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 pancreatitisrelated 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.Acute pancreatitis is a complex inflammatory disease of the pancreas that is of uncertain pathogenesis. No specific therapy for the disease has so far been identified, and as a result, treatment for this relatively common and, sometimes, lethal disease is limited to supportive care. Pancreatitis severity and disease morbidity/mortality are closely correlated leading to the widely held view that interventions that reduce the severity of an attack might have a favorable impact on clinical outcome. This concept has sparked considerable investigative interest directed at identifying factors and events that regulate pancreatitis severity in the belief that their identification would lead to therapies that might minimize disease severity. For the most part, studies pursuing that goal have employed experimental models of acute pancreatitis induced in laboratory animals, rather than clinically derived material, and the results obtained using those models have been assumed to reflect features that would be relevant to the clinical disease as well.The two best characterized experimental models of acute pancreatitis are the secretagogue-induced (1) and ...