We have found that 2 dissimilar models of experimental pancreatitis are associated with a reduction in acinar cell secretion of protein and with the appearance of large cytoplasmic vacuoles that contain digestive enzymes and lysosomal hydrolases capable of activating digestive enzymes. This has suggested that lysosomes, lysosomal enzymes and the large vacuoles may play an important role in the pathogenesis of acute panccreatitis by permitting intraacinar cell activation of digestive enzymes. We will build upon our previous observations, using diet and hyperstimulation-induced pancreatitis, by also studying insecticide-induced experimental pancreatitis and the effects of pancreatic ductal hypertension. Pancreatic acinar cell function (amino acid uptake, protein synthesis, intracellular transport, and secretion) and morphology will be evaluated. The sedimentation characteristics, contents, internal pH, and stability of lysosomal enzyme-containing organelles will be determined. The ability of lysosomal enzyme inhibitors, and oxygen free radical scavengers to prevent structural and/or functional changes related to pancreatitis in these models will be evaluated. Morphological techniques ot be employed in studies described in this proposal include conventional thin section EM, freeze-fracture, immuno-and and enzyme-cytochemistry using conventional as well as cryosections. Techniques of quantitative fluorescence microscopy will be used to determine whether the conditions within the large vacuoles noted during the early stages of pancreatitis favor digestive enzyme activation. The studies represent a continuation of studies previously initiated. They will expand our understanding of the basic cellular events underlying the development of 3 forms of experimental pancreatitis and of pancreatic ductal hypertension. It is likely that events which occur in many or all of these situations may also be of importance in clinical pancreatitis. Thus, this proejct will provide further insights into the pathogenesis of acute clinical pancreatitis and may suggest methods of treating and/or preventing that disease.
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