UMLS:C0030305 - FACTA Search

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Query: UMLS:C0030305 (pancreatitis)
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The 8th Meeting of the Alcohol and Immunology Research Interest Group (AIRIG) was held at Loyola University Medical Center, Maywood, Illinois, USA, on November 21, 2003. Reports from multiple laboratories reveal that the functional integrity of the immune system is of paramount importance to the survival of the individual after infection or injury. Evidence supports the idea that exposure to alcohol causes dysregulation of both the innate and the adaptive arms of the immune system. Gaining a better understanding of how alcohol interferes with normal inflammatory and immunoregulatory processes will aid researchers in the design of therapeutic interventions that can be used to improve these responses to better fight infection and maintain the health of the individual. At this meeting, nine speakers presented a summary of their recent work on the combined effects of ethanol and injury, infection, or inflammatory challenge. Topics were (1) T-cell activation after chronic ethanol ingestion in mice, (2) effect of ethanol consumption on the severity of acute viral-mediated pancreatitis, (3) ethanol and alveolar macrophage dysfunction, (4) impaired intestinal immunity and barrier function: a cause for enhanced bacterial translocation in alcohol intoxication and burn injury, (5) immune consequences of the combined insult of acute ethanol exposure and burn injury, (6) consequences of alcohol-induced dysregulation of immediate hemodynamic and inflammatory responses to trauma/hemorrhage, (7) regulation of tumor necrosis factor-alpha production by Kupffer cells after chronic exposure to ethanol, (8) acute exposure to ethanol and suppression of cytokine responses induced through Toll-like receptors, and (9) inhibition of antigen-presenting cell functions by alcohol: implications for hepatitis C virus infection. We anticipate that the work presented at the 8th Meeting of AIRIG, summarized in this article, and presented in the nine articles to follow in this Special Issue of Alcohol will stimulate ideas that will develop into research projects in these topical areas.
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PMID:Alcohol and immunology: introduction to and summary of the 2003 Alcohol and Immunology Research Interest Group (AIRIG) meeting. 1559 84

Alcohol consumption is a risk factor for chronic pancreatitis (CP), but the mechanism in humans remains obscure because prolonged alcohol consumption in most humans and animal models fails to produce alcoholic chronic pancreatitis (ACP). We hypothesize that the process leading to ACP is triggered by a sentinel acute pancreatitis (AP) event; this event causes recruitment of inflammatory cells, which initiates fibrosis driven by the anti-inflammatory response to recurrent AP and/or chronic oxidative stress. The aim was to determine whether chronic alcohol consumption accelerates fibrosis in response to cerulein-induced pancreatitis in the rat. Wistar male rats were pair-fed control (C) or 5% ethanol (E) Lieber-DeCarli liquid diets. Animals were studied without pancreatitis (P0), with cerulein pancreatitis induced once (P1), or with cerulein-induced pancreatitis weekly for 3 weeks (P3). AP markers, inflammation, and fibrosis were measured histologically, by gene expression profiling and protein expression. Macrophage infiltration was reduced in EP0 versus CP0 rats, but the pattern was reversed after AP. Microabscess, severe necrosis, and early calcification were only induced in the EP3 rats. Fibrosis was significantly induced in the EP3 rats versus EP1, CP1, and CP3 by histology, hydroxyproline content, and mRNA expression for collagen alpha1(1) and procollagen alpha2(1). Proinflammatory cytokine mRNAs were up-regulated shortly after induction of AP, while the anti-inflammatory cytokines (interleukin-10 and transforming growth factor-beta) were strongly up-regulated later and in parallel with fibrogenesis, especially in the EP3 rats. Pancreatic fibrosis develops after repeated episodes of AP and is potentiated by alcohol. Expression of fibrosis-associated genes was associated with expression of anti-inflammatory cytokines in alcohol-fed rats.
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PMID:Chronic alcohol consumption accelerates fibrosis in response to cerulein-induced pancreatitis in rats. 1563 3

To investigate whether interleukin-10, a potent anti-inflammatory cytokine, could have a therapeutic effect on rats on that were made pancreatitis by cerulein. Thirty Wistar Albino rats were randomized into sham, pancreatitis, and therapy groups (n = 10 in each). Nothing was applied to the sham group; pancreatitis by inject-ing cerulein (50 micro/g/kg/h) was induced in the pancreatitis and therapy groups. Interleukin-10 (10.000 U) was injected at 1 and 4 h after pancreatitis inductions in the therapy group. The rats were sacrificed at postoperative hour 24. The following parameters were investigated: the leukocyte count, blood glucose, amylase, lipase and tumor necrosis factor-alpha levels in the blood samples; histopathological search, and wet/dry weight ratios of the pancreas tissues. The ratio of wet/dry pancreatic tissue weight, serum tumor necrosis factor-alpha, amylase and lipase lev-els, and histologic damage scores in the pancreatitis and therapy groups were significantly higher when they were compared with the sham group(p < .01). However, all of these values were significantly lower in the therapy groups than in the pancreatitis group (p < .01). Interleukin-10 decreases pancreatic tissue injury induced by cerulein-induced pancreatitis in rats. Nevertheless, more experimental studies are needed to compare endogenous interleukin-10 with exogenous interleukin-10 effects before clinical usage of this drug.
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PMID:The effect of interleukin-10 on acute pancreatitis induced by cerulein in a rat experimental model. 1580 46

NADPH oxidase produces a large amount of reactive oxygen species (ROS) mainly in phagocytic cells. ROS are involved in NF-kappaB activation, cytokine expression and thus, pathogenesis of pancreatitis. However, the source of ROS in pancreatic acinar cells has not been clarified. Cerulein rapidly induces acute and edematous form of pancreatitis. We investigated whether pancreatic acinar cells contain NADPH oxidase, and whether NADPH oxidase mediates interleukin-6 (IL-6) in pancreatic acinar AR42J cells stimulated with cerulein. Expression of NADPH oxidase subunits and NADPH oxidase activity were determined in the cells by immunofluorescence staining and lucigenin luminescence, respectively. Oxidant-sensitive nuclear transcription factor NF-kappaB activation was monitored by electrophoretic mobility shift assay. IL-6 expression was determined by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbant assay. NADPH oxidase inhibitor diphenylene iodonium (DPI), antioxidant rebamipide, and antisense oligonucleotides (AS ODNs) for NADPH oxidase subunits p22phox and p47phox were used to determine the involvement of NADPH oxidase in NF-kappaB activation and IL-6 expression in AR42J cells. As a result, pancreatic acinar AR42J cells constitutively express NADPH oxidase subunits p67phox and p47phox in the cytosol and Nox1 and p22phox in the membrane. Cerulein-stimulated NADPH oxidase activity and induced NF-kappaB activation and IL-6 expression in AR42J cells. Treatment of DPI or rebamipide and transfection of AS ODNs for NADPH oxidase subunits suppressed cerulein-induced NF-kappaB activation and IL-6 expression compared to S ODNs. In conclusion, NADPH oxidase may mediate the expression of inflammatory cytokines by stimulating NF-kappaB activation in pancreatic acinar cells during the course of pancreatitis.
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PMID:NADPH oxidase mediates interleukin-6 expression in cerulein-stimulated pancreatic acinar cells. 1583 77

VitaResc (formerly Apex) is developing PHP-HT, pyridoxalated hemoglobin polyoxyethylene conjugate, for the potential treatment of nitric oxide-induced shock (characterized by hypotension), associated with various etiologies, initially in septic shock. A phase I safety study and an initial phase I/II patient trial for NO-induced shock have been completed, and VitaResc has enrolled patients in three of five planned cohorts in a continuation of these trials to include a protocol of continuous infusion and dose escalation [330680,349187,390918]. The results from the dose escalation trials are expected to provide the basis for a randomized, controlled phase II/III pivotal trial of PHP-HT [390918]. VitaResc has licensed PHP-HT exclusively from Ajinomoto for all indications, worldwide, except Japan [275263]. Ajinomoto originally developed the human derived and chemically modified hemoglobin preparation as a blood substitute, but no development has been reported by the company since 1997 [275277,303577]. The other potential indications of PHP-HT include shock associated with burns, pancreatitis, hemodialysis and cytokine therapies [275277]. VitaResc expects the annual market potential of PHP-HT to exceed 1 billion dollars [330680].
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PMID:PHP-HT (VitaResc Biotech). 1601 85

The cell-permeant MG132 tripeptide (Z-Leu-Leu-Leu-aldehyde) is a peptide aldehyde proteasome inhibitor that also inhibits other proteases, including calpains and cathepsins. By blocking the proteasome, this tripeptide has been shown to induce the expression of cell-protective heat shock proteins (HSPs) in vitro. Effects of MG132 were studied in an in vivo model of acute pancreatitis. Pancreatitis was induced in male Wistar rats by injecting 2 x 100 microug/kg cholecystokinin octapeptide intraperitoneally (ip) at an interval of 1 h. Pretreating the animals with 10 mg/kg MG132 ip before the induction of pancreatitis significantly inhibited IkappaB degradation and subsequent activation of nuclear factor-kappaB (NF-kappaB). MG132 also increased HSP72 expression. Induction of HSP72 and inhibition of NF-kappaB improved parameters of acute pancreatitis. Thus MG132 significantly decreased serum amylase, pancreatic weight/body weight ratio, pancreatic myeloperoxidase activity, proinflammatory cytokine concentrations, and the expression of pancreatitis-associated protein. Parameters of oxidative stress (GSH, MDA, SOD, etc.) were improved in both the serum and the pancreas. Histopathological examinations revealed that pancreatic specimens of animals pretreated with the peptide demonstrated milder edema, cellular damage, and inflammatory activity. Our findings show that simultaneous inhibition of calpains, cathepsins, and the proteasome with MG132 prevents the onset of acute pancreatitis.
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PMID:The proteasome inhibitor MG132 protects against acute pancreatitis. 1621 30

Enteral nutrition, as demonstrated by the many published papers, is not only safer and cheaper than parenteral supply of nutrients, but modulates an exaggerated cytokine response related to surgical trauma that leads to an increase in intestinal permeability, bacterial translocation and infection. The aim of enteral nutrition is to reduce the impact of cytokines on surgical patients and the related infectious complications. Via the enteral route the nutrients can reach the bowel lumen where enterocytes draw upon their fuel, preserving the barrier effect and modulating the cytokine response. Parenteral supply does not achieve this target since the blood supply of nutrients is not as important as the luminal supply. It is only via the enteral supply route that we can preserve the barrier effect. Since the cytokine response sets in immediately after a trauma such as surgery, we implement uninterrupted enteral nutrition, which means before, during and after surgery, plus parenteral support till the full calorie intake is achieved. In a hepatic resection study, we have demonstrated that enteral nutrition modulates the interleukin-6 immunological response and shortens both the period to bowel movement resumption and the duration of hospital stay. Aggressive enteral nutrition has also been implemented in severe pancreatitis, allowing control of the disease without the onset of septic complications. The most important target is not to achieve full calorie intake rapidly, but to supply the enteric mucosa continuously with useful immuno-nutrients, such as glutamine and fibres, to preserve the barrier effect, the mucus layer, and immunological status of the mucosa. In this way we have obtained significant results in the surgical treatment of these patients, reducing the infection rate and hospital stay. New prospects may be,possible in the fight against surgical infections by adding probiotics to enteral nutrition in order to improve the microenvironment of the colon.
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PMID:[Perioperative enteral nutrition]. 1623 16

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

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

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