Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030305 (pancreatitis)
 16,014 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The involvement of lysosomes in the normal secretory process of the exocrine pancreas and in the onset of acute, hormone-induced pancreatitis was studied. The enzymatic activities of cathepsin B and beta-galactosidase were determined in the pancreas of rats that had been stimulated by either maximal (0.25 microgram X kg-1 h-1) or supramaximal (5 micrograms X kg-1 h-1) concentrations of cerulein. Maximal stimulation led to a moderate increase in cathepsin B activity and the ultrastructural appearance of multivesicular bodies. Supramaximal stimulation resulted in formation of large cytoplasmic vacuoles and progressive destruction of acinar cells which was paralleled by a marked increase of lysosomal enzyme activity.
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PMID:Cerulein-induced pancreatitis in rats: increased lysosomal enzyme activity and autophagocytosis. 241 Mar 15

Earlier studies have indicated that lysosomal enzymes such as cathepsin B become redistributed within pancreatic acinar cells during the early stages of both diet- and secretagogue-induced acute pancreatitis. As a result, cathepsin B and digestive zymogens became colocalized within large cytoplasmic vacuoles. As cathepsin B can activate trypsinogen, this colocalization could result in intracellular digestive enzyme activation. The present study investigates the protective effects of gabexate mesilate (FOY) and camostate (FOY 305) on both of these noninvasive models of experimental pancreatitis. These esterase inhibitors prevented the hyperamylasemia, pancreatic edema, and acinar cell vacuolization that characterize secretagogue-induced pancreatitis and the hyperamylasemia and mortality that characterize diet-induced pancreatitis. In addition, FOY and FOY 305 were found to significantly decrease the subcellular redistribution of cathepsin B that occurs in both models. These findings indicate that enzyme activity sensitive to inhibition by FOY and FOY 305 may be critical to the redistribution phenomenon that characterizes both of these models of pancreatitis.
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PMID:Esterase inhibitors prevent lysosomal enzyme redistribution in two noninvasive models of experimental pancreatitis. 246 26

The activation of zymogen proteases and lysosomal enzyme cathepsin B in the pancreas was investigated in cerulein-induced pancreatitis in rats. Acute pancreatitis was induced by two intraperitoneal injections of 40 micrograms/kg of body weight of cerulein at intervals of 1 h. After the first cerulein injection, the active trypsin and elastase contents in the pancreas tissues significantly increased, and reached the highest level at 3 h after the first injection, followed by peaks at 5 h in the serum amylase and lipase levels and the pancreas wet weight. Cathepsin B contents in pancreas tissues showed a parallel increase with active zymogen enzymes during the first 3 h of pancreatitis. These findings may suggest that the intracellular activation of trypsinogen is an important step in the development of cerulein-induced acute pancreatitis and that cathepsin B plays a role in the activation of trypsinogen in pancreatic acinar cells.
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PMID:Activation of proteases in cerulein-induced pancreatitis. 247 99

The subcellular distribution of the lysosomal enzymes cathepsin B and D in the pancreas was evaluated in rats infused with saline (control) or a maximal (0.25 microgram . kg-1 . h-1) or a supramaximally stimulating dose (5 micrograms . kg-1 . h-1) of the secretagogue caerulein. The latter results in acute edematous pancreatitis, inhibition of digestive enzyme secretion, and the localization of digestive zymogens in organelles whose fragility has been increased by caerulein infusion [A. Saluja et al. Am. J. Physiol. 249 (gastrointest. Liver Physiol. 12): G702-G710, 1985]. Samples from control animals were found to have 29.9 +/- 1.8% of the cathepsin B activity in the pellet centrifuged at 1,300 g for 15 min (containing primarily zymogen granules) and 54.7 +/- 2.5% in the pellet centrifuged at 12,000 g for 12 min (containing primarily lysosomes and mitochondria). After supramaximal stimulation with caerulein for 3.5 h the pellet centrifuged at 1,300 g for 15 min had 55.1 +/- 2.5%, and the pellet centrifuged at 12,000 g for 12 min had 30.6 +/- 2.0% of cathepsin B activity. This redistribution was time dependent, noted within 1 h of starting caerulein infusion, and maximal after 2.5 h of infusion. Electron microscopic immunolabeling studies revealed localization of cathepsin D in discrete organelles that, in the samples from animals infused with a supramaximally stimulating dose of caerulein, were larger, more abundant, and more concentrated in the pellet centrifuged at 1,300 g for 15 min than in the controls. During infusion with supramaximal doses of caerulein, the cathepsin B-containing organelles were found to become progressively more fragile.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Subcellular redistribution of lysosomal enzymes during caerulein-induced pancreatitis. 282 25

When examining the level of esterolysis and that of cathepsin B or H, a significant positive correlation was found in the rat pancreas with inflammation induced by a closed duodenal loop, whereas there was a significant negative correlation between the activity of cathepsin B or H and that of its endogenous inhibitors. The levels of endogenous inhibitors of cathepsins B and H in rats with a pancreatitis were lower than in the sham-treated group. The endogenous inhibitors of cathepsins B and H were destroyed by incubation with the supernatant fraction obtained from the inflamed pancreas. These observations indicate that the activities of pancreatic cathepsins B and H are closely related to the severity of acute pancreatitis and that lesser levels of thiol proteinase inhibitors in the pancreatitis group than in the sham-treated group are due to destruction of the inhibitors by the enhanced protease activity.
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PMID:Pancreatic lysosomal thiol proteinases and inhibitors in acute pancreatitis induced in rats. 315 25

Human trypsinogens 1 and 2 were activated at the same rate by pure human cathepsin B at pH 3.8. Human trypsinogen 1 was also spontaneously activated during incubation at acidic pH, activation being most rapid at pH 5.0. In contrast, trypsinogen 2 showed little or no activation under these conditions. The presence of calcium salts (20mM) delayed the onset of activation under all conditions tested. These findings support the proposal that premature activation of the pancreatic zymogens may result from their entry into the lysosomal system in pancreatitis.
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PMID:Possible lysosomal activation of pancreatic zymogens. Activation of both human trypsinogens by cathepsin B and spontaneous acid. Activation of human trypsinogen 1. 320 69

The appearance of vacuoles inside acinar cells characterizes an early stage of development in different models of acute pancreatitis and, possibly, also in human disease. The vacuoles have been shown to contain both digestive and lysosomal enzymes. This abnormal admixture may have important implications for the pathogenesis of pancreatitis because the lysosomal enzyme cathepsin B can activate trypsinogen and may, by this way, trigger pancreatic autodigestion. For the activation process of trypsinogen by cathepsin B, however, an acidic pH is required. This study, therefore, looked for evidence of vacuole acidification in two different models of acute pancreatitis. Edematous pancreatitis was induced in rats by hyperstimulation with cerulein and hemorrhagic pancreatitis was induced in mice by feeding a choline-deficient, ethionine-supplemented diet. Pancreatic acinar cells were isolated at different times after induction of pancreatitis and incubated with 50 microM of acridine orange to identify acidic intracellular compartments. As shown in previous work, zymogen granules are the main acidic compartment of normal acinar cells; they remained acidic throughout the course of pancreatitis in both models. Vacuoles became increasingly more frequent in both models as pancreatitis progressed. Throughout development of pancreatitis, vacuoles accumulated acridine orange indicating an acidic interior. Addition of a protonophore (10 microM monensin or 5 microM carbonyl cyanide m-chlorophenylhydrazone [CCCP] or a weak base (5 mM NH4Cl) completely and rapidly abolished acridine orange fluorescence inside both zymogen granules and vacuoles providing further evidence for an acidic interior. The acidification of vacuoles seen in two different models of pancreatitis may be an important requirement for activation of trypsinogen by cathepsin B and thus for the development of acute pancreatitis.
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PMID:Intracellular vacuoles in experimental acute pancreatitis in rats and mice are an acidified compartment. 333 39

The possible role of cathepsin B in the pathogenesis of two forms of acute pancreatitis was studied using the cathepsin B inhibitor known as E-64. In an edematous, nonfatal pancreatitis induced by supramaximal doses of cerulein, increases in the serum amylase and lipase levels were less pronounced in rats pretreated with E-64. Other parameters of pancreatic injury were unaffected by inhibition of cathepsin B. In a necrohemorrhagic type of pancreatic injury induced by retrograde infusion of bile salts into the pancreatic duct, E-64 partially attenuated increases in serum levels of amylase and lipase, and in addition, reduced the activation of trypsinogen. However, the high mortality in this model of pancreatitis was not modified.
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PMID:Cathepsin B inhibition in two models of acute pancreatitis. 750 43

Blockage of the rat pancreatico-biliary duct (PBDO) for 4 hours and secretin infusion (0.2 CU [Clinical Unit]/kg/hr) caused significant rises in portal serum amylase, cathepsin B levels, pancreatic water content, and pancreatic amylase content as well as lysosomal and mitochondrial fragility. Impaired pancreatic adenylate energy charge levels were also noted. These changes tended to continue for 12 hours after the release of PBDO and disappeared after 24 hours. All the changes induced by PBDO with secretin infusion were no longer observed at 48 hours. The administration of a new potent protease inhibitor, E-3123 at a dose of 5 mg/kg/hr during PBDO markedly attenuated all the parameters examined, exerting a significant protective effect on acinar cells in this model. These results indicate the important roles of subcellular organelle fragility and impaired pancreatic energy metabolism in the pathogenesis of pancreatic injuries induced by common channel obstruction with intraductal hypertension, and also indicate the possible usefulness of E-3123 in the treatment of acute pancreatitis such as gallstone pancreatitis.
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PMID:Effect of short-term pancreatico-biliary duct obstruction with intraductal hypertension on subcellular organelle fragility and pancreatic adenylate energy metabolism in rats: protective effect of a new protease inhibitor, E-3123. 751 90

To examine the possible secretion of lysosomal enzymes into the pancreatic juice in rats stimulated with pancreatic secretagogues under both physiological and pathological conditions, we investigated the changes in the secretion of cathepsin B, as a lysosomal enzyme, into pancreatic juice with stimulation of 5 different doses (0.1, 0.2, 0.5, 1.0, and 1.5 micrograms/kg.hr) of caerulein. Control rats had only pancreatic duct cannulation. In other rats, the pancreatic duct was obstructed for 3 hours and secretin was infused (0.2 CU/kg.hr). Caerulein stimulated the secretion of cathepsin B into the pancreatic juice in a dose-dependent manner, as in amylase secretion, and caerulein in higher doses (1.0 and 1.5 microgram/kg.hr) inhibited cathepsin B output as it did amylase output. There was a significantly high positive correlation between cathepsin B output and amylase output after stimulation with caerulein. The secretion of several other lysosomal enzymes was also stimulated by caerulein. Blockage of the pancreatic duct for 3 hours caused a significant but moderate rise in serum amylase levels. Redistribution of cathepsin B activity in the pancreatic subcellular fractions was noted with an increase in the amount of cathepsin B recovered from zymogen-rich pellets after 15 min of centrifugation at 1300 x g. These changes after temporary pancreatic duct obstruction are very similar to those previously noted during the early stage of diet-and caerulein-induced experimental pancreatitis and suggest colocalization of lysosomal enzymes and digestive enzymes. In addition, in duct obstructed rats, the secretion of cathepsin B and other lysosomal enzymes stimulated by caerulein was significantly greater than in animals with free-flowing pancreatic juice. These results indicate that lysosomal enzymes are secreted into pancreatic juice after stimulation by gut hormones in the same manner as classical pancreatic digestive enzymes such as amylase. Moreover, lysosomal enzymes which colocalize with zymogen granules in rats with short-term pancreatic duct obstruction are also secreted into pancreatic juice together with digestive enzymes after stimulation with gut hormones. These findings suggest that lysosomal enzymes are present in zymogen granules under normal conditions and that they may play pathophysiological roles in pancreatic juice. They also contribute to an understanding of the pathogenesis of pancreatitis, since cathepsin B can activate trypsinogen.
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PMID:Lysosomal enzyme secretion into pancreatic juice in rats injected with pancreatic secretagogues and augmented secretion after short-term pancreatic duct obstruction. 752 87


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