Intracellular action of an exogenous low-molecular-weight synthetic protease inhibitor, E3123, in cerulein-induced acute pancreatitis in rats |
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Authors: | Naohiro Sata Yutaka Atomi Wataru Kimura Akira Kuroda Tetsuichiro Muto Chieko Mineo |
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Abstract: | The intracellular distribution and action of a new synthetic protease inhibitor, E3123, were studied in cerulein-induced acute pancreatitis in rats. Acute pancreatitis was induced by a 4-h iv infusion of a supramaximal dose of cerulein, and was treated by prophylactic (pretreatment) or therapeutic (posttreatment) continuous administration of E3123. Pancreatic edema and hyperamylasemia were ameriolated only by prophylactic treatment. A subcellular fractionation study showed that the activities of cathepsin-B and trypsin in the zymogen granule-enriched fraction of the cerulein-pancreatitis group were remarkably increased. Both prophylactic and therapeutic treatment significantly prevented the elevation of these enzyme activities. These effects were accompanied by amelioration of pancreatic histopathological features, including intracellular vacuolization and fat necrosis. A microscopic autoradiographic study using2H-labeled E3123 showed diffuse intracellular distribution of E3123, and the radioactivity of2H-E3123 in the posttreatment group was three times greater than that in the pretreatment group. This study provides the first experimental evidence that, even when administered therapeutically, exogenous protease inhibitors are transported into pancreatic acinar cells, thereby reducing the seventy of early intracellular alterations in cerulein-induced acute pancreatitis. |
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Keywords: | Acute pancreatitis cerulein pancreatitis protease inhibitor E3123, autoradiography subcellular fractionation |
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