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)

A porcine pancreatic transplantation model was used to investigate possible protease activation in the pancreatic graft during preservation. After perfusion with Perfadex and cold ischemia for 24 h, but prior to reperfusion, activated carboxypeptidase B was demonstrated in tissue samples from the graft parenchyma with a Western blot technique, indicating that graft pancreatitis may already be initiated during the preservation phase. A higher degree of carboxypeptidase B activation was observed in grafts perfused at a pressure of 130 cm H20 than after perfusion at 70 cm H20. During reperfusion, the fraction of activated carboxypeptidase B gradually declined but was still detectable after 2 h. One group of pigs received aprotinin intravenously during reperfusion, but the protease inhibitor did not influence the degree of carboxypeptidase B activation in the biopsy specimen. Immunoblotting against cationic trypsinogen/trypsin was also performed. When activated trypsin was detectable, it never presented more than a few percent of the total amount of uncomplexed immunoreactive trypsinogen/trypsin.
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PMID:Protease activation in the porcine pancreatic allograft during preservation. 857 79

This study compares the susceptibility of pancreatic acinar cells and zymogen granules against oxidative injury and analyzes the mechanisms involved. Zymogen granules and acinar cells, isolated from rat pancreas, were exposed to a reaction mixture containing xanthine oxidase, hypoxanthine, and chelated iron. Cell function and viability were assessed by various techniques. Trypsin activation was quantified by an Elisa for trypsinogen activating peptide. Integrity of granules was determined by release of amylase. The reaction mixture rapidly generated radicals as assessed by deoxyribose and luminol assays. This oxidative stress caused lysis of granules in a matter of minutes but significant cell death only after some hours. Nevertheless, radicals initiated intracellular vacuolization, morphological damage to zymogen granules and mitochondria, increase in trypsinogen activating peptide, and decrease in ATP already after 5-30 min. Supramaximal caerulein concentrations also caused rapid trypsin activation. Addition of cells but not of granules reduced deoxyribose oxidation, suggesting that intact cells act as scavengers. Caerulein pretreatment only slightly increased the susceptibility of cells but markedly that of granules. In conclusion, isolated zymogen granules are markedly more susceptible to oxidative injury than intact acinar cells, in particular, in early stages of caerulein pancreatitis. The results show that oxidative stress causes a rapid trypsin activation that may contribute to cell damage by triggering autodigestion. Zymogen granules and mitochondria appear to be important targets of oxidative damage inside acinar cells. The series of intracellular events initiated by oxidative stress was similar to changes seen in early stages of pancreatitis.
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PMID:Oxidative injury to isolated rat pancreatic acinar cells vs. isolated zymogen granules. 874 74

Acute pancreatitis is characterized by hyperamylasemia, pancreatic edema, and the presence of activated digestive enzymes within the pancreas. The secretagogue-induced model of acute pancreatitis is also characterized by pancreatic acinar cell vacuolation, subcellular redistribution of lysosomal hydrolases, and a fall in pancreatic glutathione levels. We have performed time-dependence studies to determine the sequence with which these phenomena appear and to establish their cause-and-effect relationship. Evidence of lysosomal enzyme redistribution and trypsinogen activation within the pancreas could be detected within 10-15 min of the onset of supramaximal secretagogue stimulation, while hyperamylasemia (30 min), pancreatic edema (60 min), and acinar cell vacuolation (60 min) occurred at later times. Pancreatic glutathione levels were either unchanged (15 and 30 min) or elevated (60 min) during the early times of supramaximal stimulation and were only noted to be decreased at a later time. These results support the conclusion that intrapancreatic digestive enzyme activation, possibly occurring by a mechanism involving lysosomal hydrolase redistribution, is an early and likely a critical event in the evolution of secretagogue-induced pancreatitis but that glutathione depletion is neither early nor critical to the evolution of this model of pancreatitis.
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PMID:Edema and intrapancreatic trypsinogen activation precede glutathione depletion during caerulein pancreatitis. 876 Jan 2

Acute pancreatitis following endoscopic retrograde cholangiopancreatography (ERCP) occurs in 3-18% of patients undergoing either diagnostic or therapeutic ERCP. We prospectively measured urinary trypsinogen activation peptides (TAP) by an automated anti-TAP enzyme-linked immunoassay among 107 patients 4 h after ERCP to determine whether this measurement helps in the early diagnosis of ERCP-induced pancreatitis. Pancreatitis was documented in 10 of 107 patients (9.3%). All episodes were graded as mild. Urinary TAP was not significantly increased. We conclude that measurement of urinary TAP 4 h after ERCP is not helpful in documenting mild ERCP-induced acute pancreatitis.
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PMID:Urinary trypsinogen activation peptides (TAP) are not increased in mild ERCP-induced pancreatitis. 883 Mar 37

We compared the cellular events induced by hyperstimulation of rats with caerulein which induces acute pancreatitis, to bombesin, which does not induce pancreatitis. Both secretogogues induced the intracellular activation of trypsinogen and the colocalization of lysosomal hydrolases and zymogen granules within 10-15 minutes. These data indicate that these parameters, previously thought to be crucial initiating events of pancreatitis, are not definitive cellular markers of the disease. We then compared the abilities of the two secretagogues to activate stress-activated protein kinase (SAPK). Significant effects of caerulein hyperstimulation on SAPK activity were observed within 5 minutes, the maximum (57-fold) activation was evident after 15 minutes, and levels remained above control for at least 3 hours. In comparison, hyperstimulation with bombesin induced a maximal 5-fold increase of SAPK activity which returned to basal within one hour. These data indicate that SAPK activity is the earliest and best correlated cellular marker associated with secretagogue-induced pancreatitis.
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PMID:Stress-activated protein kinase activation is the earliest direct correlate to the induction of secretagogue-induced pancreatitis in rats. 885 94

Using an assay for measurement of released type 1-prophospholipase A2 (type 1-proPLA2) propeptides (PROP assay), we have shown that human granulocytes, but not lymphocytes or macrophages, abundantly express this 'pancreatic' type 1-proPLA2 zymogen. Stimulation with tumour necrosis factor-alpha (TNF-alpha) and other cytokines results in the immediate release from granulocytes of a mixture of free propeptides and type 1-proPLA2 precursor. We also found that granulocytes contain an approximately 29 kDa trypsin-like endogenous type 1-proPLA2 activator. PROP assay and TAP (trypsinogen activation peptide) assay of plasma samples accurately predicts the segregation of acute pancreatitis into three clearly defined categories of severity--mild, intermediate and severe--at the time of first hospital admission and over the next few hours of observation. Mild and intermediate pancreatitis are associated with a degree of granulocyte stimulation limited to the release of the unactivated type 1-proPLA2 precursor. Progression to severe disease is accompanied by the activation of granulocyte type 1-proPLA2, apparently carried to completion. This identifies the approximately 29 kDa endogenous activator of type 1-proPLA2 in granulocytes as a critical mediator at a threshold stage in acute pancreatitis, which marks the transition from uncomplicated pancreatitis to the potentially lethal disease. Specific inhibitors of this key regulatory enzyme modelled on the P3-P1 domain of the type 1-proPLA2 activation peptide would seem to be promising candidates for a new class of chemotherapeutic agents.
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PMID:Activation of human granulocyte type 1-prophospholipase A2. 886 67

Ethanol abuse is a well known association of pancreatitis. Research into the pathogenesis of alcoholic pancreatitis has generally followed two directions. Firstly, factors which may predispose alcoholics to pancreatitis have been examined. To date, these studies have been negative and the predisposing factor(s) remain unknown. The second approach has involved studies on the constant metabolic effects of ethanol on the pancreas which may render the acinar cell susceptible to digestive enzyme induced injury. Recently developed models of experimental pancreatitis have implicated intracellular activation of digestive enzymes by lysosomal enzymes as an early event. Using the Lieber-DeCarli model of ethanol administration to rats, a number of changes have been described in pancreatic acinar cells which may predispose the gland to autodigestion. These changes include: (1) increased glandular content of digestive enzymes as a result of increases in mRNA levels for these enzymes; (2) increased glandular content of the lysosomal enzyme cathepsin B (known to be capable of activating trypsinogen); (3) increased fragility of lysosomes possibly mediated by cholesteryl esters and fatty acid ethyl esters; and (4) increased fragility of zymogen granules. These effects of ethanol constitute a "primed" setting (the "Drinker's Pancreas") for autodigestion. Triggering factors for autodigestion in this setting have not yet been identified.
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PMID:Ethanol induced acinar cell injury. 897 57

Pancreatic hyperstimulation with simultaneous duct obstruction does not cause the typical features of acute pancreatitis, therefore the role of an additional challenge, such as either ethanol intoxication or short-term ischemia, was studied. Alcoholic pancreatitis was induced in 28 rats by acute ethanol intoxication (0.25 LD50) and an obstruction/hyperstimulation mechanism (clip of the biliopancreatic duct for 20 min and intravenous stimulation with 5 U of cholecystokinin and secretin each). Ischemic pancreatitis was performed by obstruction/hyperstimulation and subsequent pancreatic ischemia by clamping the supplying arteries for 40 min. The macro- and microscopic alterations were evaluated and graded by a scoring system. Additionally, the pancreas was removed in 50% of the animals and the pancreatic acini were prepared. From those acini the intracellular enzymes trypsinogen, kallikreinogen, amylase, lipase, glucuronidase, and acidic phosphatases were determined. While obstruction/hyperstimulation, 40 min of ischemia, or ethanol alone did not induce acute pancreatitis, a combination of obstruction/hyperstimulation with either ethanol or ischemia resulted in acute pancreatitis in 68 and 60% of treated rats, respectively. Similarly, both models were characterized by extrapancreatic fat necrosis and acinar necrosis at the periphery of the lobules. Almost all intracellular enzymes were elevated in both pancreatitis models compared to sham-operated controls. Both alcohol and ischemia were insults that sensitize the pancreas to develop acute pancreatitis after obstruction/hyperstimulation. Since the observed morphologic and enzymatic alterations in both models are very similar, alcohol and ischemia might have some common pathways by which they make the pancreas vulnerable to enzymatic attacks.
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PMID:Similar morphological and intracellular biochemical changes in alcoholic acute pancreatitis and ischemic acute pancreatitis in rats. 898 5

Despite the fact that alcoholism is one of the major causes of pancreatitis, the pathogenesis of this disorder remains obscure. Factors such as the pattern of ethanol consumption, diet, and genetic predisposition may be contributing factors. The failure to produce alcoholic pancreatitis in experimental animals suggests that experimental provision of ethanol may only increase the predisposition to pancreatitis. To test this possibility, we developed an assay system using the in vitro model of cerulein-induced pancreatitis. In this system, pancreatic lobules were first exposed to a supraphysiologic concentration (10(-6) M) of the cholecystokinin analogue, cerulein, after which homogenates were incubated for up to 6 h. Activation of trypsinogen and chymotrypsinogen was observed only in cerulein-treated preparations. We then investigated the effects of the duration of ethanol feeding on cerulein-induced changes in rat pancreas. The pancreata from rats fed ethanol for 9-12 months were more susceptible to cerulein-induced activation of chymotrypsinogen compared to the pancreata from pair-fed control animals. This susceptibility also paralleled morphologic changes, such as dilatation of endoplasmic reticulum, only in the ethanol-fed group. In contrast, during the early stages (up to 3 months) of ethanol consumption, there was resistance (p < 0.01) to cerulein-induced changes. These results suggest that long-term ethanol consumption increases susceptibility to pancreatitis and raises the possibility that a similar mechanism may operate in human alcoholics.
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PMID:Ethanol consumption and susceptibility of the pancreas to cerulein-induced pancreatitis. 905 87

The etiology of acute pancreatitis is based on several causes, among which idiopathic nature (< 30%) is second to biliary stone disease (60-70%). It is still under debate whether alcohol as the main cause of chronic pancreatitic disease can cause acute pancreatitis. Based on Opie's "obstruction theory" of 1901 and experimental data, it is now widely accepted that the gallstone passage into or through the terminal biliopancreatic ductal system triggers acute (necrotizing) pancreatitis by causing pancreatic ductal obstruction. However, the sequential intracellular mechanisms in the pathogenesis of acute pancreatitis remain unclear. A co-localization hypothesis has been proposed to explain the premature intracellular activation of trypsinogen to trypsin: due to a yet unknown defect in the intracellular protein transport and sorting system within the acinar cell, lysosomal hydrolases (i.e. cathepsin B) and secretory proteins (i.e. trypsinogen) co-localize in a fragile postgolgi vacuole where activation can occur. In addition, alterations of exo- and endocytosis at the apical pole exist (i.e. secretion block). The pathophysiological events are characterized by local and systemic hypovolemia and (micro)circulatory failure aggravating necrosis, followed by ARDS, renal failure and several other severe complications (i.e. sepsis and DIC). The systemic overflow of proteolytic enzymes (i.e. PLA-2) and kinins plays a major role as mediating factor in severe cases, resulting in multiorgan failure.
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PMID:[Etiology, pathogenesis and pathophysiology of acute pancreatitis]. 928 10


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