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)

CD45 transduces activation signals in inflammatory cells. We investigate CD45 expression on pancreatic acinar cells and examine its role in the inflammatory response which these cells have also shown under certain circumstances. Similar CD45 mRNA levels were found in acinar cells and leukocytes (positive control). Flow cytometric and immunohistochemical analysis showed a heterogeneous CD45 distribution on acinar cells. Activation of acinar cells by incubation with pancreatitis-associated ascitic fluid as evidencied by TNF-alpha production resulted in a decreased CD45 expression, suggesting that CD45 acts as a negative regulator of cytokine production. As a validation of this finding in vivo, a decrease in the acinar CD45 expression in parallel with an increased ability to produce TNF-alpha was found in rats with acute pancreatitis. Our data show that CD45 is constitutively expressed in acinar cells and suggest that it plays an important role in negatively regulating cytokine production.
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PMID:CD45 expression on rat acinar cells: involvement in pro-inflammatory cytokine production. 1626 22

Black Tea Extract (BTE), a phytocompound has been attributed with a plethora of health-promoting actions. We have previously demonstrated that BTE inhibits chronic hepatitis in a rat model induced with high-fat and ethanol (EtOH). This study reports that BTE prevents altered pancreatic acinar cell functions, oxidative stress, inflammatory changes and DNA damage in the EtOH+cholecystokinin (CCK)-induced model of pancreatitis. The EtOH+CCK model rats were administered with BTE, and were examined the activity of pancreatic digestive enzymes (amylase and lipase), proinflammatory cytokines (IL-6 and TNF-alpha), oxidative and antioxidative enzymes (nitric oxide, NO; malondialdehyde, MDA; superoxide dismutase, SOD; catalase, CAT), antioxidant level (glutathione, GSH), histopathological changes and the integrity of genomic DNA. Results show that because of chronic EtOH treatment, serum level of amylase and lipase (two biomarkers for pancreatitis) and pancreatic levels of MDA and NO (two biomarkers of oxidative stress) increased significantly, which could be effectively blunted by BTE. BTE could normalize EtOH+CCK-induced suppressed activities of SOD and CAT, and GSH content of pancreatic tissue. Also, histopathological and inflammatory changes during EtOH+CCK-induced pancreatitis could be blunted by BTE. Furthermore, BTE could effectively reduce EtOH+CCK-induced increase in DNA fragmentation and damage. These findings suggest that BTE prevents pancreatitis caused by chronic EtOH+CCK toxicity presumably by enhancing antioxidant, anti-inflammatory and antiapoptotic activity in rats.
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PMID:Aqueous extract of black tea (Camellia sinensis) prevents ethanol+cholecystokinin-induced pancreatitis in a rat model. 1628 61

Acute pancreatitis has an incidence of approximately 40 cases per year per 100,000 adults. Although usually self-limiting, 10% to 20% of afflicted patients will progress to severe pancreatitis. The mortality rate among patients with severe pancreatitis may approach 30% when they progress to multisystem organ failure. The development of acute pancreatitis illustrates the requirement for understanding the basic mechanisms of disease progression to drive the exploration of therapeutic options. The pathogenesis of acute pancreatitis involves the interplay of local and systemic immune responses that are often difficult to characterize, particularly when results from animal models are used as a foundation for human trials. Experimental studies suggest that the prognosis for acute pancreatitis depends upon the degree of pancreatic necrosis and the intensity of multisystem organ failure generated by the systemic inflammatory response. This suggests an intricate balance between localized tissue damage with proinflammatory cytokine production and a systemic, anti-inflammatory response that restricts the inappropriate movement of proinflammatory agents into the circulation. The critical players of this interaction include the proinflammatory cytokines IL-1beta, TNF-alpha, IL-6, IL-8, and platelet activating factor (PAF). The anti-inflammatory cytokines IL-10, as well as TNF-soluble receptors and IL-1 receptor antagonist, have also been shown to be intimately involved in the inflammatory response to acute pancreatitis. Other compounds implicated in disease pathogenesis in experimental models include complement, bradykinin, nitric oxide, reactive oxygen intermediates, substance P, and higher polyamines. Several of these mediators have been documented to be present at increased concentrations in the plasma of patients with severe, acute pancreatitis. Preclinical work has shown that some of these mediators are markers for disease activity, whereas other inflammatory components may actually drive the disease process as important mediators. Implication of such mediators suggests that interruption or blunting of an inappropriate immune response has the potential to improve outcome. Although the manipulations of specific mediators in animal models may be promising, they may not transition well to the human clinical setting. However, continued reliance on experimental animal models of acute pancreatitis may be necessary to determine the underlying causes of disease. Full understanding of these basic mechanisms involves determining not only which mediators are present, but also closely documenting the kinetics of their appearance. Measurement of the inflammatory response may also serve to identify diagnostic markers for the presence of acute pancreatitis and provide insight into prognosis. Understanding the models, documenting the markers, and deciphering the mediators have the potential to improve treatment of acute pancreatitis.
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PMID:Acute pancreatitis: models, markers, and mediators. 1637 72

Inflammatory effects contribute to the pathogenesis of pancreatitis. Clearly, proinflammatory cytokines like TNF-alpha and IL-6 are involved in this process and the associated systemic complications. The MAPKAPK-2 (MK2) signaling pathway is involved in cytokine gene expression. Therefore, we hypothesized that blockade of this pathway inhibits the expression of proinflammatory cytokines and thereby protects against pancreatitis. To investigate this, we used an in vivo mouse model with a homozygous deletion of the MK2 gene. Pancreatitis was induced by injection of cerulein. The severity was determined by measuring serum lipase, pancreatic trypsin activation, pancreatic edema, and morphological changes by quantitative scoring of histological sections. Systemic inflammation was evaluated by measuring myeloperoxidase activity in lung tissue. Serum levels of TNF-alpha and IL-6 were measured using an ELISA, and mRNA levels were identified using RT-PCR and subsequent quantitative PCR analysis. Pancreatitis in animals with deletion of the MK2 gene is less severe and accompanied with reduced serum levels of TNF-alpha and IL-6. Pancreatic mRNA levels revealed a fourfold reduction of IL-6 mRNA expression in MK2 -/- mice. Effects were associated with suppression of pancreatic trypsin activity and reduced acinar cell injury. In summary, these data show that gene deletion of MK2 ameliorates cerulein-induced pancreatitis. TNF-alpha and IL-6 signaling is mediated by the MK2 pathway and therefore crucial for the regulatory inflammatory processes. TNF-alpha expression is supposably regulated by a posttranscriptional mechanism, whereas IL-6 expression is most likely regulated by transcriptional effects.
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PMID:Gene deletion of MK2 inhibits TNF-alpha and IL-6 and protects against cerulein-induced pancreatitis. 1642 21

The present investigation sought to determine the cellular mechanisms directly dependent on long-term severe sepsis/septic shock that could lead to myocardial structural changes in humans. Human hearts from eight cases of long-term severe sepsis/septic shock arising from infection, as defined by the ACCP/SCCM Consensus Conference; eight cases of acute necrotizing pancreatitis and acute lung injury, a noninfectious pathologic cause of systemic inflammatory response; and three cases of accidental death without thoracic injury selected from autopsies were studied. Transmural blocks of myocardial tissue were excised from the middle portion of the left ventricular free wall and were fixed in formalin or were frozen. Histochemical and immunohistochemical methods were used to evaluate the cross-striations of the myocardial cells, the number and size of interstitial macrophages, the intracardiomyocyte accumulation of lipid, the actin/myosin contractile apparatus, and the expression of iNOS, nitrotyrosine, and TNF-alpha in the myocardia of septic and control hearts. Greater interstitial cellular infiltration composed of larger and elongated macrophages and TNF-alpha protein expression in myofibers, interstitial macrophage cell types, and smooth muscle cells and endothelial cell in the vessels; intracardiomyocyte lipid accumulation; scattered foci of actin/myosin contractile apparatus disruption; and increased expression for iNOS and nitrotyrosine in myocytes and interstitial macrophage cell types could be observed in long-term human septic myocardium as compared with normal and acute pancreatitis control myocardia. These findings give support to an opinion that structural changes could be responsible for long-term sepsis-induced myocardial dysfunction. The higher number of macrophages, most of them with morphological features of "activation," and TNF-alpha protein expression could favor the reduction of cardiac function in septic hearts. The intramyocyte lipid accumulation in these hearts very likely reflects myocardium ventricular contractile dysfunction. In addition, the increased expression of iNOS and the evidence for the significant presence of peroxynitrite in cardiomyocytes and interstitial macrophage cell types suggest that oxidative damage may play a role in actin/myosin disruption in the hearts of septic patients.
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PMID:Myocardial structural changes in long-term human severe sepsis/septic shock may be responsible for cardiac dysfunction. 1717 74

Clusterin is overexpressed in pancreas during the acute phase of pancreatitis. We intended to clarify the role of clusterin expression in stressed exocrine pancreas. We performed in vitro experiments in transfected AR4-2J cells with modified expression levels of clusterin and in vivo studies in clusterin-deficient mice. AR4-2J cells were exposed to agents mimicking cell-stress during pancreatitis (cerulein, hydrogen peroxide, staurosporine or lysophosphatidylcholine). Clusterin-overexpressing AR4-2J cells showed higher viability after cell stress and accordingly reduced rates of apoptosis and lessened caspase-3 activation. Blockage of endogenous clusterin expression reduced viability and enhanced apoptosis. Presence of clusterin reduced NF-kappaB activation and expression of the NF-kappaB target genes TNF-alpha and MOB-1 under cell stress. Clusterin-deficient mice showed a more severe course of acute experimental pancreatitis with enhanced rates of apoptosis and inflammatory cell infiltration. We concluded that clusterin was protective during inflammation of exocrine pancreas because of its anti-apoptotic and anti-inflammatory functions.
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PMID:Clusterin is protective in pancreatitis through anti-apoptotic and anti-inflammatory properties. 1735 35

The markers of oxidative stress and inflammation were studied in acute pancreatitis in transgenic rats exhibiting activated polyamine catabolism. In addition, the effect of bismethylspermine (Me(2)Spm) pretreatment, preventing pancreatitis in this model, on these mediators was investigated. Lipid peroxidation was increased at 6 and 24 h after induction of pancreatitis. These changes as well as the markedly decreased superoxide dismutase activity at 24 h were abolished by Me(2)Spm pretreatment. Glutathione level and catalase activity changed transiently, and the effect of Me(2)Spm was clear at 24 h. Serum inflammatory cytokine levels increased already at 4 h whereas NF-kappaB was distinctly activated only at 24 h. Me(2)Spm prevented the increase in TNF-alpha and IL-6 while it had no effect on NF-kappaB activation. These results show that typical inflammatory and, to a lesser degree, some oxidative stress mediators are involved and beneficially affected by the disease-ameliorating polyamine analogue in our pancreatitis model.
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PMID:Oxidative stress and inflammation in the pathogenesis of activated polyamine catabolism-induced acute pancreatitis. 1741 Mar 33

Despite clinical evidence of myocardial dysfunction, there is no pathological evidence of myocardial injury in hantavirus pulmonary syndrome (HPS). The dominant opinion is that the primary cardiac lesion is functional rather than structural. The present study describes hantaviral antigen and particles in the cardiac endothelium and interstitial macrophages in association with a typical myocarditis in HPS. Human hearts from 14 individuals who died of HPS were compared with hearts from 14 individuals who died of acute necrotizing pancreatitis associated with acute lung injury and 4 individuals who died accidental deaths without thoracic injury (as controls); all cases were selected from autopsies. Transmural blocks of myocardial tissue were excised from the middle portion of the left-ventricular free wall and fixed in formalin. Small samples of myocardial tissue from 4 HPS cases and 4 non-HPS controls were fixed in glutaraldehyde for electron microscopic study. Histomorphometric, immunohistochemical, and ultrastructural methods were employed to detect the presence of hantavirus in the myocardium and to evaluate interstitial edema and the minor diameter of myocytes, to characterize the immunophenotype, and to estimate the number of inflammatory cells and in situ cytokine-producing cells and the T helper cell subset 1 and 2 immune responses (tumor necrosis factor [TNF]-alpha, interferon-gamma, interleukin [IL]-10, and IL-4). Cardiac remodeling; hantaviral antigen and particles in the endothelium and macrophages; scattered foci of myofiber necrosis; greater interstitial cellular infiltration, mainly composed of macrophages and memory T lymphocytes and a significant number of T helper and B lymphocytes; and TNF-alpha protein expression in macrophage-type cells and cardiomyocytes were observed to a greater extent in HPS myocardium than in normal and acute pancreatitis control myocardium. These findings give support to the opinion that structural changes could be responsible for myocardial depression and shock in HPS, and it should be properly named as "hantavirus cardiopulmonary syndrome" (HCPS).
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PMID:Hantavirus infection induces a typical myocarditis that may be responsible for myocardial depression and shock in hantavirus pulmonary syndrome. 1743 35

TNF-alpha plays a pivotal role in the pathogenesis of acute pancreatitis. Recent studies have shown that TNF-alpha inhibition significantly ameliorates the course of experimental acute pancreatitis, but in this context, the effects of Etanercept, a novel anti-TNF-alpha agent, have not been investigated so far. The aims of the present study are (i) to assess the effects of pharmacological inhibition of TNF-alpha by means of Etanercept on the inflammatory response and apoptosis in a murine model of necrotizing acute pancreatitis and (ii) to compare the results to those observed in TNF-alpha receptor 1 knockout (TNFR1-KO) mice. Necrotizing acute pancreatitis was induced in TNF-alpha wild type for TNFR1 (WT) and TNFR1-KO mice by intraperitoneal injection of cerulein (hourly x5, 50 microg/kg). In another group of WT mice, Etanercept was administered (5 or 10 mg/kg, s.c.) at 1 h after first cerulein injection. Control groups received saline treatment. After 24 h, biochemical, histological, and immunohistochemical evidences of acute pancreatitis developed in all cerulein-treated mice; apoptosis was also present in the pancreas. Contrarily, pancreatitis histological features, amylase and lipase levels, pancreas water content, and myeloperoxidase activity were reduced in a similar degree in Etanercept-treated and TNFR1-KO mice. Likewise, in these two groups, immunohistochemical stainings and terminal deoxynucleotidyltransferase-mediated UTP nick-end labeling assay were found negative. TNF-alpha receptor 1 gene deletion and Etanercept administration ameliorate the course of experimental acute pancreatitis in a similar degree. Future studies on clinical applications of Etanercept in pancreatitis seem promising.
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PMID:Etanercept attenuates the development of cerulein-induced acute pancreatitis in mice: a comparison with TNF-alpha genetic deletion. 1743 60

Activation of the inhibitor of NF-kappaB kinase/NF-kappaB (IKK/NF-kappaB) system and expression of proinflammatory mediators are major events in acute pancreatitis. However, the in vivo consequences of IKK activation on the onset and progression of acute pancreatitis remain unclear. Therefore, we modulated IKK activity conditionally in pancreatic acinar cells. Transgenic mice expressing the reverse tetracycline-responsive transactivator (rtTA) gene under the control of the rat elastase promoter were generated to mediate acinar cell-specific expression of IKK2 alleles. Expression of dominant-negative IKK2 ameliorated cerulein-induced pancreatitis but did not affect activation of trypsin, an initial event in experimental pancreatitis. Notably, expression of constitutively active IKK2 was sufficient to induce acute pancreatitis. This acinar cell-specific phenotype included edema, cellular infiltrates, necrosis, and elevation of serum lipase levels as well as pancreatic fibrosis. IKK2 activation caused increased expression of known NF-kappaB target genes, including mediators of the inflammatory response such as TNF-alpha and ICAM-1. Indeed, inhibition of TNF-alpha activity identified this cytokine as an important effector of IKK2-induced pancreatitis. Our data identify the IKK/NF-kappaB pathway in acinar cells as being key to the development of experimental pancreatitis and the major factor in the inflammatory response typical of this disease.
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PMID:Constitutive IKK2 activation in acinar cells is sufficient to induce pancreatitis in vivo. 1752 99


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