INTRACELLULAR ACTION OF AN EXOGENOUS LOW-MOLECULAR-WEIGHT SYNTHETIC PROTEASE INHIBITOR, E3123, IN CERULEIN-INDUCED ACUTE-PANCREATITIS IN RATS

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 supr amaximal dose of cerulein, and was treated by prophylactic (pretreatme nt) or therapeutic (posttreatment) continuous administration of E3123. Pancreatic edema and hyperamylasemia were ameriolated only by prophyl actic treatment. A subcellular fractionation study showed that the act ivities of cathepsin-B and trypsin in the zymogen granule-enriched fra ction of the cerulein-pancreatitis group were remarkably increased. Bo th prophylactic and therapeutic treatment significantly prevented the elevation of these enzyme activities. These effects were accompanied b y amelioration of pancreatic histopathological features, including int racellular vacuolization and fat necrosis. A microscopic autoradiograp hic study using H-3-labeled E3 123 showed diffuse intracellular distri bution of E3 123, and the radioactivity of H-3-E3 123 in the posttreat ment 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 transp orted into pancreatic acinar cells, thereby reducing the severity of e arly intracellular alterations in cerulein-induced acute pancreatitis.