Protease-activated receptor-2 (PAR2) is a widely expressed tethered ligand receptor that can be activated by trypsin and other trypsin-like serine proteases. In the exocrine pancreas, PAR2 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.
Researchers in the Boston Pancreas Group hypothesized that trypsin, acting via PAR2, might regulate the severity of that disease, and to test this hypothesis, we examined the effect of either genetically deleting or pharmacologically activating PAR2 on the severity of secretagogue-induced experimental pancreatitis.
We found that experimental acute pancreatitis is more severe in PAR2-/- mice than in wild-type mice and that in vivo activation of PAR2, achieved by parenteral administration of the PAR2-activating peptide SLIGRL-NH2, reduces the severity of pancreatitis. In the pancreas during the early stages of pancreatitis, the MAPK ERK1/2 is activated and translocated to the nucleus, but nuclear translocation is reduced by activation of PAR2.
Our findings indicate that PAR2 exerts a protective effect on caerulein induced pancreatitis and that activation of PAR2 ameliorates pancreatitis, possibly by inhibiting ERK1/2 translocation to the nucleus. Our observations suggest that PAR2 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, PAR2 may have evolved in the pancreas as a protective mechanism designed to dampen the injurious effects of intrapancreatic trypsinogen activation.