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)

Interleukin (IL)-11 has anti-inflammatory activity in animal models of gut inflammation, endotoxemia, and radiation-induced thoracic injury. The aim of the present study was to investigate the protective role of IL-11 in a model of acute necrotizing pancreatitis in mice. Acute pancreatitis was induced by administration of seven intraperitoneal injections of cerulein (50 microg/kg) at hourly intervals. Lipopolysaccharide (LPS) was injected 5 hours after the first cerulein injection. Treatment with recombinant human IL-11 (rhIL-11) was started 30 minutes before the first cerulein injection and repeated 4 hours later. Serum levels of amylase, lipase, and tumor necrosis factor (TNF)-alpha were measured at the end of the experiments. The severity of pancreatitis was evaluated by histological scoring using a semiquantitative analysis of hematoxylin and eosin-stained sections of the pancreas. Competitive reverse transcription-polymerase chain reaction (RT-PCR) was performed to quantify the intrapancreatic TNF-alpha mRNA levels. Serum amylase and lipase levels progressively increased with a maximum reached between 8 and 11 hours. Treatment with rhIL-11 significantly decreased amylase and lipase levels at 6 and 8 hours. Serum TNF-alpha peaked at 6 hours and rapidly decreased thereafter. The elevation of serum TNF-alpha was markedly inhibited by treatment with rhIL-11. Histologically, treatment of rhIL-11 reduced the severity of pancreatic injury including edema, inflammatory cell infiltration, and hemorrhage at 6 hours. Intrapancreatic TNF-alpha mRNA levels were reduced by >50% in the rhIL-11-treated group at 6 hours. In conclusion, rhIL-11 decreased the severity of experimental pancreatitis early on but not later and inhibited the intrapancreatic TNF mRNA expression in vivo, suggesting that the protective effect of IL-11 during the early stage of acute pancreatitis may be mediated, at least in part, through modulation of TNF production.
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PMID:Recombinant human interleukin-11 decreases severity of acute necrotizing pancreatitis in mice. 1097 6

Prior stress ameliorates caerulein-induced pancreatitis in rats. NF-kappaB is a proinflammatory transcription factor activated during caerulein pancreatitis. However, the effects of prior stress on pancreatic NF-kappaB activation are unknown. In the current study, the effect of prior water immersion stress on caerulein and tumor necrosis factor-alpha (TNF-alpha)-induced NF-kappaB activation in the pancreas was evaluated. Water immersion of rats for up to 6 h prevents supramaximal caerulein-induced pancreatic IkappaB-alpha degradation and NF-kappaB activation in vivo. NF-kappaB activity is also inhibited in vitro in pancreatic acini prepared from water-immersed animals. TNF-alpha-induced NF-kappaB activation in pancreas or in pancreatic acini is unaffected by prior water immersion. Chelation of intracellular Ca(2+) by 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetate/acetoxymethyl ester has similar effects to water immersion in preventing caerulein but not TNF-alpha-induced NF-kappaB activation in pancreas. Both the spike response and the sustained rise in [Ca(2+)](i) in response to supramaximal caerulein stimulation are reduced markedly in acini prepared from water-immersed animals as compared with normal animals. Our findings indicate that, in addition to Ca(2+)-dependent mechanisms, Ca(2+)-independent signaling events also may lead to NF-kappaB activation in pancreatic acinar cells. Water immersion stress prevents supramaximal caerulein-induced NF-kappaB activation in pancreas in vivo and in vitro by affecting intracellular Ca(2+) homeostasis.
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PMID:Water immersion stress prevents caerulein-induced pancreatic acinar cell nf-kappa b activation by attenuating caerulein-induced intracellular Ca2+ changes. 1127 54

To clarify the pathophysiological significance of cytokines in chronic pancreatitis (CP), we analyzed tissue expressions of various cytokines in the onset and progression of spontaneous CP in the WBN/Kob rat. Four-week-old male WBN/Kob rats were fed a special pellet diet (MB-3) for 20 weeks, and 6 rats were killed every 4 weeks. Pathologically, CP occurred at 12 weeks and progressed thereafter. The inflammation and fibrosis peaked at 12 and 16 weeks, respectively. By semiquantitative reverse transcription-polymerase chain reaction, the expression of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and interferon (IFN)-gamma mRNAs peaked at 8, 12, and 16 weeks, respectively. Immunohistochemistry showed IL-6 expression in infiltrating inflammatory cells and vascular endothelial cells, whereas TNF-alpha was expressed in both acinar and infiltrating cells. IFN-gamma was localized to acinar, infiltrating and ductal cells, and its expression intensity showed significant correlation with those of fibrosis, type III collagen and alpha-smooth muscle actin. The in situ hybridization results were consistent with the RT-PCR data. These results suggest that tissue expressions of TNF-alpha and IL-6 are involved in the onset of pancreatitis and that IFN-gamma expression is related to the progression of CP.
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PMID:Expression of tumor necrosis factor-alpha, interleukin-6, and interferon-gamma in spontaneous chronic pancreatitis in the WBN/Kob rat. 1134 42

The molecular mechanisms that lead from acute pancreatitis (AP) to multiple organ failure remain to be clarified. We previously reported that ascitic fluids from a rat model of severe acute pancreatitis (pancreatitis-associated ascitic fluids, PAAF) transcriptionally activated endothelial cells and leukocytes in vitro. To clarify the role of ascitic fluids on the development of multiple organ failure in AP, we examined the effects of PAAF on the prognosis and immunohistologic findings in cerulein pancreatitis, an experimental model of mild pancreatitis in vivo. Intraperitoneal injection of PAAF decreased the survival rates in a dose-dependent manner. Histologically, destruction of vessels, alveolar septal thickening, interstitial hypertrophy, and infiltration of inflammatory cells were prominent in the lung of PAAF-injected rats. Transcription factor, nuclear factor KB (NF-kappaB) was activated and the mRNA levels of tumor necrosis factor-alpha and interleukin-1beta were increased in the lung of the PAAF-injected rats. The permeability index assessed by Evans blue assay and the lung myeloperoxidase activity levels were significantly higher in the PAAF-injected rats than in controls. Inhibition of NF-kappaB ameliorated the histologic findings and improved the survival rates. Our results suggest that PAAF play a role in the pathogenesis of lung injury in severe AP, at least in part through the activation of NF-kappaB.
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PMID:Ascites of rat experimental model of severe acute pancreatitis induces lung injury. 1134 43

Transcription factor nuclear factor-kappaB (NF-kappaB) is activated in cerulein pancreatitis and mediates cytokine expression. The role of transcription factor activation in other models of pancreatitis has not been established. Here we report upregulation of NF-kappaB and inflammatory molecules, and their correlation with local pancreatic injury, in a model of severe pancreatitis. Rats received intraductal infusion of taurocholate or saline, and the pancreatic head and tail were analyzed separately. NF-kappaB and activator protein-1 (AP-1) activation were assessed by gel shift assay, and mRNA expression of interleukin-6, tumor necrosis factor-alpha, KC, monocyte chemoattractant protein-1, and inducible nitric oxide synthase was assessed by semiquantitative RT-PCR. Morphological damage and trypsin activation were much greater in the pancreatic head than tail, in parallel with a stronger activation of NF-kappaB and cytokine mRNA. Saline infusion mildly affected these parameters. AP-1 was strongly activated in both pancreatic segments after either taurocholate or saline infusion. NF-kappaB inhibition with N-acetylcysteine ameliorated the local inflammatory response. Correlation between localized NF-kappaB activation, cytokine upregulation, and tissue damage suggests a key role for NF-kappaB in the development of the inflammatory response of acute pancreatitis.
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PMID:Localized pancreatic NF-kappaB activation and inflammatory response in taurocholate-induced pancreatitis. 1135 13

It is thought that tumor necrosis factor (TNF) plays an important role in pathogenesis of acute lung injury or ARDS. So we want to get insight into the relationship between intrapulmonary expression of TNF-alpha gene and lung injury during acute necrotizing pancreatitis (ANP). In our study, acute edematous pancreatitis (AEP) and ANP were induced in rats by caerulein and sodium taurocholate respectively. After acute pancreatitis was induced, serum TNF-alpha was assessed by ELISA assay while endotoxin was assessed by limulus lysate test. Intrapulmonary expression of TNF-alpha mRNA was detected by semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) technique. Moreover, content of pulmonary lesion was investigated and graded with microscope. It was found that TNF-alpha concentration in blood elevated markedly after acute pancreatitis was induced, especially in ANP group. Results of RT-PCR revealed that no TNF-alpha mRNA could be detected in lung tissue from those rats undergoing sham-operation, but marked expression appeared 1 hour after AEP or ANP was induced. Upregulation of expression of TNF-alpha gene in the early 3 hours was similar in the two groups with pancreatitis, and since then expression of TNF-alpha mRNA in ANP group was stronger than that in AEP group. Serum endotoxin increased significantly 6 hours after ANP was induced, with a higher level at 12 hour. However, there was no marked change of endotoxin level in AEP group and control group. It is noted that intrapulmonary expression of TNF-alpha gene in ANP group reached its peak as soon as serum endotoxin increased markedly. Lung damage in ANP group was more serious than that in AEP group significantly. Score of lung injury correlated well with TNF-alpha concentration in blood and expression of its gene in lung tissue in either AEP group or ANP group, as well as with serum endotoxin in ANP group. So overwhelm expression of some harmful cytokines like TNF-alpha in lung tissue may be the main cause of lung injury during acute necrotizing pancreatitis, and stimulation of endotoxiemia can at least partly explain the upregulation of expression of TNF-alpha gene.
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PMID:[Intrapulmonary expression of tumor necrosis factor alpha mRNA and its significance in rats with acute pancreatitis]. 1138 45

The objectives of the study were to investigate the changes of leukocyte adhesiveness and tumor necrosis factor (TNF) in the early stage of acute necrotizing pancreatitis (ANP), to go further into the relation of those changes to lung injury of ANP, and to evaluate the prohibitive effect of ta chengchi tang Decoction on leukocyte adhesion and TNF secretion. 14 canines were randomly divided into 3 groups. The treatment group (n = 5): experimental ANP model treated with ta chengchi tang Decoction; the saline control group (n = 5): experimental ANP model treated with normal saline; and the sham operative group (n = 4). The adhesion of leukocytes to vascular endothelial cells and TNF activities in serum and in bronchi-alveolar lavage fluid (BALF) were observed and measured, and the degrees of lung injury were assessed. The results showed that the adhesiveness of leukocytes was markedly increased and the activities of TNF were elevated in peripheral blood and BALF during ANP; that the leukocyte adhesiveness in the treatment group was weaker than that in the saline group (P < 0.05) and the serum and BALF TNF activities were also significantly lower than those in the saline group (P < 0.01); and that the degrees of lung injury in the treatment group were significantly milder than those in the saline group. These indicate that the increased leukocyte adhesiveness and hypersecretion of TNF take part in the pathogenesis of lung injury in ANP, and ta chengchi tang Decoction is demonstrated an efficacious medicine for alleviating the degree of lung injury mediated by both the leukocyte adhesion and TNF in ANP.
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PMID:[Experimental study of ta chengchi tang decoction for relieving lung injury during acute necrotizing pancreatitis]. 1138 50

The aim of this study was to identify fibrogenic mediators stimulating activation, proliferation, and/or matrix synthesis of rat pancreatic stellate cells (PSC). PSC were isolated from the pancreas of normal Wistar rats and from rats with cerulein pancreatitis. Cell activation was demonstrated by immunofluorescence microscopy of smooth muscle alpha-actin (SMA) and real-time quantitative RT-PCR of SMA, fibronectin, and transforming growth factor (TGF)-beta(1). Proliferation was measured by bromodeoxyuridine incorporation. Matrix synthesis was demonstrated on the protein and mRNA level. Within a few days in primary culture, PSC changed their phenotype from fat-storing to SMA-positive myofibroblast-like cells expressing platelet-derived growth factor (PDGF) alpha- and PDGF beta-receptors. TGF-beta(1) and tumor necrosis factor (TNF)-alpha accelerated the change in the cells' phenotype. Addition of 50 ng/ml PDGF and 5 ng/ml basic fibroblast growth factor (bFGF) to cultured PSC significantly stimulated cell proliferation (4.37 +/- 0.49- and 2.96 +/- 0.39-fold of control). Fibronectin synthesis calculated on the basis of DNA was stimulated by 5 ng/ml bFGF (3.44 +/- 1.13-fold), 5 ng/ml TGF-beta(1) (2.46 +/- 0.89-fold), 20 ng/ml PDGF (2.27 +/- 0.68-fold), and 50 ng/ml TGF-alpha (1.87 +/- 0.19-fold). As shown by RT-PCR, PSC express predominantly the splice variant EIII-A of fibronectin. Immunofluorescence microscopy and Northern blot confirmed that in particular bFGF and TGF-beta(1) stimulated the synthesis of fibronectin and collagens type I and III. In conclusion, our data demonstrate that 1) TGF-beta(1) and TNF-alpha accelerate the change in the cell phenotype, 2) PDGF represents the most effective mitogen, and 3) bFGF, TGF-beta(1), PDGF, and, to a lesser extent, TGF-alpha stimulate extracellular matrix synthesis of cultured rat PSC.
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PMID:Identification of mediators stimulating proliferation and matrix synthesis of rat pancreatic stellate cells. 1144 52

The hallmark of severe acute pancreatitis (SAP) is massive acinar cell death by necrosis. However, programmed, apoptotic acinar cell death has also been observed. Little is known about the dynamics, localization, and inductive factors of acinar cell apoptosis in SAP. We therefore induced SAP in rats by retrograde infusion of 3% sodium taurocholate. Starting as early as 5 minutes after taurocholate administration, small scattered groups of acinar cells showed zymogen degranulation, loss of cell polarity, cytoplasmic microvacuolization, and nuclear shrinkage, but no DNA degradation, thus featuring necrosis. The areas of necrotic acini extended at later time points giving rise to larger areas of complete parenchymal breakdown after 6 hours. Parenchymal degradation was paralleled by neutrophil infiltration and significant tumor necrosis factor (TNF)-alpha mRNA up-regulation. Up to the 12-hour interval, apoptotic acinar cells detected by TUNEL were as rare as in healthy pancreata. At 24 hours, however, the acinar apoptotic rate in nonnecrotic parenchyma had dramatically increased. Pretreatment of rats with anti-ICAM-1 antibody prior to pancreatitis induction led to a significant reduction of neutrophil infiltration along with decreased TNF-alpha mRNA expression throughout the 24-hour observation period without affecting the presence and dynamics of necrosis. However, anti-ICAM-1 pretreatment decreased the extent of acinar cell damage by necrosis and extensively suppressed acinar cell apoptosis. We conclude that taurocholate induces two sequential patterns of acinar cell death in terms of very early necrosis followed by late apoptosis during the postacute phase of SAP. The progression of necrosis and the late apoptotic acinar cell death seem to be influenced by the local presence of neutrophils via a TNF-alpha-dependent mechanism. In addition to augmenting necrosis, neutrophils might have an apoptosis-inducing potential in SAP.
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PMID:Anti-ICAM-1 antibody modulates late onset of acinar cell apoptosis and early necrosis in taurocholate-induced experimental acute pancreatitis. 1145 Nov 52

There is recent experimental evidence that inhibition of caspase-1/interleukin-1beta converting enzyme (ICE) significantly ameliorates overall severity and survival in severe acute experimental pancreatitis. However, little is known about the effects of this approach on the dynamics and mechanisms of local acinar cell damage, which we aimed to investigate in the present study. Severe acute pancreatitis (SAP) was induced by retrograde infusion of 4% sodium taurocholate in rats treated with isotonic saline or a highly selective, irreversible inhibitor of ICE. After 3, 6, and 24 hours, 3 and 7 days, acinar cell death by necrosis and apoptosis, as well as intrapancreatic and systemic interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) expression, was assessed. Treatment with the ICE inhibitor significantly reduced the extent of acinar cell necrosis accounting for major parenchymal destruction. In contrast, apoptosis was confined to the postacute course of the disease and was closely related to tubular complex formation, both remaining unchanged. Whereas intrapancreatic IL-1beta mRNA expression was highly up-regulated in both treated and untreated animals, active IL-1beta protein expression and subsequent neutrophil tissue infiltration was dramatically decreased in the ICE-inhibited group. Parallel to the onset of enhanced apoptotic acinar cell death and tubular complex formation, TNF-alpha mRNA and protein expression was up-regulated, with levels being lower in ICE inhibitor-treated rats. We conclude that activation of caspase-1/ICE plays a central role in the progression of acinar cell death by necrosis in SAP. Herein, IL-1beta-mediated neutrophil infiltration seems to be a crucial step in enhanced cellular destruction. In contrast, acinar cell apoptosis contributes to ductal transformation and is independent of this mechanism, but may be influenced by TNF-alpha.
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PMID:Differential effects of caspase-1/interleukin-1beta-converting enzyme on acinar cell necrosis and apoptosis in severe acute experimental pancreatitis. 1145 89


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