Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001339 (acute pancreatitis)
 10,593 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of different cytokines in the pathogenesis of L-arginine (Arg)-induced acute pancreatitis in rat, and the ability of KSG-504, a novel cholecystokinin receptor antagonist, to exert protection in this type of acute pancreatitis was evaluated. Male Wistar rats received 250 mg/100 g body weight of Arg intraperitoneally twice, at an interval of 1 h. Control rats received instead the same amount of glycine at the same times. Fifty mg/kg KSG-504 was injected subcutaneously 0.5 h before and 6, 18 and 36 h after the first Arg administration. Rats were examined 12, 24 and 48 h after pancreatitis induction. To assess the severity of inflammation, the edema was quantified, the serum amylase level was measured, and histologic examinations were performed. Serum tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) levels were determined by bioassay, using the TNF-sensitive WEHI 164 and the IL-6-dependent B9 cell lines, respectively. In Arg-induced acute pancreatitis, the amylase level was increased significantly at 12 h (48.600 +/- 3.980 U/l) and 24 h (30.800 +/- 3.813 U/l) vs. the control group (6.382 +/- 184 U/l). No significant alteration in the ratio pancreatic weight/body weight was found in the different groups. However, in Arg-induced acute pancreatitis, both the TNF-alpha (15.1 +/- 6.9 U/ml) and the IL-6 (39.6 +/- 19.2 pg/ml) levels were already elevated significantly at 12 h vs. the controls (3.1 +/- 0.8 U/ml and 15.2 +/- 3.1 pg/ml, respectively) and remained elevated at 24 and 48 h. Simultaneous KSG-504 administration did not modify the measured cytokine levels. No significant changes in plasma CCK levels were observed. In Arg-induced acute pancreatitis, histological evaluation revealed diffuse but microfocal necrobiotic alterations. No marked protective effects of KSG-504 were observed on histological sections. These results suggest that excessive doses of Arg induce severe acute pancreatitis in rat, with a simultaneous cytokine level elevation. Endogenous CCK does not seem to play an essential role in the pathogenesis of Arg-induced acute pancreatitis.
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PMID:Cytokine level changes in L-arginine-induced acute pancreatitis in rat. 904 61

Interleukin-1 beta (IL-1 beta) is produced in large amounts during acute pancreatitis and is believed to play a role in disease progression. Because secretion of IL-1 beta is dependent on intracellular processing of pro-IL-1 beta by IL-1 converting enzyme (ICE), we aimed to determine the efficacy of a novel ICE inactivator (VE-13045) in inhibiting secretion of active IL-1 beta in vivo and if the loss of ICE activity would affect the severity and mortality of experimental pancreatitis. Severe hemorrhagic pancreatitis was induced in adult rats by infusion of bile acid into the pancreatic duct. Animals were randomized to receive VE-13045 or vehicle before induction of pancreatitis. To confirm our findings and to ensure that the results were not model dependent, a second series of experiments was conducted using mice possessing a homozygous knockout of the ICE gene in which lethal pancreatitis was induced by feeding a choline-deficient, ethionine-supplemented diet. The severity of pancreatitis was assessed for both experiments by standard surrogate markers, blind histologic grading, and serum IL-1 beta and tumor necrosis factor-alpha (TNF-alpha) levels. Pancreatic IL-1 beta mRNA induction was assessed by differential RT-PCR. Acute pancreatitis was associated with a 120-fold increase in IL-1 beta mRNA, which was not affected by ICE inhibition or gene deletion. Cytokine processing and secretion were affected, as evidenced by decreased serum levels of IL-1 beta and TNF-alpha (p < 0.001) in all animals with an inactive ICE enzyme. This lack of cytokine production increased survival from 32% to 78% following bile salt pancreatitis (p < 0.01) and from 24% to 80% following diet-induced pancreatitis (p < 0.005). Both ICE-defective groups demonstrated decreased pancreatic necrosis, edema, inflammation, wet weight (all p < 0.05), and amylase and lipase (p < 0.01). In vivo blockade or genetic deletion of ICE inhibits pancreatitis-induced secretion of proinflammatory cytokines without altering IL-1 mRNA production and is associated with decreased pancreatitis severity and dramatic survival benefits.
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PMID:Severity and mortality of experimental pancreatitis are dependent on interleukin-1 converting enzyme (ICE). 905 18

We investigated the effects of the xanthine derivative propentofylline on lung injury in rats with cerulein-induced acute pancreatitis and endotoxemia. Pancreatitis was induced by four intramuscular injections of cerulein (50 micrograms/kg at 1-h intervals). Pancreatitis rats were injected intraperitoneally with 30 mg/kg lipopolysaccharide (LPS) 6 h following the first cerulein injection as a septic challenge. Propentofylline (50 mg/kg) was injected intravenously 15 min before the administration of LPS. Rats were divided randomly into five experimental groups: group I, normal rats; group II, pancreatitis; group III, LPS injection; group IV, pancreatitis and LPS injection; and group V, pancreatitis and LPS injection with propentofylline pretreatment. Serum amylase concentrations in groups II, IV, and V increased significantly 8 h after the first cerulein injection compared to those in groups I and III. Serum tumor necrosis factor (TNF)-alpha concentrations, cytokine-induced neutrophil chemoattractant (CINC) concentrations in serum or bronchoalveolar (BAL) fluid, lung myeloperoxidase (MPO) activity, and extent of pulmonary polymorphonuclear cell infiltration in group IV were significantly higher than those observed in group III. Pretreatment with propentofylline inhibited the rise in TNF-alpha levels (group V). However, propentofylline did not prevent the elevation of CINC levels in group V. In contrast, propentofylline reduced lung MPO and pulmonary PMN infiltration in group V. In addition, lung compliance was improved by pretreatment with propentofylline. These results suggest that propentofylline attenuates lung injury in an experimental model of pancreatitis complicated by endotoxemia but has differential effects on cytokine production.
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PMID:Effects of propentofylline on tumor necrosis factor-alpha and cytokine-induced neutrophil chemoattractant production in rats with cerulein-induced pancreatitis and endotoxemia. 909 57

Clinically detectable signs of lung injury develop in up to 50-70 percent of patients with acute pancreatitis. Despite that, the physiopathology of the lung injury associated with acute pancreatitis is unclear so far. Pulmonary edema is the main respiratory complication in acute pancreatitis. Increased permeabilities of the pulmonary endothelial and alveolar epithelial barriers are the causes of the pulmonary edema. Several factors have been regarded as the cause to pulmonary edema: release of pancreatic-derived proteolytic enzymes, oxygen-free radicals, phospholipase A2, free fat acids, tumor necrosis factor, platelet activating factor, arachidonic acid metabolites and pulmonary embolization. Understanding lung injury physiopathology enables physicians to a better therapeutic approach of the patients with acute pancreatitis. The aim of this paper is to expose the theories that explain the pancreatic-derived lung injury.
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PMID:[Physiopathology of lung injury in acute pancreatitis]. 923 97

Oxidative stress and the inflammatory response may play roles in the pathogenesis of acute pancreatitis. Herein, we characterized pancreatic expression of oxidative stress-responsive genes [c-fos, heme oxygenase-1 (HO-1), and metallothionein-I (MT-I)] and cytokine genes [interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha)] during caerulein-induced acute pancreatitis in the mouse. c-fos, HO-1, and MT-I mRNAs were coordinately and rapidly (3-7 h) upregulated, and HO-1 and MT-I protein levels were increased slightly in the pancreas during acute pancreatitis. In addition, IL-1 beta, IL-6, and TNF-alpha mRNAs were rapidly (7 h) upregulated in the pancreas, and intrapancreatic IL-1 beta and IL-6 protein levels rapidly increased (3-fold and 6.4-fold, respectively) during acute pancreatitis. These studies suggest that oxidative stress and inflammation each occur in the pancreas during the early stages of acute pancreatitis. However, under a limited set of experimental conditions, we found that an insult that causes pancreatic oxidative stress (diethylmaleate) or one that induces an inflammatory response (bacterial lipopolysaccharide), or a combination of these agents, did not cause the changes characteristic of acute pancreatitis. Therefore, simply inducing oxidative stress and/or inflammation may be insufficient to initiate acute pancreatitis.
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PMID:Expression of oxidative stress-responsive genes and cytokine genes during caerulein-induced acute pancreatitis. 931 74

The role of cytokines has been well documented in the pathogenesis of acute pancreatitis. Antibodies against specific cytokines have been used to treat pancreatitis, with mixed results. The transcription factor nuclear factor (NF)-kappa B is a pleiotropic regulator of many genes involved in stress and inflammatory responses. The aim of this study was to prevent the NF-kappa B binding activity and tumor necrosis factor (TNF)-alpha gene overexpression as a possible therapeutic intervention for acute pancreatitis. Reversible acute biliary pancreatitis was induced in male Sprague Dawley rats as established in this laboratory. The animals were sacrificed at 0, 5, 15, 30 min and 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours after the induction of pancreatitis. NF-kappa B binding activity was determined by electrophoretic mobility shift assay, and TNF-alpha gene expression was assayed by reverse transcription-PCR. NF-kappa B binding activity was markedly higher around 4 hours and persisted up to 24 hours after pancreatitis induction in animals with acute pancreatitis, whereas TNF-alpha mRNA levels peaked at 24 hours. When amobarbital (to block NF-kappa B activation) was given (60 mg/kg body weight, I.P.) 3 hours before induction of pancreatitis, the activation of NF-kappa B and the overexpression of TNF-alpha gene was prevented, with significantly decreased severity of pancreatitis as assessed by amylase and clinical recovery. We conclude that 1) preventing the activation of NF-kappa B eliminates the induced overexpression of inflammatory cytokines (TNF-alpha) in acute pancreatitis, 2) such intervention correlates with clinical improvement in pancreatitis, and 3) this genetic modification offers a possible therapeutic intervention in acute pancreatitis.
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PMID:Therapeutic modification of nuclear factor kappa B binding activity and tumor necrosis factor-alpha gene expression during acute biliary pancreatitis. 939 50

The morbidity and mortality associated with acute pancreatitis are primarily a result of pancreatic parenchymal necrosis and the development of marked pulmonary dysfunction. Recent evidence suggests that both of these conditions are propagated by interleukin (IL)-1 beta and tumor necrosis factor (TNF)-alpha, which are produced in large quantities within these organs. Because the generation of these cytokines occurs in a predictable manner early in the development of acute pancreatitis, we aimed to determine whether cytokine gene processing could be inhibited in vivo and what effects this would have on pancreatitis severity. Mild [caerulein, 50 micrograms/kg/hour intraperitoneally (IP) x 4; n = 40] or severe (choline-deficient diet; n = 40) necrotizing pancreatitis was induced in NIH swiss mice. Animals were randomly given a novel small molecule (CNI-1493; 10 mg/kg IP) known to inhibit macrophage production of TNF and IL-1 in vitro by inhibiting translation of TNF mRNA into protein. Control animals received IP vehicle. All animals with acute pancreatitis showed dramatic up-regulation of the IL-1 beta and TNF-alpha genes. Those animals receiving CNI-1493 demonstrated attenuated production of both species of mRNA in pancreatic as well as pulmonary tissue (P < 0.01). Markers of pancreatitis severity such as serum amylase and lipase, as well as pancreatic necrosis, were decreased in animals treated with CNI-1493 (all P < 0.05). Posttranscriptional blockade of TNF production precludes induction of the proinflammatory cytokine cascade that normally occurs during acute pancreatitis. This lack of cytokine gene processing in the pancreas and lungs results in dramatic reductions in tissue damage and pancreatitis severity, which is not model dependent. This is the first time that a small molecule has been shown to influence this disease.
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PMID:Small molecule inhibition of tumor necrosis factor gene processing during acute pancreatitis prevents cytokine cascade progression and attenuates pancreatitis severity. 939 51

Pancreatic encephalopathy is a severe complication of acute pancreatitis. Proinflammatory cytokines may play a role in the development of multi-organ failure during pancreatitis. In the present study, we measured the changes in the blood-brain barrier (BBB) permeability concomitantly with the determination of serum tumor necrosis factor (TNF) and interleukin-6 (IL-6) levels in rats before, as well as 6, 24 and 48 h after the beginning of intraductal taurocholic acid-induced acute pancreatitis. Cytokine concentrations were measured in bioassays with specific cell lines (WEHI-164 for TNF and B-9 for IL-6), while the BBB permeability was determined for a small (sodium fluorescein, molecular weight (MW) 376 Da), and a large (Evans' blue-albumin, MW 67000 Da) tracer by spectrophotometry in the parietal cortex, hippocampus, striatum, cerebellum and medulla of rats. The serum TNF level was significantly (P < 0.05) increased 6 and 24 h after the induction of pancreatitis, while the IL-6 level increased after 24 and 48 h. A significant (P < 0.05) increase in BBB permeability for both tracers developed at 6 and 24 h in different brain regions of animals with acute pancreatitis. We conclude that cytokines, such as TNF and IL-6, may contribute to the vasogenic brain edema formation during acute pancreatitis.
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PMID:Experimental acute pancreatitis results in increased blood-brain barrier permeability in the rat: a potential role for tumor necrosis factor and interleukin 6. 953 Sep 27

Substantial quantities of interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) are produced within the pancreatic parenchyma during acute pancreatitis. Recent evidence suggests that IL-1 beta and TNF-alpha propagate acute pancreatitis and intensify the resulting pancreatic acinar cell death. This study examines the direct effect of IL-1 beta and TNF-alpha on pancreatic acinar cells. Human pancreata (n = 6), harvested during organ procurement, were perfused ex vivo through the splenic artery using a sterile, oxygenated colloid solution. Each pancreas was perfused with either recombinant human IL-1 beta or TNF-alpha for 2 h and subsequently with the cholecystokinin analogue caerulein (positive control). Venous effluent was collected continuously and amylase and lipase were determined at 15-min intervals. Pancreatic histology was graded at baseline and following cytokine and caerulein perfusion. To examine the long-term effects of these cytokines on acinar cell viability, additional in vitro studies utilized the AR42J acinar cell line which was exposed to either IL-1 beta or TNF-alpha with survival determined daily by MTT assay. Perfusion of the human pancreas with either IL-1 beta or TNF-alpha did not alter amylase, lipase, or histology. Caerulein did induce pancreatitis as measured by increased amylase, lipase, and pancreatic histology. Survival of pancreatic acinar cells decreased when they were incubated with TNF-alpha but not IL-1 beta. Although present in large amounts within the pancreas during acute pancreatitis, IL-1 beta and TNF-alpha have no direct effect on acinar cell viability or exocrine function acutely nor do they induce pancreatitis. When present for more than 24 h, however, TNF-alpha but not IL-1 beta has a dramatic effect on acinar cell survival.
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PMID:TNF but not IL-1 decreases pancreatic acinar cell survival without affecting exocrine function: a study in the perfused human pancreas. 953 64

Glutamine, a conditionally essential amino acid, is important for immune function. It is now being formulated for incorporation into total parenteral nutrition (TPN). The aims of this study were to examine the effect of glutamine administration on lymphocyte proliferation and proinflammatory cytokine release in patients with severe acute pancreatitis. Fourteen patients were randomized (in a double-blind fashion) to receive either conventional or isocaloric, isonitrogenous glutamine-supplemented (0.22 g glutamine x kg(-1) x d(-1) as glycyl-glutamine) TPN for 7 d. DNA synthesis (index of lymphocyte proliferation) and the 24-h release of tumor necrosis factor (TNF), interleukin (IL)-6, and IL-8 from peripheral blood mononuclear cells were measured in vitro on days 0, 4, and 7. Thirteen patients completed the study protocol (6 glutamine TPN, 7 conventional TPN). Glutamine supplementation increased median DNA synthesis by 3099 cpm over the study period against 219 cpm in the conventional group (increase not significantly different between the two groups) . Glutamine supplementation did not significantly influence TNF or IL-6 release, but, in contrast, median IL-8 release was reduced by day 7 in the glutamine group while it was increased in the conventional group (-17.7 ng/mL (median change over study period) versus +43.3 ng/mL, respectively; P=0.045). Small patient numbers and substantial interindividual variation limit the conclusions, but there is a trend for the glutamine group to have improved lymphocyte proliferation, and in the case of IL-8, reduced proinflammatory cytokine release.
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PMID:Glutamine-supplemented total parenteral nutrition reduces blood mononuclear cell interleukin-8 release in severe acute pancreatitis. 958 68


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