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)

In insulin dependent diabetes mellitis (IDDM) beta cell destruction is associated with infiltration of the pancreatic islets by T lymphocytes and macrophages. Cytokine products from the infiltrating immunocytes not only have powerful immunoregulatory actions but also are capable of impairing islet cell functions and have thus been postulated to assume a central role in mediating anti-beta cell immunity and beta cell destruction. In an effort to explore further the role of cytokines in the pathogenesis of IDDM, we examined clinical, metabolic and pathological features of NOD/Wehi mice injected intraperitoneally with multiple doses of IFN-gamma and/or TNF-alpha. Blood glucose profiles were not significantly altered by injection of cytokines alone or in combination. Except for a hypoglycaemic rebound in mice injected with TNF-alpha, arginine stimulation tests revealed no disturbances in islet secretory function in cytokine injected mice. Compared with vehicle and cytokines alone, injection of IFN-gamma + TNF-alpha was associated with a variety of clinical and pathological changes including abdominal distention, piloerection, ascites, oedema, thymic atrophy, splenic enlargement and pancreatic distention. Histological examination of the pancreas in these mice revealed moderate to severe pancreatitis which included focal haemorrhagic necrosis, oedema and polymorphonuclear and mononuclear cell infiltration. The islets in these mice appeared normal morphologically and when stained for insulin. The injection of IFN-gamma + TNF-alpha, and to a lesser extent TNF-alpha alone, was associated with a significant reduction in the severity of insulitis. Examination of pancreatic MHC-class I and class II molecule expression revealed in mice given IFN-gamma + TNF-alpha, as compared with controls, significant and uniform induction of both these molecules on ductal and acinar cells; low level MHC-class II expression was also detectable on beta cells in these mice. MHC-class I molecules which were expressed at high levels by beta cells in control mice did not appear to change following administration of the cytokines alone or in combination. We conclude that despite their immunostimulatory actions in vitro and in other models in vivo, systemic administration of the cytokines IFN-gamma and/or TNF-alpha to NOD/Wehi mice does not activate or enhance, and may actually suppress, anti-beta cell immunity in this model.
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PMID:Reduction in insulitis following administration of IFN-gamma and TNF-alpha in the NOD mouse. 190 36

In necrotizing pancreatitis a high interleukin-6 (IL-6) serum level has been proposed as a prognostic criterium. However, literature does not report any information about the role of IL-6 in the function of pancreatic acinar cells. Cholecystokinin, gastrin binding, amylase release and intracellular calcium measurement were performed on a rat pancreatoma cell line, AR4-2J, which has been recognized as a useful tool for studies on the long-term regulation of pancreatic acinar cells. The addition of IL-6 (400 pM) for 48hrs to the AR4-2J cells induced no change in the binding affinities but there was a 2 fold increase in the binding capacity of cholecytokinin (CCKA R) and gastrin (CCKB R) receptors. Although IL-6 treatment did not change directly the secretory capacity and did not activate the intracellular calcium mobilization of AR4-2J, it indirectly increased the sensitivity of the cells to the stimulation of amylase release and the intracellular calcium mobilization by cholecystokinin and gastrin. It is most likely this effect was due to the IL-6-induced increase in the numbers of CCKA R and CCKB R. Therefore this report suggests that the cytokine IL-6 acts on the CCK regulation of pancreatic enzyme secretion.
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PMID:Interleukin-6 regulation of CCK/gastrin receptors and amylase secretion in a rat pancreatic acinar cell line (AR4-2J). 753 49

Transforming growth factor-beta 1 (TGF-beta 1) is a multifunctional cytokine which modifies tissue stromal matrix synthesis, cell proliferation and immune function. In the present study, we have used a mouse monoclonal antibody to the latent (intracytoplasmic) form of TGF-beta 1 to compare its expression in 144 cases of human chronic pancreatitis (both obstructive and chronic calcifying) with that of 10 control pancreatic specimens. In all the control specimens, and most of those with chronic pancreatitis, cytoplasmic immunoreactivity was identified in pancreatic duct and ductular epithelium, in islet cells and in vascular smooth muscle and endothelium. Two distinct patterns of ductular epithelial staining emerged: in morphologically normal tissues, only individual distal ductular/centroacinar cells stained but in chronic pancreatitis (whether chronic calcifying or chronic obstructive) the staining was panductular. Positive cytoplasmic immunostaining of acinar epithelial cells was found in 3% of pancreatitis specimens but in none of the normal controls. There was no staining of fibroblasts. Synthesis of TGF-beta 1 appears to be normally restricted to a population of epithelial cells located in terminal/centroacinar regions of the ductules (together with occasional ductal cells) whereas in chronic pancreatitis, TGF-beta 1 is expressed in most ductular and ductal epithelial cells.
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PMID:Expression of transforming growth factor-beta 1 in chronic pancreatitis. 765 50

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

Interleukin-1 (IL-1) gene expression is selectively induced in tissues involved in multisystem organ failure during acute pancreatitis, suggesting a role in the pathogenesis of distant organ dysfunction. This study was undertaken to investigate the mechanism of pancreatitis-induced end organ cytokine production and to better understand the processes by which IL-1 production is regulated. Seventy adult male transgenic mice in which the type 1 IL-1 receptor had been deleted by gene targeting in embryonic stem cells were utilized (homozygous -/- IL-1R knockout). Acute pancreatitis was induced by one of two methods: (A) IP injections of caerulein (50 microgram/kg/hr x 4) with animals sacrificed at 0, .5, 1, 2, 4, 6, and 8 hr; (B) 48-hr exposure to a choline deficient ethionine supplemented (CDE) diet with animals sacrificed at 0 and 72 hr. Knockout animals were compared to strain-specific control mice expressing the normal wild-type IL-1 receptor gene in which pancreatitis was similarly induced. The severity of pancreatitis was stratified by serum amylase, lipase, and blind histologic grading. IL-1 mRNA production was determined within the pancreas, lungs, liver, and spleen by quantitative differential RT-PCR. Deletion of the IL-1R1 attenuated the severity of pancreatitis, reaching statistical significance in the less severe edematous model. There was little or no constitutive expression of IL-1 mRNA within any of the tissues examined from wild-type animals; however, knockout animals showed elevated steady-state levels in each tissue. IL-1 mRNA became detectable in all tissues of wild-type animals shortly after either form of pancreatitis became apparent and increased significantly with worsening pancreatitis. Despite the attenuated pancreatitis, knockout animals produced significantly greater levels of IL-1 mRNA in each tissue, typically demonstrating a 30-50% increase over time matched IL-1 mRNA production in wild-type animals which was not pancreatitis model dependent. We conclude that genetic deletion of IL-1 receptors results in the overproduction of IL-1 mRNA in organs known to produce cytokines during pancreatitis even when the severity of pancreatitis is lessened. This suggests that a negative feedback loop exists between the IL-1 receptor and IL-1 gene expression.
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PMID:Transgenic animals demonstrate a role for the IL-1 receptor in regulating IL-1beta gene expression at steady-state and during the systemic stress induced by acute pancreatitis. 866 Dec 3

Severe, acute pancreatitis is commonly associated with a systemic illness which may result in multiple organ failure. There is evidence that an aberrant immune response, involving increased secretion of proinflammatory cytokines from activated monocytes and mononuclear phagocytes, is responsible for another systemic illness--septic shock. Previous studies have investigated whether there is a correlation between plasma cytokine levels and severity of pancreatitis. However, these results may not reflect mononuclear phagocyte activation. In this paper, monocytes (collected from patients with severe pancreatitis) were cultured in vitro and secreted cytokine levels measured after 24 hours by ELISA. Secretion of tumour necrosis factor alpha, interleukin-6 and interleukin-8 was higher in cells taken from patients who later developed systemic complications. There was no difference in the secretion of interleukin-1 beta. The mechanism by which mononuclear phagocytes are activated in acute pancreatitis, and the role of genetic predisposition, are discussed.
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PMID:Mononuclear phagocyte activation and acute pancreatitis. 886 69

Cytokines and their endogenous antagonists are released from inflammatory cells during acute pancreatitis, in particular its severe form. They can be found early in the course of the disease as is shown in animal models and in endoscopic retrograde cholangio-pancreatography (ERCP) induced human pancreatitis. Cytokine measurements can predict the course of the disease. This can, however, be achieved using more simple parameters, such as clinical judgement and leucocyte elastase. Anticytokine strategies in the treatment of severe acute pancreatitis should be further evaluated since some positive effects have been found in experimental settings. Interleukin 10 or soluble TNF alpha-receptors may be good candidates. Plasmapheresis seems to change cytokine-anticytokines patterns and this also needs to be explored in controlled trials.
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PMID:Interleukins in acute pancreatitis. 886 70

The intercellular adhesion molecule-1 (ICAM-1), a membrane glycoprotein, is important in the adhesion of cytokine-stimulated leukocytes to the endothelium of microvessels and their transendothelial migration. Circulating isoforms of ICAM-1 (cICAM-1) are known to be elevated in human serum as an indirect consequence of inflammatory responses. The aim of this study was to investigate whether cICAM-1 levels are elevated in patients with acute pancreatitis within 48 h of the onset of abdominal pain and whether cICAM-1 levels correlate with the severity of the tissue damage. Twenty-five consecutive patients admitted to a medical ICU had elevated cCAM-1 concentrations of 548 +/- 68 ng/ml, significantly different when compared to a control group of 18 healthy subjects (343 +/- 29; p = 0.018). According to the findings of contrast-enhanced CT or laparotomy patients were further divided in a group with acute edematous pancreatitis and a group with acute necrotizing pancreatitis. Pancreatic necrosis was associated with cICAM-1 levels of 729 +/- 106 ng/ml, significantly different from patients with mild disease (367 +/- 48) and controls (p < 0.001). Plasma cICAM-1 levels were not significantly different between healthy subjects and patients with mild pancreatitis. A significant correlation was found between cICAM-1 and C-reactive protein, an acute phase reactant and marker of necrotizing pancreatitis (r = 0.62; p < 0.01). The sensitivity and specificity for the detection of edematous or necrotizing pancreatitis of cICAM-1 plasma concentrations (cutoff point at 500 ng/ml) were 75% and 85%, respectively. These results suggest an enhanced release of ICAM-1 into plasma in the early stage of acute necrotizing pancreatitis. Leukocyte-endothelial cell adhesion may be associated with the inflammatory process of necrotizing tissue damage in acute pancreatitis. It could thus serve as a marker or predictor of a severe clinical course of pancreatitis.
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PMID:Increased plasma concentrations of circulating intercellular adhesion molecule-1 (cICAM-1) in patients with necrotizing pancreatitis. 887 97

The role of bronchoalveolar macrophages (BAMs) in the aggravation of cerulein-induced pancreatitis was studied by measuring expression of cytokine-induced neutrophil chemoattractant (CINC) in vitro. Pancreatitis was induced by four intramuscular injections of cerulein (50 microg/kg at 1-hr intervals). Pancreatitis rats were injected intraperitoneally with 30 mg/kg lipopolysaccharide (LPS) 6 hr following the first cerulein injection as a septic challenge. Rats were divided into four groups: group I, nonpancreatitis without LPS; group II, pancreatitis without LPS; group III, nonpancreatitis with LPS; and group IV, pancreatitis with LPS. Hyperactivity of BAMs in response to LPS was assessed as a function of in vitro CINC production. CINC concentrations of the serum and bronchoalveolar lavage fluid in group IV were significantly higher than those in groups I, II, and III. BAMs in group II harvested 6 hr following the first cerulein injection had significantly greater CINC production than those in group I. Northern blot analysis revealed abundant CINC mRNA transcripts in BAMs from groups III and IV. Additionally, myeloperoxidase activity in the lung of group IV rats 8 and 12 hr following the first cerulein injection was significantly higher than that in group I, II, and III rats. Significant differences in static lung compliance in group IV were found compared with groups I, II, and III. These results indicate that BAMs from rats with cerulein-induced pancreatitis were primed and had enhanced release of CINC following LPS exposure. Enhanced expression of CINC may modulate the pathogenesis of pancreatitis-associated lung injury complicated with sepsis.
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PMID:Enhanced expression of cytokine-induced neutrophil chemoattractant (CINC) by bronchoalveolar macrophages in cerulein-induced pancreatitis rats. 900 32

The acute phase response (APR) that follows injury or infection is characterized by a decrease in serum zinc concentrations, which we hypothesized benefits the host. Additionally, we proposed that preventing this decline by supplementing zinc would result in an exaggerated APR as indicated by elevated temperatures, increased serum cytokine concentrations, interleukin 6 and the acute phase protein (ceruloplasmin). A prospective, randomized, double-blinded, clinical trial was conducted. Patients on home parenteral nutrition with a diagnosis of catheter sepsis and patients with a diagnosis of pancreatitis, also on total parenteral nutrition (TPN), were recruited for the study. Following enrollment, block randomization was used to assign patients to receive 0 mg (n = 23) or 30 mg (n = 21) of zinc per day for the first 3 d of TPN. Blood samples for measurement of serum zinc, copper, ceruloplasmin and interleukin-6 were obtained upon enrollment and on d 1 through 3 of TPN. The highest temperatures reported on these days in the medical record were also recorded. Repeated measures ANOVA was used to determine differences in the primary outcome variables over time. No significant differences between groups were observed in serum interleukin-6 or ceruloplasmin concentrations. A significantly higher (P = 0.035) temperature was observed in the zinc-supplemented group compared with the control group on d 3 of parenteral nutrition. We conclude that parenteral zinc supplementation in patients experiencing a mild APR resulted in an exaggerated APR as evidenced by a significantly higher febrile response.
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PMID:Parenteral zinc supplementation in adult humans during the acute phase response increases the febrile response. 904 May 47


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