UMLS:C0030305 - FACTA Search

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Query: UMLS:C0030305 (pancreatitis)
16,014 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autoimmune diabetes is caused by the CD4(+), T helper 1 (Th1) cell-mediated apoptosis of insulin-producing beta cells. We have previously shown that Th2 T cells bearing the same T cell receptor (TCR) as the diabetogenic Th1 T cells invade islets in neonatal nonobese diabetic (NOD) mice but fail to cause disease. Moreover, when mixed in excess and cotransferred with Th1 T cells, Th2 T cells could not protect NOD neonates from Th1-mediated diabetes. We have now found, to our great surprise, the same Th2 T cells that produced a harmless insulitis in neonatal NOD mice produced intense and generalized pancreatitis and insulitis associated with islet cell necrosis, abscess formation, and subsequent diabetes when transferred into immunocompromised NOD.scid mice. These lesions resembled allergic inflamation and contained a large eosinophilic infiltrate. Moreover, the Th2-mediated destruction of islet cells was mediated by local interleukin-10 (IL-10) production but not by IL-4. These findings indicate that under certain conditions Th2 T cells may not produce a benign or protective insulitis but rather acute pathology and disease. Additionally, these results lead us to question the feasibility of Th2-based therapy in type I diabetes, especially in immunosuppressed recipients of islet cell transplants.
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PMID:T helper 2 (Th2) T cells induce acute pancreatitis and diabetes in immune-compromised nonobese diabetic (NOD) mice. 922 59

Over the past few years, evidence has accumulated that implicates proinflammatory cytokines as the mediators responsible for the escalation of acute pancreatitis into a multisystem disease. It has been shown that the degree of serum cytokine elevation, particularly the macrophage-derived cytokines interleukin-1, interleukin-6, and tumor necrosis factor-alpha, correlates with the severity and outcome of acute pancreatitis. Interleukin-10 is an anti-inflammatory cytokine that inhibits cytokine production from the macrophage. The aim of this study was to determine whether interleukin-10 would decrease both the severity of acute pancreatitis and the level of circulating proinflammatory cytokines. Ninety female mice were divided into three equal groups. Group 1 (controls) received intraperitoneal saline solution. Groups 2 and 3 received intraperitoneal cerulein (50 mg/kg/hr) for 7 hours. In addition, group 3 was given 1500 units of intraperitoneal interleukin-10, beginning 1 hour after the induction of acute pancreatitis and every 3 hours thereafter. Animals were killed at 3-hour intervals. Blood samples were obtained for serum amylase and cytokine determinations (interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha). Pancreata were dissected free and fixed in formalin for blinded histologic scoring. Interleukin-10 reduced the serum levels of interleukin-1beta, interleukin-6, tumor necrosis factor-alpha, and amylase in comparison to untreated animals with pancreatitis (P < 0.05). Pancreatic edema, necrosis, and inflammatory cell infiltrate were also reduced in those animals given interleukin-10 (P <0.05). Histologic score, serum cytokines, and amylase levels are elevated during acute pancreatitis. Interleukin-10 given therapeutically, that is, after the onset of acute pancreatitis, lessened the severity of disease, probably through inhibition of the macrophage. This was associated with a decrease in circulating cytokine levels.
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PMID:Interleukin-10 reduces circulating levels of serum cytokines in experimental pancreatitis. 983 43

Inflammatory cytoklines derived from the liver may cause distant organ failure and death in severe pancreatitis. To minimize liver cytokine release, we studied the effects of Kupffer cell blockade on the mortality rate and severity of inflammation in a model of that disease. Thirty mice were divided into three groups. Group I received gadolinium chloride (l mg/100 g intravenously), which blocks Kupffer cell activity, and regular food. Groups 2 and 3 were fed a choline-deficient, ethionine-supplemented diet and developed severe pancreatitis. Group 2 (control) received intravenous saline solution, and group 3 received gadolinium chloride. Animals were killed at 72 hours. Serum levels of tumor necrosis factor-alpha and interleukin-1Beta, interleukin-6, and interleukin-10 were determined by enzyme-linked immunosorbent assay. Lung neutrophil infiltration was assessed by myeloperoxidase assay. Pancreatic inflammation was scored in a blinded manner. In a separate experiment, mortality rates were determined in saline- and gadolinium-treated animals (n=100). Gadolinium reduced the levels of all the cytoklines and lung myeloperoxidase (P<0.05). Gadolinium also reduced the mortality rate (52% vs. 86%; P <0.001). However, the degree of pancreatic inflammation was unchanged by gadolinium treatment. These data support the hypothesis that mortality in severe pancreatitis may in part be related to the secondary release of hepatic cytokines.
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PMID:Hepatic Kupffer cell blockade reduces mortality of acute hemorrhagic pancreatitis in mice. 984 2

During the past decade, a considerable number of experimental studies have confirmed the hypothesis that microcirculatory derangements play a pivotal role in the pathogenesis of acute pancreatitis, including the process of conversion from edematous to necrotizing injury. Predominant microcirculatory disorders are nutritive capillary perfusion failure, with the consequence of prolonged focal hypoxia or anoxia, and inflammation-associated microvascular leukocyte recruitment, CD11b- and intercellular adhesion molecule (ICAM)-1-mediated leukocyte-endothelial cell interaction and loss of endothelial integrity, which may result in both edema formation and necrosis. A variety of proinflammatory mediators, such as oxygen radicals, leukotrienes, platelet-activating factor, and interleukins, but also bradykinin and endothelins, seem to be involved in triggering the manifestations of these microcirculatory disorders. In contrast, the anti-inflammatory interleukin-10, as well as nitric oxide, are thought to be capable of protecting from these pancreatitis-associated microvascular injuries. This knowledge may be encouraging for the development of novel therapeutic strategies, aiming at the attenuation of microcirculatory disorders, and, thus, preventing tissue injury in acute pancreatitis.
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PMID:Microcirculatory derangements in acute pancreatitis. 1145 78

Hepatocyte growth factor (HGF) overexpression was reported in experimental and clinical acute pancreatitis. These observations prompted us to determine the effect of HGF administration on the development of caerulein-induced pancreatitis in rats. Acute pancreatitis was induced by s.c. infusion of caerulein (10 microg/kg/h) for 5 h. HGF was administrated twice (30 min before caerulein or saline infusion and 3 h later) at the doses: 0.4, 2, 10 or 50 microg/kg s.c. Immediately after cessation of caerulein or saline infusion, the pancreatic blood flow, plasma amylase and lipase activity, plasma cytokines concentration, cell proliferation, and morphological signs of pancreatitis were examined. Caerulein administration induced acute edematous pancreatitis manifested by 41% decrease in DNA synthesis, 53% inhibition of pancreatic blood flow, a significant increase in plasma amylase and lipase activity, plasma interleukin-1beta and interleukin-6 concentration, as well as, the development of the histological signs of pancreatic damage (edema, leukocyte infiltration, and vacuolization). Administration of HGF without induction of pancreatitis increased plasma interleukin-10. Treatment with HGF, during induction of pancreatitis, increased plasma interleukin-10 and attenuated the pancreatic damage, what was manifested by histological improvement of pancreatic integrity, the partial reversion of the drop in DNA synthesis and pancreatic blood flow, and the reduction in pancreatitis evoked increase in plasma amylase, lipase, and interleukin-1beta and interleukin-6 levels. HGF administrated at the dose 2 microg/kg exhibited a similar beneficial effect as administration of HGF at the doses 10 or 50 microg/kg. Treatment with HGF at the dose 0.4 microg/kg was less effective. We conclude that: (1) administration of HGF attenuates pancreatic damage in caerulein-induced pancreatitis; (2) this effect seems to be related to the increase in production of interleukin-10, the reduction in release of interleukin-1beta and interleukin-6, and the improvement of pancreatic blood flow.
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PMID:Hepatocyte growth factor attenuates pancreatic damage in caerulein-induced pancreatitis in rats. 1169 71

Leptin is involved in the regulation of food intake and previous studies have shown that leptin affects the inflammatory response in various tissues. The objective of this study was to examine the influence of leptin administration on the development and the course of acute ischemic pancreatitis. Acute pancreatitis was induced by limitation of pancreatic blood flow by clamping of inferior splenic artery for 30 min, followed by reperfusion. Leptin was administered three times daily at the dose 10 or 50 microg/kg. Animals were sacrificed 1, 3, 5, 10 and 21 days after removal of vascular clips. Administration of leptin reduced development of pancreatic damage and accelerated pancreatic regeneration what was manifested by the improvement of pancreatic histology, the decrease in serum lipase and amylase activity, and the reduction in serum interleukin-1beta concentration. Also, treatment with leptin caused the increase in the pancreatic blood flow and pancreatic DNA synthesis. Leptin administration was without effect on serum interleukin-10 concentration. Leptin at the dose 50 microg/kg was more effective than 10 microg/kg. We conclude that leptin reduces the pancreatic damage in the course of ischemic pancreatitis and accelerates the pancreatic tissue repair. The beneficial effects of leptin appear to be dependent on the improvement of pancreatic blood flow, the increase in pancreatic cell growth, and the limitation of pro-inflammatory interleukin-1beta release.
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PMID:Influence of leptin administration on the course of acute ischemic pancreatitis. 1251 Aug 63

Acute pancreatitis still represents the most common complication after procedures involving Vater's papilla; the reported incidence of this complication varies from less than 1% up to 40%. Attempts at preventing post-ERCP pancreatitis have been carried out using technical measures, pharmacological prophylaxis, or patient selection. Balloon sphincter of Oddi dilatation, difficult papillary cannulation, pancreatic sphincterotomy and multiple pancreatic duct injections have been found to be risk factors for postprocedure pancreatitis. Therefore, technique-related prevention of post-ERCP pancreatitis includes careful pancreatic duct injection, avoiding cannulation trauma, and maintaining adequate pancreatic drainage after the ERCP procedure. Pancreatic stent placement has been shown to be the most effective technique-related prevention of postprocedure pancreatitis. Apart from technique-related risk factors, operator experience also seems to be a potential risk-factor for post-ERCP/ES complications. The experience of the endoscopist rather than other patient- or technique-related conditions could probably constitute the major risk factor for postprocedure pancreatitis. Pharmacological prevention of pancreatitis after ERCP or sphincterotomy has been the topic of several investigations in recent years but still remains a debated question. Pharmacological prevention has been mainly aimed at either reducing the amount of intrapancreatic enzymes, preventing intra-cellular co-localization of enzymes and lysosomal hydrolases or blocking some steps of the enzyme-activated inflammatory cascade. Somatostatin, octreotide, gabexate mesilate and, more recently, recombinant interleukin-10 have been the most investigated drugs. Somatostatin, gabexate mesilate and recombinant interleukin-10, but not octreotide, have been found to be able to prevent post-ERCP pancreatitis in non-selected cases; however, a strategy of routine pharmacological prophylaxis in all patients is not likely to be cost-effective. A strategy of pharmacological prevention only in high-risk cases is cost-effective, but, up to now, only recombinant interleukin-10 has been proven effective. The "on demand" postprocedure treatment should also be of paramount importance, but no data are at present available regarding the potential efficacy of some drugs; on the basis of the mechanism of action, we can argue that recombinant interleukin-10 could be the only drug candidate for such a strategy. Post-ERCP pancreatitis can also be prevented by patient selection. Patient-related risk factors are now well-known, so an increased risk of developing pancreatitis is predictable "a priori" in these subjects, independently of the type of endoscopic procedure performed. Furthermore, the risk of pancreatitis escalates when multiple risk factors occur in the same patient or some technique-related risk factor comes up during the procedure. In these patients diagnostic ERCP should be avoided in routine practice and magnetic resonance cholangio-pancreatography should be used as the first diagnostic step. When either diagnostic or therapeutic ERCP is indicated, these high-risk patients should be informed about their own specific risk of postprocedure pancreatitis.
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PMID:Preventing post-ERCP pancreatitis: where are we? 1255 13

Acute pancreatitis is a major complication of endoscopic retrograde cholangiopancreatography (ERCP), its incidence varying with the indications for the procedure (<5% for the management of common bile duct stones and up to 20% in the case of sphincter of Oddi dysfunction) and also with events occurring during the ERCP such as acinarization and pancreatic sphincterotomy. If the triggering event of premature intra-acinar activation of trypsinogen is unknown, the acinar cell injury leads to oxidative stress, nuclear translocation of nuclear factor kappa B and subsequent transcription of chemo- and pro-inflammatory cytokines. These events are followed by chemoattraction and activation of monomacrophages, T lymphocytes and neutrophils which are responsible for acinar necrosis and amplification of the pro-inflammatory cascade. Finally, after amplification by Kupffer cells, systemic inflammatory response syndrome and multiple organ failure occur. All these events take place within a very short period of time, thus offering a very short therapeutic window during which it is theoretically possible to modulate the severity of human pancreatitis. Prophylactic immunomodulation of this pro-inflammatory cascade is attractive, using anti-inflammatory cytokines, specific inhibitors of pro-inflammatory cytokines or inhibitors of the nuclear translocation of the nuclear factor kappa B. Good results have been obtained in experimental models, reducing the acute pancreatitis severity and its systemic complications. The use of immunomodulators in the prevention of human post-ERCP pancreatitis is actually restricted to recombinant interleukin-10. Three of four randomized clinical trials, confirmed by a meta-analysis, have shown that prophylactic injection of recombinant interleukin-10 can significantly reduce the incidence of acute pancreatitis and may decrease the length of the hospital stay. The use of recombinant interleukin-10 in this indication has to be established in a multicenter prospective trial and we need to investigate the safety and efficacy of other immunomodulatory drugs and develop new specific targets.
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PMID:New frontiers in the pharmacological prevention of post-ERCP pancreatitis: the cytokines. 1255 16

The incidence of clinically significant pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) ranges from 1-13.5%. It is more common after therapeutic procedures such as sphincterotomy or balloon dilatation of the sphincter, and diagnostic procedures such as biliary or pancreatic manometry. The severity of post-ERCP pancreatitis may vary from very mild to extremely severe disease with multiple organ failure and fatal outcome. Several factors including papillary oedema, injection of hyperosmolar contrast-material, introduction of previously activated enzymes during repeated cannulation, bacterial contamination and thermal injury from endoscopic sphincterotomy have been implicated as triggering factors that initiate the sequential cascade of pancreatic autodigestion and release of proinflammatory cytokines leading to acute pancreatitis. Recovery from post-ERCP pancreatitis is usually rapid when the injury is confined to the pancreas. However, systemic production of inflammatory mediators may lead to the development of more serious manifestations including multiorgan failure.A wide range of pharmacological agents has been tested in experimental and clinical trials, but the results have been largely disappointing. Several drugs are discussed in this review, but only somatostatin and gabexate (gabexate mesilate) have consistently shown a moderate beneficial effect. In clinical trials, both gabexate and somatostatin appear equally effective in reducing the incidence of pancreatitis by two-thirds compared with controls. However, both drugs need to be given by continuous infusion for about 12 hours and this makes them less cost-effective than conventional treatment. One potential strategy is to reserve these drugs for high-risk patients undergoing ERCP. Preliminary studies have shown encouraging results with nitroglycerin, antibacterials and heparin. However, these observations need to be corroborated in a rigorous fashion in large, randomised, double-blind, controlled trials. If these drugs are found to be effective in further trials, it may become cost-effective to use them routinely for the prevention of post-ERCP pancreatitis. Despite the theoretical benefits, interleukin-10 has not shown a consistent benefit in clinical trials. It is probable that other cytokine inhibitors or modulators may become available for future trials to prevent pancreatitis or more probably, to reduce the severity of pancreatitis. Further research also should focus on developing newer molecules or the use of a combination of currently available drugs to prevent pancreatitis in high-risk patients undergoing therapeutic ERCP procedures.
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PMID:Pharmacological prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis. 1292 86

Hepatocyte growth factor (HGF) overexpression is observed in experimental and clinical acute pancreatitis. Moreover, previous studies have shown that administration of HGF reduces pancreatic damage in experimental pancreatitis. The aim of our studies was to determine the role of cyclooxygenase-1 and cyclooxygenase-2 in the protective effect of HGF administration against caerulein-induced pancreatitis. Acute pancreatitis was induced in rats by infusion of caerulein. HGF was administered twice at the dose 10 microg/kg s.c. The activity of cyclooxygenase-1 and cyclooxygenase-2 was inhibited by resveratrol and rofecoxib, respectively (10 mg/kg). Immediately after cessation of caerulein or saline infusion, pancreatic blood flow, pancreatic cell proliferation, pancreatic prostaglandin E(2) generation, plasma lipase activity, plasma interleukin-1 beta and interleukin-10 concentration were measured and morphological signs of pancreatitis were examined. Expression of cyclooxygenase-1 and cyclooxygenase-2 mRNA transcripts was determined by reverse transcriptase-polymerase chain reaction (RT-PCR). Cyclooxygenase protein production was analyzed by Western blot. Administration of HGF or caerulein alone, or their combination, was without effect on cyclooxygenase-1 mRNA expression in pancreatic tissue. Expression of cyclooxygenase-2 mRNA was increased by HGF and caerulein. The maximal increase in cyclooxygenase-2 mRNA expression was observed when HGF administration was combined with caerulein infusion. A similar effect was observed when we studied the influence of HGF and caerulein on pancreatic cyclooxygenase-2 production, as determined by Western blot. Administration of HGF without induction of acute pancreatitis increased pancreatic prostaglandin E(2) generation and plasma interleukin-10, and this effect was abolished by the cyclooxygenase-2 inhibitor, rofecoxib. Treatment with HGF, during the development of pancreatitis, increased the plasma interleukin-10 concentration and attenuated pancreatic damage, as evidenced by: (a) histological improvement of pancreatic integrity; (b) the partial reversal of the decrease in DNA synthesis and pancreatic blood flow; (c) the reduction in pancreatitis-evoked increase in plasma lipase and interleukin-1 beta. Administration of resveratrol and rofecoxib alone was without effect on the development of pancreatitis. Combination of rofecoxib with HGF reduced the HGF-evoked increase in plasma interleukin-10 concentration and pancreatic prostaglandin E(2) generation, and abolished the protective effect of HGF against pancreatic damage in pancreatitis. Resveratrol did not affect the protective effect of HGF. We conclude that: (1) HGF induces cyclooxygenase-2 but not cyclooxygenase-1 expression; (2) inhibition of cyclooxygenase-2 in HGF-treated rats decreases the release of anti-inflammatory interleukin-10, increases the production of pro-inflammatory interleukin-1 beta and reduces pancreatic blood flow; (3) cyclooxygenase-2 activity is necessary for the protective effect of HGF in acute pancreatitis.
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PMID:Inhibition of cyclooxygenase-2 reduces the protective effect of hepatocyte growth factor in experimental pancreatitis. 1475 15

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