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)

Bile salts in the intestinal lumen act to inhibit the release of cholecystokinin (CCK). Recent studies have shown that CCK may play a permissive role in the development of acute pancreatitis. In this study, the amount of luminal bile salts in female Swiss Webster mice was either decreased by feeding 4% (wt/wt) cholestyramine or increased by feeding 0.5% sodium taurocholate for 1 wk. Plasma levels of CCK were stimulated by cholestyramine and inhibited by taurocholate. Then, acute pancreatitis was induced either by caerulein injections, or by feeding a choline-deficient, ethionine-supplemented (CDE) diet. Feeding of cholestyramine significantly decreased survival from 25% to 0% in the CDE pancreatitis, and increased the magnitude of elevation of serum amylase levels and the extent of pancreatic necrosis in both models of pancreatitis; CCK-receptor blockade with CR-1409 completely abolished the adverse effects of cholestyramine. In contrast, feeding of taurocholate significantly increased survival to 100% and decreased the elevation of serum amylase and pancreatic necrosis; CCK-8 antagonized these actions of taurocholate. Luminal bile salts appear to provide a physiologic protection against necrotizing pancreatitis, at least in part, both by inhibiting the release of CCK and by promoting resistance of the pancreas to CCK excessive stimulation in vivo.
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PMID:Protective action of luminal bile salts in necrotizing acute pancreatitis in mice. 169 66

Lysosomal hydrolases such as cathepsin B are apically secreted from rabbit pancreatic acinar cells via a regulated as opposed to a constitutive pathway. Intravenous infusion of the cholecystokinin analogue caerulein results in highly correlated apical secretion of digestive and lysosomal enzymes, suggesting that they are discharged from the same presecretory compartment (zymogen granules). Lysosomal enzymes appear to enter that compartment as a result of missorting. After 7 h of duct obstruction is relieved, caerulein-stimulated apical secretion of cathepsin B and amylase is increased, but the ratio of cathepsin B to amylase secretion is not different than that following caerulein stimulation of animals never obstructed. These findings indicate that duct obstruction causes an increased amount of both lysosomal and digestive enzymes to accumulate within the secretagogue releasable compartment but that duct obstruction does not increase the degree of lysosomal enzyme missorting into that compartment. Pancreatic duct obstruction causes lysosomal hydrolases to become colocalized with digestive enzymes in organelles that, in size and distribution, resemble zymogen granules but that are not subject to secretion in response to secretagogue stimulation. These organelles may be of importance in the development of pancreatitis.
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PMID:Apical secretion of lysosomal enzymes in rabbit pancreas occurs via a secretagogue regulated pathway and is increased after pancreatic duct obstruction. 170 67

In a variety of animal models of acute pancreatitis, cholecystokinin-receptor antagonists have ameliorated the injury response. These results suggest that cholecystokinin may play a primary role in the pathogenesis of pancreatitis initiated by multiple stimuli. In an effort to test this theory, a sensitive and high affinity cholecystokinin-receptor antagonist L364,718 was administered to four different models of acute pancreatitis that were produced in the ex vivo perfused canine pancreas preparation. The four models of pancreatitis were initiated by cerulein infusion, partial duct obstruction with secretin stimulation, oleic acid infusion, and a 2-hour period of ischemia. In each model, pancreatitis was manifest by edema formation, weight gain, and hyperamylasemia during a 4-hour perfusion. In cerulein infusion-induced pancreatitis L364,718 inhibited edema formation and weight gain (31 +/- 5 gm versus 7 +/- 6 gm; p less than 0.05) and significantly decreased plasma amylase activity (36,605 +/- 21,216 U/dl versus 9421 +/- 5149 U/dl; p less than 0.05). The acute pancreatitis induced by the other three stimuli was not ameliorated by L364,718 treatment. We conclude that in the ex vivo-perfused canine pancreas preparation cerulein-induced pancreatitis is mediated at least in part by the cholecystokinin receptor. Early blockade of the cholecystokinin receptor was of no benefit in treating the other models of pancreatitis, suggesting that cholecystokinin is not involved in the early pathogenesis.
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PMID:The role of cholecystokinin in the pathogenesis of acute pancreatitis in the isolated pancreas preparation. 170 26

This study examines the influence of ovariectomy and administration of a pharmacologic dose of estradiol on amylase release from isolated-dispersed rat pancreatic acini and cholecystokinin receptors on rat acinar cell membranes. Rats were sham ovariectomized (intact) or ovariectomized (Ovx) and 21 day timed release pellets containing either estradiol (2.5 mg) or vehicle, were implanted subcutaneously. Eighteen days later, pancreatic acini were isolated from rats by collagenase digestion and differential centrifugation. Total cellular amylase, basal and cholecystokinin octapeptide (CCK8) stimulated amylase release and CCK membrane receptors were measured. Acini isolated from estradiol treated Ovx rats had significantly greater total cellular amylase, compared to acini isolated from either intact or Ovx rats. The amplitude of both total stimulated amylase release and percent total stimulated amylase release were significantly greater for acini isolated from vehicle treated Ovx rats, than acini isolated from either intact or estradiol treated Ovx rats. The magnitude of percent total amylase release of acini isolated from estradiol treated Ovx rats was significantly lower than that of acini isolated from intact rats. Cholecystokinin receptor concentration was significantly greater on membranes prepared from vehicle treated Ovx rats, compared to membranes prepared from either intact or estradiol treated Ovx rats. These data indicate that ovariectomy is associated with increased responsiveness of pancreatic acini to CCK stimulation, while chronic estradiol treatment of ovariectomized rats is associated with increased total cellular amylase and decreased acinar cell responsiveness to CCK8. Estrogen mediated alterations in acinar cell amylase content and amylase release may play a role in estrogen related pancreatitis.
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PMID:Estrogens influence cholecystokinin stimulated pancreatic amylase release and acinar cell membrane cholecystokinin receptors in rat. 170 70

Availability of specific cholecystokinin (CCK) receptor antagonists has the potential for contributing to delineation of the role of CCK in the development of pancreatitis and, perhaps, development of new therapeutic agents for treatment of the disorder. The purpose of this study was to evaluate the effect of a potent CCK receptor antagonist, CR 1409, on bile reflux pancreatitis. The opossum pancreatic duct enters the common duct in such a position that it is possible to ligate the common duct distal to the pancreatic duct, resulting in bile refluxing into the pancreatic duct and producing pancreatitis. CR 1409 was administered to opossums at the time of distal common duct ligation and at the time of cystic- and common ducts ligations. In a separate group, CR 1409 administration was begun 24 hours following onset of pancreatitis. Control experiments were performed, in which CR-1409 was not administered. Serum amylase, pancreas gland weights, inflammation, and systemic venous insulin, glucagon, and CCK concentrations were evaluated. Bile duct ligation resulted in significant hyperamylasemia, pancreas gland edema, inflammation, hyperglucagonemia, hypercholecystokinemia, and hypoinsulinemia. CR 1409, administered at the onset of pancreatitis, significantly decreased amylase concentrations, gland weight, and inflammation, when compared to control values. Hormonal changes associated with pancreatitis were also significantly altered by CR 1409 administration. When administered 24 hours following onset of pancreatitis, CR 1409 was not effective in altering the pancreatitis produced by bile duct ligation. The results suggest that CCK plays a permissive or contributory role in the inflammatory process and in associated hormonal changes during development of bile reflux pancreatitis in the opossum.
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PMID:The effect of the CCK receptor antagonist CR 1409 on bile reflux pancreatitis in the opossum. 171 73

The essential role of cholecystokinin (CCK) in pancreatic regeneration after pancreatitis or resection has been supposed, but not yet clearly demonstrated. In rats, 6-8 weeks after 60% distal resection of the pancreas a gradual increase in pancreatic weight and contents of DNA, protein, trypsin, chymotrypsin and amylase, occurred (there was no increase in lipase); Pancreatic regeneration stopped thereafter. Nonparallel increases in enzyme values were similar to those seen after CCK administration. Indeed, basal CCK levels increased significantly by the 6th week and declined thereafter. A one month s.c. administration of CCK-octapeptide (CCK-8) (3 x 300 ng/kg/d) accelerated regeneration in the first month, but it had almost no effect during the second or third postoperative months. A two week s.c. administration of a specific CCK antagonist, CR 1409 (3 x 4 mg/kg/d) totally prevented regeneration by the fifth and sixth weeks, but did not diminish pancreatic weight or DNA and protein contents during the first two weeks. Alcohol administration (12 g/kg/d) reduced CCK release and prevented pancreatic regeneration during the three-month experimental period. These data indicate that CCK has an essential role in pancreatic regeneration and that the deleterious effect of alcohol on regeneration involves inhibition of CCK release.
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PMID:Essential role of cholecystokinin in pancreatic regeneration after 60% distal resection in rats. 802 68

Inhibition of pancreatic digestive enzyme secretion in the acinar cell is a significant phenomenon which can trigger acute pancreatitis. It has been shown that microtubules are responsible for the intracellular vesicular transport. The effect of taxol, a microtubule stabilizer, was examined in a model of acute edematous pancreatitis induced in rats by supramaximal stimulation with cholecystokinin analogue, caerulein. Prophylactic administration of taxol ameliorated inhibition of pancreatic digestive enzyme secretion, increased level of serum amylase, pancreatic edema, and histological alterations in this model. Immunofluorescence studies revealed that taxol stabilized the arrangement of microtubules by promoting tubulin polymerization. On the other hand, microtubule disorganization was found in rats without prophylactic taxol treatment. In caerulein-treated rats, there is microtubule disorganization which causes interference with intracellular vesicular transport leading to inhibition of pancreatic digestive enzyme secretion--a forerunner of acute pancreatitis. Taxol was found to prevent these events.
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PMID:The effect of microtubule stabilizer on rat caerulein-induced pancreatitis. 171 41

To explore the secretory profiles of lysosomal enzyme in pancreatic juice, we stimulated the secretion of lysosomal enzyme by intravenous pancreatic secretagogues and intraduodenal instillation of liquid meals in rats. Lysosomal hydrolases, such as cathepsin B, are secreted from the apices of pancreatic acinar cells via a hormone-regulated pathway, as in the secretion of pancreatic digestive enzymes. The intravenous infusion of the cholecystokinin analogue caerulein, or the intraduodenal administration of nutrients results in a closely related secretion of both amylase and cathepsin B from the apices of acinar cells, suggesting that they are discharged from the same presecretory compartment (zymogen granules). Lysosomal enzymes appear to enter into the secretory compartment as a result of malsorting, but the cause of this anomaly is not known. We found small amounts of lysosomal enzymes colocalized with digestive enzymes within zymogen granules in normal acinar cells and in normal pancreatic juice, suggesting some physiological roles of lysosomal enzymes in pancreatic ducts. Furthermore, lysosomal enzymes appear to play important roles in the pathogenesis of pancreatic disease, such as pancreatitis, from both inside and outside the pancreas, since cathepsin B can probably activate trypsinogen.
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PMID:Pancreatic lysosomal enzyme secretion via gut-hormone-regulated pathway in rats. 172 54

The mechanism by which digestive zymogens become activated during acute pancreatitis remains poorly understood. Given the ability for cholecystokinin (CCK) to induce pancreatitis in vivo, the effects of high dose CCK on preparations of isolated pancreatic acini were examined. Using an immunologic technique for the detection of zymogen activation, CCK was found to stimulate the conversion of procarboxypeptidase A1 to a 35-kD form having the same net charge and electrophoretic mobility as purified recombinant carboxypeptidase A1. This enhanced conversion was proportional to the dose of CCK (maximal at 100 nM), and time dependent. CCK also produced changes in the electrophoretic mobility of procarboxypeptidase B and chymotrypsinogen 2 immunoreactivity, consistent with activation of these zymogens. These events were detectable only within acinar cell pellets and not in the incubation medium, suggesting an intracellular site of conversion. The conversion of procarboxypeptidase A1 to its active form was inhibited by pretreatment with the weak base chloroquine (40 microM) and the protonophore monensin (10 microM). This conversion was also inhibited by pretreatment with the serine protease inhibitor benzamidine (10 mM) but not the cysteine protease inhibitor E64 (100 microM). The results suggest that high dose CCK stimulates the intracellular activation of digestive zymogens within isolated pancreatic acini. This event appears to require an acidic subcellular compartment and serine protease activity.
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PMID:Intracellular activation of digestive zymogens in rat pancreatic acini. Stimulation by high doses of cholecystokinin. 198 9

Infusion of supramaximal doses of the cholecystokinin analog cerulein is well established as an in vivo technique for inducing experimental pancreatitis in small animals. An attempt was made to simulate this model and initiate pancreatitis in the ex vivo isolated perfused canine pancreas. Control preparations gained minimal weight (mean 8.3 +/- 5.1 gm), demonstrated no edema accumulation, and did not develop hyperamylasemia (mean 1342 +/- 790 units) after 4 hours of perfusion. Electron microscopy after 4 hours of perfusion remained normal. Intraarterial cerulein infusion produced significant weight gain (mean 27.6 +/- 12.3 gm; p less than 0.001), edema formation, and marked hyperamylasemia (mean 26,838 +/- 21,341 units; p less than 0.001) after 4 hours of perfusion. During the 4-hour perfusion, electron microscopy of cerulein preparations demonstrated depletion of zymogen granules, condensing vacuole formation, and basolateral exocytosis. Pretreatment of cerulein preparations with the free radical scavengers superoxide dismutase and catalase and the iron chelator deferoxamine did not modify the pancreatitis. Continuous infusion of the nonpeptide cholecystokinin antagonist L364,718 reduced cerulein-induced weight gain (4.3 +/- 3.4 gm; p less than 0.001) and hyperamylasemia (9392 +/- 6718 units; p less than 0.05). We conclude that cerulein pancreatitis in the ex vivo isolated perfused canine pancreatic preparation is identical physiologically, biochemically, and morphologically with that seen in intact animals.
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PMID:Cerulein-induced pancreatitis in the ex vivo isolated perfused canine pancreas. 200 56


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