Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A severe burn leads to hypermetabolism and catabolism resulting in compromised function and structure of essential organs. The massive release of cytokines is implicated in this hypermetabolic response. The aim of the present study was to compare cytokine expression profiles from severely burned children without signs of infections or inhalation injury (n = 19) to the cytokine profiles from normal, noninfected, nonburned children (n = 14). The Bio-Plex suspension array system was used to measure the concentration of 17 cytokines. The expression of proinflammatory and anti-inflammatory cytokines was maximal during the first week after thermal injury. Significant increases were measured for 15 mediators during the first week after thermal injury: interleukin (IL) 1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 p70, IL-13, IL-17, interferon gamma, monocyte chemoattractant protein 1, macrophage inflammatory protein 1beta, and granulocyte colony-stimulating factor (P < 0.05). Granulocyte-macrophage colony-stimulating factor was significantly increased during the second week after burn (P < 0.05). Within 5 weeks, the serum concentrations of most cytokines decreased, approaching normal levels. When compared with the cytokine levels measured in normal children, a total of 16 cytokines were significantly altered (P < 0.05). After severe burn, a specific cytokine expression profile is observed in patients without complications such as inhalation injury or sepsis. The cytokine concentrations decrease during 5 weeks after burn but remain elevated over nonburned values. Furthermore, the elevation in most serum cytokine levels during the first week after burn may indicate a potential window of opportunity for therapeutic intervention.
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PMID:Cytokine expression profile over time in severely burned pediatric patients. 1678 92

Hyperglycemia in critical illness is a common complication and a strong independent risk factor for morbidity and death. Intensive insulin therapy decreases this risk by up to 50%. It is unclear to what extent this benefit is due to reversal of glucotoxicity or to a direct effect of insulin, because antiinflammatory effects of insulin have already been described, but the underlying mechanisms are still poorly understood. The insulin receptor is expressed on resting neutrophils, monocytes, and B cells, but is not detectable on T cells. However, significant up-regulation of insulin receptor expression is observed on activated T cells, which suggests an important role during T cell activation. Exogenous insulin in vitro induced a shift in T cell differentiation toward a T helper type 2 (Th2)-type response, decreasing the T helper type 1 to Th2 ratio by 36%. This result correlated with a corresponding change in cytokine secretion, with the interferon-gamma to IL-4 ratio being decreased by 33%. These changes were associated with increased Th2-promoting ERK phosphorylation in the presence of insulin. Thus, we demonstrate for the first time that insulin treatment influences T cell differentiation promoting a shift toward a Th2-type response. This effect of insulin in changing T cell polarization may contribute to its antiinflammatory role not only in sepsis, but also in chronic inflammation associated with obesity and type 2 diabetes.
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PMID:Potential antiinflammatory role of insulin via the preferential polarization of effector T cells toward a T helper 2 phenotype. 1700 95

This study investigated the effects of fish oil (FO) diet on plasma intercellular adhesion molecule 1 (ICAM-1) levels and leucocyte integrin expression in polymicrobial sepsis. Mice were randomly assigned to a control group and an FO group. The control group was fed a medium-fat diet containing soyabean oil, whereas in the FO group, 70 % of the soyabean oil was replaced by FO for 3 weeks. After that, sepsis was induced by caecal ligation and puncture (CLP) in the experimental groups and mice were killed at 0, 6, 12 and 24 h, respectively, after CLP. Results showed that compared with the control group, plasma ICAM-1 levels were higher in the FO group 6 h after CLP. Intra-lymphocyte interferon-gamma expression in the FO group was lower, whereas IL-4 expression was higher than in the control group 12 and 24 h after CLP. The expression of leucocyte integrin was significantly higher in the FO group 12 and 24 h after CLP. The FO group had higher IL-6 levels at 12 h in the lungs, at 6 and 12 h in the kidneys, and at 6, 12 and 24 h in the intestines after CLP. The survival rate did not differ between the two groups after CLP. The present findings suggest that pretreatment with an FO diet enhances adhesion molecule and inflammatory cytokine expressions during sepsis, which might aggravate the inflammatory reaction and increase neutrophil infiltration into tissues. In addition, FO diet promotes the Th2-type response and suppresses cellular immune response in polymicrobial sepsis.
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PMID:Dietary fish oil enhances adhesion molecule and interleukin-6 expression in mice with polymicrobial sepsis. 1709 73

The aim of this study was to assess the prognostic value of tumor necrosis factor (TNF) alpha, interleukin (IL)-8, IL-4, and IL-10 in combat casualties. Fifty-six casualties with severe trauma (blast and explosive) who developed sepsis and 20 casualties with the same severity of trauma without sepsis were enrolled in this study. Fifty-five casualties developed multiple organ dysfunction syndrome; 36 died. Blood was drawn on the first day of trauma. Concentrations of IL-8, TNF-alpha, IL-4, and IL-10 were determined in plasma using enzyme-linked immunosorbent assays. Mean values of IL-8 were 230-fold, IL-10 were 42-fold, and TNF-alpha were 17-fold higher in trauma and sepsis group (p < 0.01). Mean values of IL-8 were 60-fold, TNF-alpha were 43.5-fold, and IL-10 were 70-fold higher in the multiple organ dysfunction syndrome group (p < 0.01). Mean values of IL-8 were 2.3-fold and IL-10 were 1.4-fold higher in nonsurvivors and TNF-alpha were 2.2-fold higher in survivors (p < 0.01). IL-4 had no significance as a predictor of severity and outcome.
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PMID:Immune cytokine response in combat casualties: blast or explosive trauma with or without secondary sepsis. 1735 75

We investigated the efficacy of amino acids 55-76 of the synthetic shrimp anti-lipopolysaccharide factor peptide (SALF(55-76) cyclic peptide), the C-terminal part of the shrimp anti-lipopolysaccharide factor. This study was conducted to elucidate the effects of the antiseptic action of this peptide. The SALF(55-76) cyclic peptide was tested against bacterial clinical isolates and showed broad-spectrum antimicrobial activity. Transmission electron microscopic (TEM) examination of SALF(55-76) cyclic peptide-treated Pseudomonas aeruginosa showed that severe swelling preceded cell death and breakage of the outer membrane; the intracellular inclusion was found to have effluxed extracellularly. When mice were treated with the SALF(55-76) cyclic peptide before bacterial challenge with P. aeruginosa, the peptide highly protected mice against death by sepsis. The P. aeruginosa recovered from SALF(55-76) cyclic peptide-treated mice after 4 h exhibited reduced bacterial growth similar to that recovered from vancomycin-treated mice. In addition, the syntheses of inflammatory cytokines, such as interleukin (IL)-2, IL-4, IL-10, IL-12, IL-13, interferon-gamma, and tumor necrosis factor [TNF]-alpha, were significantly upregulated 4 h after SALF(55-76) cyclic peptide treatment except for IL-4 in the liver. The expressions of Toll-like receptor 4 (Tlr4), Irf3, myd88, and Tram, were considerably elevated, but only Tlr4 existed in the spleen 4 h after SALF(55-76) cyclic peptide treatment. The prophylactic administration of SALF(55-76) cyclic peptide was begun the TNF-alpha response in comparison to untreated mice by an ELISA analysis. Due to its multifunctional properties, the SALF(55-76) cyclic peptide may become an important prophylaxis against and therapy for bacterial infectious diseases, as well as for septic shock.
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PMID:Shrimp (Penaeus monodon) anti-lipopolysaccharide factor reduces the lethality of Pseudomonas aeruginosa sepsis in mice. 1738 16

Sepsis, the leading cause of death in intensive care units, reflects a detrimental host response to infection in which bacteria or LPS act as potent activators of immune cells, including monocytes and macrophages. In this report, we show that LPS raises the level of the transcriptional regulator hypoxia-inducible factor-1alpha (HIF-1alpha) in macrophages, increasing HIF-1alpha and decreasing prolyl hydroxylase mRNA production in a TLR4-dependent fashion. Using murine conditional gene targeting of HIF-1alpha in the myeloid lineage, we demonstrate that HIF-1alpha is a critical determinant of the sepsis phenotype. HIF-1alpha promotes the production of inflammatory cytokines, including TNF-alpha, IL-1, IL-4, IL-6, and IL-12, that reach harmful levels in the host during early sepsis. HIF-1alpha deletion in macrophages is protective against LPS-induced mortality and blocks the development of clinical markers including hypotension and hypothermia. Inhibition of HIF-1alpha activity may thus represent a novel therapeutic target for LPS-induced sepsis.
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PMID:Cutting edge: Essential role of hypoxia inducible factor-1alpha in development of lipopolysaccharide-induced sepsis. 1754 84

Apoptosis of CD4(+) T cells and T(H)2 polarization are hallmarks of sepsis-induced immunoparalysis. In this study, we characterized sepsis-induced adaptive immune dysfunction and examined whether improving T-cell effector function can improve outcome to sepsis. We found that septic mice produced less antigen-specific T-cell-dependent IgM and IgG(2a) antibodies than sham-treated mice. As early as 24 hours after sepsis, CD4(+) T cells proliferated poorly to T-cell receptor stimulation, despite normal responses to phorbol myristate acetate and ionomycin, and possessed decreased levels of CD3zeta. Five days following immunization, CD4(+) T cells from septic mice displayed decreased antigen-specific proliferation and production of IL-2 and IFN-gamma but showed no difference in IL-4, IL-5, or IL-10 production. Treatment of mice with anti-GITR agonistic antibody restored CD4(+) T-cell proliferation, increased T(H)1 and T(H)2 cytokine production, partially prevented CD3zeta down-regulation, decreased bacteremia, and increased sepsis survival. Depletion of CD4(+) T cells but not CD25(+) regulatory T cells eliminated the survival benefit of anti-GITR treatment. These results indicate that CD4(+) T-cell dysfunction is a key component of sepsis and that improving T-cell effector function may be protective against sepsis-associated immunoparalysis.
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PMID:Treatment with GITR agonistic antibody corrects adaptive immune dysfunction in sepsis. 1769 Feb 55

Infection, sepsis, and multiple organ failure continue to be significant factors leading to morbidity and mortality after severe injury. Studies by our laboratory and others have identified injury-induced defects in both innate and adaptive components of host defense. We previously reported that CD1d-restricted natural killer T (NKT) cells actively suppress effector T-cell immunity after burn injury via production of excess IL-4 and failure to produce IFN-gamma. alpha-Galactosylceramide (alpha-GalCer) is a synthetic NKT cell-specific ligand presented exclusively to invariant NKT cells and is known to improve immunity against tumors and infection by promoting IFN-gamma production. Here, we confirmed the role of Valpha14-Jalpha281 invariant NKT cells in mouse model of burn injury-induced suppression of T-cell immunity and further asked whether alpha-GalCer can improve immunity after injury via similar mechanisms. We observed that systemic treatment with alpha-GalCer prevented the injury-induced suppression of Ag-specific T-cell responsiveness both in vitro and in vivo and restored the ability of splenic lymphocytes to produce both IL-2 and IFN-gamma. Moreover, burn injury was associated with diminished expression of major histocompatibility complex II and CD40 on antigen presenting cells that were both restored by alpha-GalCer treatment to levels seen in sham-treated mice. Collectively, these data suggest that, via manipulation of the NKT cell population, we may be able to maintain T-cell function and improve host defense after burn injury.
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PMID:Prevention of injury-induced suppression of T-cell immunity by the CD1d/NKT cell-specific ligand alpha-galactosylceramide. 1769 34

Neutrophils (polymorphonuclear leukocytes [PMNs]) are critical to the immune response, including clearance of infectious pathogens. Sepsis is associated with impaired PMN function, including chemotaxis. PMNs express peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a ligand-activated nuclear transcription factor involved in immune and inflammatory regulation. The role of PPAR-gamma in PMN responses, however, is not well characterized. We report that freshly isolated human PMNs constitutively express PPAR-gamma, which is up-regulated by the sepsis-induced cytokines TNF-alpha and IL-4. PMN chemotactic responses to formylmethionyl-leucyl-phenylalanine (fMLP) and IL-8 were dose-dependently inhibited by treatment with the PPAR-gamma ligands troglitazone and 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) and by transfection of PMN-like HL-60 cells with a constitutively active PPAR-gamma construct. Inhibition of chemotaxis by PPAR-gamma ligands correlated with decreases in extracellular signal-regulated kinase-1 and -2 activation, actin polymerization, and adherence to a fibrinogen substrate. Furthermore, PMN expression of PPAR-gamma was increased in sepsis patients and mice with either of 2 models of sepsis. Finally, treatment with the PPAR-gamma antagonist GW9662 significantly reversed the inhibition of PMN chemotaxis and increased peritoneal PMN recruitment in murine sepsis. This study indicates that PPAR-gamma activation is involved in PMN chemotactic responses in vitro and may play a role in the migration of these cells in vivo.
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PMID:Sepsis-induced inhibition of neutrophil chemotaxis is mediated by activation of peroxisome proliferator-activated receptor-{gamma}. 1853 3

Lipids and lipoproteins have emerged as key constituents of the immune response to microbial infection. We, therefore, sought to understand the complex interaction between lipoprotein metabolism and sepsis. Apolipoprotein E (apoE), a component of plasma lipoproteins, has been suggested to bind and traffic Ags for NKT cell activation. However, apoE's role in sepsis has not been demonstrated. In this study, we examined the effect of exogenous apoE in a rat model of septic peritonitis, induced by cecal ligation and puncture. We demonstrate that 48 h after serial injections of apoE, septic mortality increased in a dose-dependent manner. While sepsis resulted in increased splenic and decreased hepatic and circulating NKT cell populations, serial injections of apoE for 24 h after cecal ligation and puncture increased the frequency, cell number, and BrdU uptake in splenic and hepatic NKT cell populations, while concomitantly depleting these populations in the circulation. These changes were correlated with elevated alanine amino transferase levels, an indicator of liver injury. Interestingly, while sepsis increased hepatic T cell apoptosis and necrosis, apoE reversed these changes. apoE also promoted increases in predominantly Th1 cytokine levels in sera and a decrease in IL-4, the main NKT cell-derived Th2 cytokine. Consequently, apoE treatment is associated with increased sepsis-induced mortality, and increased NKT cell frequency and proliferation in the liver and spleen, with concomitant decreases in these NKT cell parameters in the peripheral circulation. apoE treatment also promoted a Th1 cytokine response, increased the degree of liver injury, and decreased apoptosis in hepatic lymphocytes.
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PMID:Apolipoprotein E-mediated immune regulation in sepsis. 1860 94


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