We hypothesized that trypsin, acting via PAR-2, might regulate the severity of that disease and, to test this hypothesis, we examined the effect of either genetically deleting or pharmacologically activating PAR-2 on the severity of secretagogue-induced experimental pancreatitis. We found that experimental acute pancreatitis is more severe in PAR-2-/- than in WT mice and that in-vivo activation of PAR-2, achieved by parenteral administration of the PAR-2 activating peptide SLIGRL-NH2, reduces the severity of pancreatitis. In the pancreas during the early stages of pancreatitis, the mitogen-activated protein kinase ERK1/2 is activated and translocated to the nucleus but, nuclear translocation is reduced by activation of PAR-2. Our findings indicate that PAR-2 exerts a protective effect on pancreatitis and that activation of PAR-2 ameliorates pancreatitis, possibly by inhibiting ERK1/2 translocation to the nucleus. Our observations suggest that PAR-2 activation may be of therapeutic value in the treatment and/or prevention of severe clinical pancreatitis and they lead us to speculate that, from a teleological standpoint, PAR-2 may have evolved in the pancreas as a protective mechanism designed to dampen the injurious effects of intrapancreatic trypsinogen activation.
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