Protease-activated receptor-2 exerts contrasting model-specific effects on acute experimental pancreatitis.
Protease-activated receptor-2 (PAR2) is a 7-transmembrane G-protein-coupled tethered ligand receptor that is expressed by pancreatic acinar and ductal cells. It can be physiologically activated by trypsin. Previously reported studies (Namkung, W., Han, W., Luo, X., Muallem, S., Cho, K. H., Kim, K. H., and Lee, M. G. (2004) Gastroenterology 126, 1844-1859; Sharma, A., Tao, X., Gopal, A., Ligon, B., Andrade-Gordon, P., Steer, M. L., and Perides, G. (2005) Am. J. Physiol. 288, G388-G395) have shown that PAR2 activation exerts a protective effect on the experimental model of pancreatitis induced by supramaximal secretagogue (caerulein) stimulation. We now show that PAR2 exerts a worsening effect on a different model of experimental pancreatitis, i.e. one induced by retrograde pancreatic ductal infusion of bile salts. In vitro studies using freshly prepared pancreatic acini show that genetic deletion of PAR2 reduces bile salt-induced pathological calcium transients, acinar cell injury, and activation of c-Jun N-terminal kinase, whereas genetic deletion of PAR2 has the opposite or no effect on these pancreatitis-related events when they are elicited, in vitro, by caerulein stimulation. Studies employing a combination of trypsin inhibition and activation of PAR2 with the activating peptide SLIGRL show that all these differences indeed depend on the activation of PAR2. These studies are the first to report that a single perturbation can have model-specific and opposite effects on pancreatitis, and they underscore the importance of performing mechanistic pancreatitis studies using two dissimilar models of the disease to detect idiosyncratic, model-specific events. We suggest PAR2 activation exerts a worsening effect on the severity of clinical pancreatitis and that interventions interfering with PAR2 activation may be of benefit in the treatment of patients with severe pancreatitis.
Department of Surgery, Tufts Medical Center, 750 Washington Street, Boston, MA 02111, USA.
Johanna M
JM
Laukkarinen
Eric R
ER
Weiss
Gijs J D
GJ
van Acker
Michael L
ML
Steer
George
G
Perides
D000208:Acute Disease; D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology; D002108:Ceruletide / Q000494:pharmacology; D004789:Enzyme Activation; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010179:Pancreas / Q000166:cytology; D010195:Pancreatitis / Q000201:enzymology* / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D017434:Protein Structure, Tertiary; D044464:Receptor, PAR-2 / Q000378:metabolism / Q000502:physiology*
D001647:Bile Acids and Salts; D010455:Peptides; D044464:Receptor, PAR-2; D002108:Ceruletide