While in recent decades, considerable progress has been made in elucidating the cell biology of the exocrine pancreas, our knowledge of its pathophysiology as well as our ability to either prevent or treat pancreatitis remains very limited. This can be attributed in part to the relative inaccessibility to clinical material for experimental studies, which has necessitated the development of several models of experimental pancreatitis to explore its etiology, pathophysiology and treatment. The mouse is an ideal experimental animal in view of the availability of several genetic manipulations, accessibility to the complete mouse genome and the relatively lower cost and ease of maintenance, in fact, the most commonly used investigative model in experimental pancreatitis is that induced by caerulein in mice. However, caerulein only induces relatively mild form of the disease. While the CDE diet-induced model of pancreatitis does result in severe hemorrhagic pancreatitis that bears some resemblance to human disease, that model has several serious limitations restricting its usefulness. Clearly, there is a need to develop another mouse model of acute pancreatitis. We have been successful in inducing severe acute pancreatitis in mice by administration of arginine and the present proposal aims at characterizing this model extensively. The following four aims will be pursued to fully characterize this model: (1) To characterize dose, time and strain dependence of arginine-induced pancreatitis in mice; (2) To determine the mechanisms responsible for the onset of arginine-induced pancreatitis; (3) To elucidate the role of inflammatory mediators in the development and progression of arginine-induced acute pancreatitis in mice; and (4) Characterization of pancreatitis-associated lung injury. Successful completion of these studies will provide an excellent model of pancreatitis for future studies dealing with therapeutic interventions.
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