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)

Severe acute pancreatitis is often complicated by intraperitoneal infection, resulting in multiple organ failure (MOF). It is known to elevate serum tumor necrosis factor (TNF-alpha) in patients with sepsis and/or MOF. In order to study the role of TNF-alpha in the aggravation of acute pancreatitis, we investigated TNF-alpha production by peritoneal macrophages in acute pancreatitis rat using the cerulein-induced pancreatitis model. TNF-alpha production by isolated peritoneal macrophages following lipopolysaccharide (LPS) stimulation was significantly increased in pancreatitis rats as compared with nonpancreatitis control rats (p < 0.001). Serum TNF-alpha activity was elevated following intraperitoneal administration of LPS as the septic challenge both in pancreatitis rats and in control rats, being significantly higher in the former (p < 0.05). Histological findings and liver function tests revealed that LPS induced more severe liver damage in pancreatitis rats than in control rats within 24 h after LPS administration. These results indicate that increased TNF-alpha production by peritoneal macrophages in acute pancreatitis augmented LPS-induced liver injury and suggest the possibility that TNF-alpha may play a role in the development of MOF during acute pancreatitis complicated by intraabdominal sepsis.
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PMID:The role of tumor necrosis factor-alpha in the aggravation of cerulein-induced pancreatitis in rats. 828 75

Tumor necrosis factor (TNF) is an inflammatory cytokine that may be an important mediator in the development of the systemic sequelae associated with severe acute pancreatitis. The purpose of this study was to determine whether the neutralization of TNF-alpha with a polyclonal antibody could ameliorate selected biochemical parameters of severe pancreatitis in a rat model. Pancreatitis was induced by an antegrade injection of artificial bile into the bile duct. Forty rats were randomized into 4 groups: no surgery (controls), saline infusion to bile duct (sham), placebo treatment in animals with pancreatitis (placebo + Px), and pretreatment with a polyclonal antibody (PAb) in animals with pancreatitis (PAb + Px). Serum TNF-alpha, amylase, calcium, hematocrit, glucose, and ascites volume were measured 2 hours after bile duct infusion. Pretreatment with the PAb produced a significant improvement in all parameters when compared with pancreatitis animals treated with placebo (p < 0.001). In addition, TNF-alpha, which was elevated in animals with pancreatitis, was reduced significantly in treated animals (p < 0.001). These results suggest that TNF-alpha may be an important mediator in the evolution of the systemic manifestations of severe acute pancreatitis.
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PMID:Amelioration of the physiologic and biochemical changes of acute pancreatitis using an anti-TNF-alpha polyclonal antibody. 831 Nov 36

The effects of pancreatic secretory trypsin inhibitor (PSTI) on cerulein-induced pancreatitis were studied in a rat model. Arg44 of PSTI was replaced by Ser using site-directed mutagenesis (R44S-PSTI). R44S-PSTI has a longer half-life than the natural form. Pancreatitis was induced by four intramuscular injections of cerulein (50 microgram/kg at 1 h intervals). Continuous intravenous infusion of R44S-PSTI began at a dose of 20 micrograms/kg/h 30 min before the first cerulein injection, and was completed 3 h after the last cerulein injection. Tumour necrosis factor (TNF-alpha) production by isolated peritoneal macrophages from rats with cerulein-induced pancreatitis increased following lipopolysaccharide stimulation, compared to control rats (P < 0.01). R44S-PSTI administration significantly decreased the TNF-alpha production by peritoneal macrophages from rats with cerulein-induced pancreatitis (P < 0.05). In addition, R44S-PSTI significantly reduced serum amylase activity (P < 0.01) and pancreatic wet weight after pancreatitis induction (P < 0.05). Histological examination revealed marked acinar cell vacuolization, interstitial oedema, and cellular infiltration in cerulein-induced pancreatitis, but a lesser degree of histological change in rats that were treated with R44S-PSTI. Prophylactic use of intravenous R44S-PSTI infusion may reduce the severity of acute pancreatitis either histologically or serologically.
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PMID:The protective effects of long-acting recombinant human pancreatic secretory trypsin inhibitor (R44S-PSTI) in a rat model of cerulein-induced pancreatitis. 867 1

Tumour necrosis factor (TNF) alpha, interleukin (IL) 1 beta, IL-6 and IL-8 are thought to play a central role in the pathophysiology of sepsis but their role in acute pancreatitis is unknown. In the present study, monocytes were isolated from the peripheral blood of 26 patients with moderate or severe acute pancreatitis without biliary sepsis. Secretion of these cytokines in vitro was measured at intervals during the first week of illness. Sixteen patients developed systemic complications. Peak TNF-alpha secretion was significantly higher in patients who developed systemic complications (median (interquartile range (i.q.r.)) 18.5 (5.5-28.5) ng/ml) than in those with an uncomplicated course (3.7 (2.3-6.4) ng/ml, P < 0.01). Similarly, peak IL-6 and peak IL-8 secretion were significantly higher in the complicated group (IL-6: complicated median (i.q.r.) 48.9 (12.1-71.0) ng/ml, uncomplicated 16.3 (14.2-37.9) ng/ml, P < 0.05; IL-8: complicated 748 (643-901) ng/ml, uncomplicated 608 (496-749) ng/ml), P < 0.05). No significant difference in peak IL-1 beta secretion was observed between the two groups. Systemic complications of acute pancreatitis are associated with a significant increase in monocyte secretion of TNF-alpha, IL-6 and IL-8 suggesting that, as in sepsis, these cytokines play a central role in the pathophysiology of the disease.
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PMID:Increased monocyte cytokine production in association with systemic complications in acute pancreatitis. 881 75

Activated leukocytes and cytokines have important roles in the multi-system involvement during acute pancreatitis. The changes in the serum level of tumor necrosis factor-a (TNF-alpha) and interleukin-6 (IL-6) over time were investigated in two experimental acute pancreatitis models in rats. Mild edematous pancreatitis was induced with an overdose of cholecystokinin octapeptide (CCK-8), while a severe hemorrhagic form of pancreatitis was induced by ligation of the common bilio-pancreatic duct. The rats were examined 2, 4, 8, 16, 24 and 48 h after pancreatitis induction. The severity of the inflammation was assessed by measurement of the serum amylase activity, quantification of the edema, and histological examination. Serum TNF-alpha and IL-6 were determined by bioassay, using the TNF-sensitive WEHI 164 and the IL-6-dependent B9 cell lines, respectively. In CCK-8-induced acute pancreatitis, the pancreatic weight/body weight ratio (pw/bw) and amylase level were significantly elevated at 2 h, and the maximum levels were observed at 4 h (8.19 +/- 1.13 mg/g and 69.4 +/- 12.8 x 10(3) U/ml, respectively). Both parameters subsequently decreased continuously during the observation period. The serum IL-6 level was significantly increased at 4 h relative to the controls (123.3 +/- 5.8 vs 37.5 +/- 15 pg/ml), and then decreased continuously. In this model, only a moderate level of serum TNF-alpha was observed at 2 h. In the biliary type of acute pancreatitis, the ratio pw/bw increased continuously during the study and reached the maximum level at 48 h relative to the sham-operated control (8.8 +/- 1.4 vs 5.3 +/- 0.8 mg/g). The serum amylase level was significantly elevated at 2 h (43.2 +/- 13 x 10(3) U/ml), but then decreased continuously. The serum IL-6 reached its maximum level at 16 h (3800 +/- 447 pg/ml). In this model, increased TNF-alpha levels (75-300 U/ml) were measured 8, 16 and 24 h after pancreatitis induction. The results led to correlations between the serum IL-6 levels and the biochemical and morphological severity of acute pancreatitis in both experimental models. The data suggest that IL-6 and TNF-alpha may participate in the pathogenesis of these types of acute pancreatitis.
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PMID:Time-course changes in serum cytokine levels in two experimental acute pancreatitis models in rats. 887 1

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

Infectious complications are the leading cause of death in acute pancreatitis. Individual factors of immune defence could be of significance, whether or not a patient develops a severe course with infectious complications. In a prospective 5-year trial including 72 patients, we investigated 29 cellular and humoral markers of the body's defence system for their potential to indicate the severity and course of acute pancreatitis. Complement factors C3 and C4 as well as immunoglobulins IgG, IgM and IgA were normal, in general. Measurable levels of IL-1 alpha, IL-1 beta, IL-2 and sIL-2R could be detected only occasionally. Values of alpha 1-AT, TNF-alpha, TNF alpha-Rp75, neopterin, sICAM-1, IL-8, IL-1RA and sIL-6R did not correlate with a severe course. Due to the high magnitude of increase, CRP, IL-6 and granulocyte elastase were the best indicators of the inflammatory process. Delayed-type hypersensitivity response was the only early predictor of a severe course. It was superior over other cellular markers such as monocyte count or CD4+/CD8+ ratio. In vitro function of polymorphonuclear granulocytes (PMN) was not adequate to the severity of the disease already during the first week of illness. During further course, PMN motility and capacities to produce reactive oxygen species even worsened. The compromized PMN function could explain the frequent development of infectious complications in patients suffering from severe pancreatitis. These results should encourage new concepts of infection prophylaxis using stimulants of cellular defence.
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PMID:[Cellular and humoral functions in acute pancreatitis]. 913

beta-Chemokines and their receptors mediate the trafficking and activation of a variety of leukocytes including the lymphocyte and macrophage. An array of no less than eight beta-chemokine receptors has been identified, four of which are capable of recognizing the chemokines MIP1alpha and RANTES. Genetic deletion of one of the MIP1alpha and RANTES receptors, CCR5, is associated with protection from infection with HIV-1 in humans, while deletion of the ligand MIP1alpha protects against Coxsackie virus-associated myocarditis. In this report we show that the deletion of another receptor for MIP1alpha and RANTES, the CCR1 receptor, is associated with protection from pulmonary inflammation secondary to acute pancreatitis in the mouse. The protection from lung injury is associated with decreased levels of TNF-alpha in a temporal sequence indicating that the activation of the CCR1 receptor is an early event in the systemic inflammatory response syndrome.
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PMID:Targeted disruption of the beta-chemokine receptor CCR1 protects against pancreatitis-associated lung injury. 932 66

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


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