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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide (NO) is normally produced in the endothelium by the constitutive isoform of the NO synthase. This physiological production of NO is important for blood pressure regulation and blood flow distribution. Several lines of evidence suggest that a hyperproduction of NO by the inducible form of NO synthase (iNOS) may contribute to the hypotension, cardiodepression and vascular hyporeactivity in septic shock. Lipopolysaccarides and cytokines, such as tumor necrosis factor, interleukin-1 and interferon-gamma, have been shown to induce iNOS in the endothelium, vascular smooth muscle cells, macrophages and different parenchymal cells. Treatment with inhibitors of NO synthesis has been shown to improve hemodynamic variables and survival in several animal models of septic shock. In human septic shock, inhibition of NO synthesis has been shown to alter hemodynamic variables in short-term studies, but it is uncertain whether this treatment has beneficial long-term effects. The aim of this review is to give an overview of the physiological role of NO and to discuss the role of NO in sepsis and the potential therapeutic implications of NO as a target in treatment of human septic shock. A main new aspect of this review is a critical discussion of previous reports measuring plasma nitrite/nitrate during septic shock and an evaluation of the validity of interpreting these data as evidence for a hyperproduction of NO. This review also emphasizes that many septic patients have preexisting endothelial dysfunction and lung diseases, which may contribute to adverse effects by systemic inhibition of NO synthesis. Another new aspect of the present review is a focus on the lack of direct evidence of iNOS expression in human septic shock.
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PMID:The role of nitric oxide in sepsis--an overview. 1008 33

1. The major pathological responses to Gram-negative bacterial sepsis are triggered by endotoxin or lipopolysaccharide. As endotoxin is shed from the bacterial outer membrane, it induces immunological responses that lead to release of a variety of cytokines and other cellular mediators. As part of a program aimed at developing a therapeutic agent for septic shock, we have developed E5531, a novel synthetic lipopolysaccharide antagonist. 2. As measured by release by tumour necrosis factor-alpha, human monocytes or whole blood can be activated by lipopolysaccharide, lipid A, and lipoteichoic acid (from Gram-positive bacteria). E5531 potently antagonizes activation by all these agents while itself being devoid of agonistic activity. 3. The inhibitory activity of E5531 was dependent on time of addition. When 10 nM E5531 was added simultaneously with lipopolysaccharide or 1 - 3 h before addition of lipopolysaccharide, production of tumour necrosis factor-alpha was inhibited by more than 98%. The addition of E5531 1 h after lipopolysaccharide reduced the efficacy of E5531 by 47%. 4. Antagonistic activity of E5531 was specific for lipopolysaccharide as it was ineffective at inhibiting interferon-gamma mediated NO release of RAW 264.7 cells, phorbor 12-myristate 13-acetate stimulated superoxide anion production in human neutrophils, concanavalin A stimulated mitogenic activity in murine thymocytes and tumor necrosis factor-alpha induced E-selectin expression in human umbilical vein endothelial cells. 5. E5531 as well as MY4, an anti-CD14 antibody, inhibited radiolabelled lipopolysaccharide binding in human monocytes. 6. These results support our contention that E5531 is a potent antagonist of lipopolysaccharide-induced release of tumour necrosis factor-alpha and other cellular mediators and may be an effective therapeutic agent for human septic shock due to Gram-negative bacteria.
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PMID:E5531, a synthetic non-toxic lipid A derivative blocks the immunobiological activities of lipopolysaccharide. 1043 91

Clinical and experimental evidence suggests that granulocyte-colony stimulating factor (G-CSF) acts as an anti-inflammatory modulator with beneficial effects in severe inflammatory diseases, e.g., sepsis and septic shock. Excessive production of nitric oxide (NO) is regarded as a potent mediator of the vascular changes leading to systemic hypotension that occurs during sepsis. Therefore, the aim of the present study was to investigate the influence of G-CSF on inducible nitric oxide synthase (iNOS) gene expression and NO synthesis in vascular smooth muscle cells (VSMC). Qualitative and quantitative analyses of iNOS cDNA revealed that G-CSF significantly reduced interferon-gamma/lipopolysaccharide (IFN-gamma/LPS) dependent iNOS gene expression (P < 0.05) following 6, 18, 24, and 48 h incubation periods. In addition, the co-application of G-CSF resulted in a decreased IFN-gamma/LPS mediated iNOS protein generation as detected by immunoblotting methods after 24 and 48 h. Measurement of the stable NO metabolites showed a significant reduction of nitrite/nitrate concentrations following co-incubation of VSMC with G-CSF + IFN-gamma/LPS (242.57 +/- 10.73 nmol NO2-/NO3-/mg cell protein, n = 8) as compared to IFN-gamma/LPS treatment (306.20 +/- 19.26 nmol NO2-/NO3-/mg cell protein, n = 8, P < 0.05) following a 24-h incubation protocol. This inhibitory effect of G-CSF was still present after a 48 h incubation period (G-CSF + IFN-gamma/LPS: 319.56 +/- 6.26 nmol NO2-/NO3-/mg cell protein; IFN-gamma/LPS: 489.20 +/- 27.15 nmol NO2-/NO3-/mg cell protein (P < 0.05), n = 8, respectively). The present findings suggest that inhibition of iNOS gene expression and NO generation in VSMC might be one of the protective anti-inflammatory effects of G-CSF during sepsis.
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PMID:Inhibition of inducible nitric oxide synthase gene expression and nitric oxide synthesis in vascular smooth muscle cells by granulocyte-colony stimulating factor in vitro. 1043 53

Recent studies suggest that increased lymphocyte apoptosis (Ao) detected in peripheral blood T cells from burn patients appears to contribute to decreased lymphocyte immunoresponsiveness. However, while it is known that sepsis induces a marked depression in the splenocyte immune response (i.e. decreased interleukin-2, interferon-gamma production and proliferation) in response to the T-cell mitogen concanavalin A (Con A), it is unknown whether this depression is associated with an increase in inducible Ao and if so, which mediators control this process. To assess this, splenocytes were harvested from mice at 24 hr (a period associated with decreased Con A response) after the onset of polymicrobial sepsis [caecal ligation and puncture (CLP)] or sham-CLP (Sham) and then stimulated with 2.5 microg Con A/ml (24 hr). Septic mouse splenocytes stimulated with Con A, while not showing a change in their phenotypic make-up, did exhibit a marked increase in the percentage of splenocyte that were Ao+ which was associated with altered cytokine release. This appears to be due to an increase in the percentage of Ao+ cells in the CD4+ CD8- population and was associated with enhanced Fas antigen expression as well as an increase in mRNA for the Fas-FasL gene family. To determine if the changes in Ao are due to either endotoxin (a product of Gram-negative bacteria seen in CLP mice) or the expression of Fas ligand (FasL; a mediator of activation-induced lymphocyte Ao), a second set of studies examining Con A-inducible Ao was performed with splenocytes harvested from septic endotoxin-tolerant C3H/HeJ and the FasL-deficient C3H/HeJ-Fasl gld mice. The results show that increased splenocyte Ao detected following CLP is due to a FasL-mediated process and not to endotoxin. Thus the inadvertent up-regulation of FasL-mediated splenocyte Ao may contribute to the depression of splenocyte immune responses seen during polymicrobial sepsis.
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PMID:Increased inducible apoptosis in CD4+ T lymphocytes during polymicrobial sepsis is mediated by Fas ligand and not endotoxin. 1044 13

In earlier studies it has been shown that prolactin (PRL) is a stimulating factor for the immune system, and it has been suggested that PRL might antagonize immunosuppressive effects of glucocorticoids. PRL has been reported to affect the cytokine secretion pattern, by elevating cytokine gene expression in macrophages, after the onset of sepsis. It also promotes the antibody response in mice where it increases the production of interferon-gamma (IFN-gamma) and inhibits interleukin-1 (IL-1) production. Due to these properties, PRL might influence the development of autoimmune type 1 diabetes. The aim of the present study was to examine the effects of two drugs; PRL and bromocriptine (BC) in vivo on the development of hyperglycemia and pancreatic insulitis in mice treated with multiple doses of streptozotocin (STZ) (40 mg/kg body weight, i.p.). The dopaminergic agonist BC is known to inhibit PRL secretion. In another set of experiments, the direct effects of PRL on the function of pancreatic islets exposed to STZ in vitro were studied. Mice treated with STZ became gradually hyperglycemic, and concomitant treatment with PRL (4 mg/kg body weight) for 21 days significantly reduced the elevation in blood glucose levels from day 10 onwards (P<0.05). Morphologic examinations of the pancreas on day 21 of mice receiving STZ injections revealed a marked insulitis, but only moderate insulitis in the STZ treated animals given PRL. BC administration (10 mg/kg body weight) in combination with STZ did not significantly affect the elevation in blood glucose levels or the insulitis. PRL or BC administration alone did not change the serum glucose concentration. This study indicates that PRL may affect hyperglycemia in the early phase of autoimmune diabetes. We suggest that it might be due to counteraction of autoimmune immunologic mechanisms and/or enhancement of beta-cell regeneration.
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PMID:Prolactin protects against diabetes induced by multiple low doses of streptozotocin in mice. 1055 72

Tyrosine phosphorylation pathways are essential components of the process of macrophage activation and the resultant production of inflammatory mediators such as tumor necrosis factor (TNF) and nitric oxide (NO). Several lines of evidence suggest that members of the src family of protein tyrosine kinases play important roles in macrophage activation by gram-negative bacterial lipopolysaccharide (LPS) or the cytokine interferon-gamma (IFN-gamma), but targeted disruption of three members of the src family (hck, fgr, and lyn) in mice failed to demonstrate a requirement for these particular kinases in macrophage activation. We report that the pyrazolopyrimidine PP1, a src family-selective tyrosine kinase inhibitor, potently inhibits the production of TNF and inducible nitric oxide synthase (iNOS) in RAW 264.7 murine macrophages stimulated with LPS, rlFN-gamma, or LPS + rIFN-gamma. Furthermore, the tested concentrations of PP1 inhibit LPS- and rlFN-gamma-mediated tyrosine phosphorylation of the hck tyrosine kinase and its putative substrate, vav, but fail to block rlFN-gamma-mediated JAK2 tyrosine phosphorylation. These findings provide additional support for a model of macrophage activation involving one or more src-related kinases. Selective inhibitors of this signaling pathway should be studied in animal models of sepsis.
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PMID:The src family-selective tyrosine kinase inhibitor PP1 blocks LPS and IFN-gamma-mediated TNF and iNOS production in murine macrophages. 1056 9

Animal experiments suggest that hyperproduction of nitric oxide (NO) by the inducible isoform of the enzyme NO synthase (iNOS) may contribute to hypotension, cardiodepression and vascular hyporeactivity in septic shock. Lipopolysaccarides and cytokines, like tumor necrosis factor, interleukin-1 and interferon-gamma, have been shown to induce iNOS in the endothelium, vascular smooth muscle cells, macrophages and different parenchymal cells. In several animal models of septic shock, treatment with inhibitors of NO synthesis has been shown to improve haemodynamic variables and survival. In human septic shock, inhibition of NO synthesis has been shown to alter haemodynamic variables in short term studies. However, a large multicentre study was recently stopped due to increased mortality in patients in septic shock treated with the NO synthase inhibitor NG-monomethyl-L-arginine. The aim of this review is to discuss the role of NO in sepsis and the potential therapeutic implications of NO as a target in treatment of human septic shock. We emphasize that many septic patients have preexisting endothelial dysfunction or lung diseases, which may predispose to severe adverse effects during systemic inhibition of NO synthesis. We also focus on the lack of direct evidence for iNOS expression in human septic shock and on the discrepancy between animal and human data.
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PMID:[Nitric oxide--an important mediator in sepsis?]. 1061 98

The CD14 molecule, which is known to be a receptor for endotoxin, is expressed on monocytes and neutrophils. It is found as a soluble CD14 (sCD14) in circulation, and the plasma level has been shown to be increased in some infectious diseases, including sepsis. To investigate the potential significance of circulating sCD14 in Kawasaki disease (KD), the plasma level of sCD14 was measured using ELISA in patients with KD, patients with a Gram-negative bacterial infection (GNBI) including sepsis, patients with viral infection (VI), and healthy controls. We also analysed CD14 receptor expression in monocytes and neutrophils using flow cytometry and a semiquantitative reverse transcription-polymerase chain reaction. Although KD patients had significantly lower counts of peripheral neutrophils and monocytes than GNBI patients, KD patients had significantly higher levels of sCD14 than GNBI. No significant correlations were observed between sCD14 levels and clinical laboratory values or the cytokine (interferon-gamma, tumour necrosis factor-alpha) levels in the acute phase. The mean intensity of CD14 receptor expression on neutrophils markedly increased in the acute phases of KD and GNBI compared with that in their convalescent phases, while that on monocytes decreased. The expression of CD14 mRNA in neutrophils increased in the acute phases of KD and GNBI, while that in monocytes did not decrease but instead remained quite abundant. The present findings suggest that the elevated level of circulating sCD14 appears to be an important parameter for KD and that sCD14 shedding is accompanied by different kinetics regarding the expression of CD14 antigen and CD14 gene between monocytes and neutrophils.
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PMID:Increased levels of circulating soluble CD14 in Kawasaki disease. 1063 78

Interleukin-12 (IL-12) is thought to play an important role as a modulator of levels of IL-10 and interferon-gamma (IFN-gamma). To address the therapeutic effects of rIL-12 in an endogenous sepsis model in mice, which closely mimics the pathophysiology of septicaemia in man, the effects of rIL-12 on the levels of cytokines such as IL-10 and IFN-gamma, and on the survival of septic mice infected with Pseudomonas aeruginosa PAO1 were examined. First, in the endogenous sepsis model, the serum levels of IFN-gamma and IL-10 remained normal until days 8 and 10, respectively, when significant rises were seen. On day 11, levels of IFN-gamma returned to normal, but levels of IL-10 remained high. Interestingly, the IL-10 serum level reached a maximum 2 days later than the IFN-gamma serum level. In the light of these results, septic mice were given 0.01 microg of rIL-12 by intraperitoneal injection and the serum levels of endogenous cytokines and the survival times were examined. Mice treated with rIL-12 on days 5, 6 and 7 after infection survived significantly longer than control septic mice treated with saline only. Treatment with rIL-12 also led to a significant increase of the serum IFN-gamma level and a decrease of the serum IL-10 level on day 11. These results suggest that rIL-12 exerts therapeutic activity against endogenous sepsis caused by P. aeruginosa by stimulating proinflammatory responses and attenuating anti-inflammatory responses.
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PMID:Prolonged survival of mice with Pseudomonas aeruginosa-induced sepsis by rIL-12 modulation of IL-10 and interferon-gamma. 1093 54

Interleukin-18 (IL-18) is a recently identified immunoregulatory cytokine that shares biochemical features with IL-1beta and acts in part by inducing interferon-gamma (IFN-gamma). Endotoxic bacterial lipopolysaccharide (LPS) (1 or 2 ng/kg) was insufficient to increase plasma IL-18 in five healthy adults measured 3, 12, and 24 hr following challenge. In contrast, in the first 96 hr of admission to the surgical intensive care unit, mean maximal serum IL-18 was elevated (1,122 +/- 259 pg/ml) in nine septic patients compared to six healthy adults (191 +/- 42 pg/ml), P < 0.01). Serum IL-18 concentrations in septic patients did not correlate with other measured inflammatory mediators: tumor necrosis factor, IL-6, IL-10, or secretory leukocyte protease inhibitor. Therefore, IL-18 circulates in healthy adults and is a component of the human systemic inflammatory response. Further, stimuli other than LPS may induce IL-18 production in vivo in human sepsis.
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PMID:Elevation of IL-18 in human sepsis. 1094 29


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