Pathophysiology of acute pancreatitis. If you believe in mice--it's time for conditional gene targeting!

tion of bile acid into the main pancreatic duct. In CD-1 mice severe acute pancreatitis can be induced with a choline-defi cient, ethionine-supplemented diet. These models are mostly used to investigate the systemic infl ammatory response, multiorgan failure and to evaluate therapeutic interventions. Although all these models have in common that they do not recapitulate the human disease, we use them as tools and hope that they are helpful in understanding the pathophysiology of acute pancreatitis in humans. It is important to keep in mind that there is no proof that these models are predictive for the pathophysiology or treatment of the human disease. The pathogenesis of acute pancreatitis is far from being understood. There is good evidence that autodigestion of the gland is involved, however, the initial trigger which converts digestive proenzymes into their active forms is unknown. As pancreatitis starts, a pancreatic defense program is initiated involving important reorientation of the gene expression pattern within the acinar cell. Furthermore, the relationship between pancreatic injury and the uncontrolled systemic infl ammatory response is unclear. In the last few years a number of signaling pathways have been identifi ed to be activated in the course of acute pancreatitis [2–4] . At least some of these signaling cascades are induced in a rapid fashion with a kinetic similar to the activation of proenzymes [5] . On the one hand, these pathways might contribute to the pancreatic defense program; on the other hand, they may trigger the synthesis of pro-infl ammatory cytokines. Acute pancreatitis is a common condition with a selflimiting course in most cases and a severe form associated with a signifi cant risk of morbidity and mortality. High mortality is due to the systemic infl ammatory response syndrome (SIRS) leading to multiple organ failure (MOF) [1] . The study of early events in acute pancreatitis in humans is restricted to the model of endoscopic retrograde cholangiopancreatography (ERCP)-induced pancreatitis and limited to imaging studies and measurement of biochemical markers in the serum including cytokines. The anatomic position and relationships of the pancreas make direct observation of pancreatic pathology and biopsies diffi cult or almost impossible. Therefore, most of our pathophysiological concepts are based on animals studies. Several animal models of acute pancreatitis have been developed mostly in rodents, although these models fail to reproduce the human disease. Gallstone-induced acute pancreatitis cannot be reproduced in mice or rats. Acute or chronic ethanol feeding does not lead to acute pancreatitis. Nevertheless, there are experimental models which mimic some aspects of acute pancreatitis in humans. A mild self-limiting form of acute pancreatitis in rodents can be induced by injection of the secretagogue cerulein in supramaximal doses. This model has been utilized to study events inside the acinar cell including activation of digestive proenzymes, alterations of the cytoskeleton, activation of signaling pathways and synthesis of cytokines. In rats severe acute pancreatitis can be produced by injecPublished online: June 2, 2005