The proposed studies will further elucidate the pahtophysiology of experimental acute pancreatitis. Previous studies have focused on experimental acute pancreatitis. Previous studies have focused on experimental pancreaties induced by feeding young female mice a choline-deficient ethionine supplemented (CDE) diet. This CDE diet was found to block digestive enzyme discharge while causing only a slight reduction in enzyme synthesis. As a result, the digestive enzyme content of the pancreatic acinar cell increases and zymogen granules accumulate. Eventually, crinophagy (i.e. fusion of zymogen granules and lysosomes) occurs and digestive enzymes are """"""""dumped"""""""" into lysosomes. Proteolytic digestive enzyme precursors are activated by lysosomal hydrolases and leak into the cytoplasm eventually resulting in hemorrhagic pancreatitis. The proposed studies will apply techniques used to characterize diet-induced pancratitis to other models of experimental pancreatitis which may more closely resemble clinical pancreatitis. Three such models, each probably related to pancreatic ductal hypertension, will be studied. These models are (1) supra-maximal secretagogue stimulation; (2) administration of an insecticide containing a cholinesterase-inhibitor; (3) stimulation of secretion into a blocked pancreatic duct. The processes of digestive enzyme synthesis, intracellular transport, and secretion during the evolution of these forms of pancreatitis will be studied. Intrapancratic activation of zymogens and liberation of lysosomal hydrolases from lysosomes will be evaluated. Evidence for crinophagy and for increased lysosomal frigility will be sought. It is hoped that events common to the development of these various forms of pancreatitis will be detected sine it is likely that such common features are also involved in the pathophysiology of clinical pancreatitis. The proposed studies, by elucidating the pathophysiology of acute pancreatitis, will suggest methods by which this frequently fatal disease can be prevented and/or more effectively treated.
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