UMLS:C0036690 - FACTA Search

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

In vitro plasma perfusion experiments were performed using small columns containing either resin or charcoal adsorbents to assess the removal of cytokines and endotoxin. 125I-labelled tumor necrosis factor-alpha (TNF-alpha; 500 pg/ml) and interleukin-6 (IL-6; 10 ng/ml) were added individually to human plasma. Over 4 hr of perfusion, Amberlite XAD-7 resin removed 32.5% +/- 3.3% (n = 5) of the initial amount of TNF-alpha and 71.4% +/- 3.8% (n = 5) of the initial amount of IL-6. DHP-1 polyhema-coated activated charcoal removed 17.2% +/- 6.2% (n = 5) of TNF-alpha and 48.5% +/- 7.4% (n = 5) of IL-6. Preliminary experiments were performed with lipopolysaccharide (LPS; 100 ng/ml) and interleukin-1 alpha (IL-1 alpha; 500 pg/ml), which showed that, over 4 hr, Amberlite XAD-7 removed 10.3% of the initial LPS and 29.1% of IL-1 alpha, whereas DHP-1 charcoal removed 23.2% of the initial LPS and 65.3% of IL-1 alpha. In vitro plasma ultrafiltration with either polysulfone or polyacrylonitrile membranes, as used clinically in haemodialysis, was performed with recirculation of plasma containing LPS or TNF-alpha. Neither of the substances was filtered to a significant degree. In conclusion, direct removal of these inflammatory mediators from the circulation of patients with multiorgan failure due to fulminant hepatic failure or sepsis would be possible by perfusion of plasma through adsorbents but not by haemodialysis.
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PMID:In vitro plasma perfusion through adsorbents and plasma ultrafiltration to remove endotoxin and cytokines. 129 81

We investigated plasma levels of cytokines and endotoxin in septic shock to clarify the roles of various cytokines in this type of shock. Endotoxemia was observed in 16 of 22 septic shock patients. Plasma levels of tumor necrosis factor-alpha (TNF-alpha), interleukin 1 beta (IL-1 beta) IL-2, and IL-6 were significantly higher in septic shock than in sepsis without shock. Strong correlations were noted between TNF-alpha and IL-2 levels and between IL-1 beta and IL-6 levels. Patients with high TNF-alpha and IL-2 levels also showed endotoxemia. We defined two types of septic shock from these data, i.e., endotoxin+TNF-alpha + IL-2 shock and IL-beta + IL-6 shock. In the former type, high TNF-alpha and IL-2 levels were present before the onset of shock, and shock itself was associated with endotoxemia. The second type showed simultaneous elevation of IL-1 beta and IL-6 levels at the onset of septic shock, and endotoxin was detected in some of them. These results suggest that endotoxin and extremely high levels of TNF-alpha and IL-2, or the simultaneous elevation of IL-1 beta and IL-6, are related to the onset of septic shock.
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PMID:Two types of septic shock classified by the plasma levels of cytokines and endotoxin. 129 90

Cytokines have been studied intensively to delineate their role in the altered pathophysiology observed in septic shock. We studied the role of TNF in the lethality of two well characterized models of septic shock by inhibiting TNF's activity with a specific antibody. In the first model, sepsis was induced by cecal ligation and puncture (CLP), and in the second model sepsis was induced by either an i.p. or i.v. injection of LPS. After CLP, plasma endotoxin was detectable within 4 h and reached a peak at 8 h (136 +/- 109 ng/ml). TNF bioactivity peaked at 12 h (528 +/- 267 pg/ml) at a significantly higher level than sham-operated control mice (64 +/- 31 pg/ml). After i.p. LPS, TNF peaked much more quickly (90 min) compared with CLP and at a significantly higher level (107,900 +/- 25,000 pg/ml). Another cytokine studied in septic shock, IL-6, peaked at 12 h after CLP at 1011 +/- 431 pg/ml, and at 90 min after lethal LPS at 16,300 +/- 3,700 pg/ml. Mice were treated with an anti-TNF antibody that has been shown previously to inhibit in vivo TNF activity. Antibody treatment of mice subjected to CLP significantly reduced TNF bioactivity but did not reduce mortality or pulmonary neutrophilic infiltration. In the i.v. LPS model, anti-TNF antibody treatment concomitant with LPS injection reduced plasma TNF activity from 80,000 +/- 20,000 pg/ml to undetectable levels. However, anti-TNF treatment immediately before either i.v. or i.p. LPS did not reduce mortality. Additionally, when the antibody was administered 4 h before the lethal i.v. LPS, there was no reduction in lethality. These data show that in two separate models of septic shock blockade of TNF biologic activity will not prevent lethality.
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PMID:Anti-tumor necrosis factor antibody therapy fails to prevent lethality after cecal ligation and puncture or endotoxemia. 131 57

Although studies indicate that simple hemorrhage induces profound depression of cell-mediated immunity and enhances the host's susceptibility to sepsis, the mechanism for this remains unknown. Since the Kupffer cells (KC) are positioned to have constant exposure to various immunomodulators and antigens released during hypotension, we have examined whether antigen presentation by KC, a critical component in eliciting an antigen specific immune response or those processes associated with it, are depressed following hemorrhage. C3H/HeN mice were bled to and maintained at a mean BP of 35 mmHg for 60 min, and then resuscitated with their own blood and adequate fluids. The mice were killed at varying periods of time after hemorrhage to obtain KC from the liver, and assessed for their capacity to present antigen to a sensitized clone Th/cell line (D10.G4.1). Hemorrhaged mice exhibited a marked decrease in antigen presenting capacity beginning as little as 2 h and lasting up to 3-5 days post-hemorrhage. The ability of KC to express mouse interleukin 1 (mIL-1) showed a significant decline at 2 h following hemorrhage, but this effect was not apparent at 24 h post-hemorrhage. In contrast, KC capacity to produce IL-1, IL-6 and tumour necrosis factor (TNF) (cytokines which can co-stimulate T cell antigen presentation) was markedly enhanced during the first 24 h following hemorrhage. A marked decrease was observed in both the mean of the average fluorescence per KC and the percent of Ia antigen-positive KC which persisted for at least 3 days after hemorrhage. The ability of ibuprofen (a cyclooxygenase blocker) to partially restore the antigen presenting capacity of KC from hemorrhaged mice in vitro indicates that prostaglandins are involved in this dysfunction. Thus, the depression of KC antigen presentation, as well as the enhanced capacity of these cells to release inflammatory mediators (TNF, IL-1, IL-6 and prostanoids) which may produce cell and organ dysfunction, could contribute to the host's enhanced susceptibility to sepsis following hemorrhage.
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PMID:Differential effects of hemorrhage on Kupffer cells: decreased antigen presentation despite increased inflammatory cytokine (IL-1, IL-6 and TNF) release. 131 64

Several studies in human patients and in laboratory animals have revealed a correlation between serum interleukin (IL)-6 levels and outcome in clinical sepsis and in related animal models, respectively. In the present study, two monoclonal antibodies were used to investigate the contribution of IL-6 in the lethal action of tumor necrosis factor (TNF) and of lipopolysaccharide (LPS) in mice. We studied the potential protective properties of an anti-murine (m) IL-6 antibody and of an anti-mIL-6 receptor antibody. In controlled experiments, we observed that both monoclonal antibodies conferred a dose-dependent protection to a lethal dose of mTNF. Detailed studies with the monoclonal antibodies indicate, however, that protection was no longer observed when the mTNF dose was slightly higher than the lethal dose. Likewise, the anti-IL-6 monoclonal antibody protected against injections of LPS at a lethal-dose concentration, but here too failed to protect against higher doses of LPS. The anti-IL-6 monoclonal antibody was unable to protect against mTNF in mice sensitized by galactosamine, the corticoid receptor antagonist RU38486 or human (h) IL-1 beta. Protection did not correlate with the serum concentrations of IL-6. Finally, we demonstrate that hIL-6 injection did not change the sensitivity of mice towards mTNF. We conclude that, although IL-6 levels may be of value as a marker for the outcome in septic shock, this cytokine contributes only marginally in the pathogenesis leading to death. The small, but real, contribution of IL-6 in some situations might be due to its ability to up-regulate the level of TNF receptors.
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PMID:Limited involvement of interleukin-6 in the pathogenesis of lethal septic shock as revealed by the effect of monoclonal antibodies against interleukin-6 or its receptor in various murine models. 132

Patients suffering from serious bacterial infection present to the hospital after early inflammatory events, such as release of tumor necrosis factor (TNF), have been initiated. The role of other cytokines, such as interleukin-8 (IL-8), a neutrophil chemoattractant and activator, in the pathophysiology of human sepsis is not well characterized, and there are only limited data on IL-6. We studied serial concentrations of TNF, IL-6 (involved in the acute-phase response), and IL-8 in plasma and leukocyte levels of mRNA for these cytokines in patients with localized and septicemic Pseudomonas pseudomallei infection on admission to the hospital and during a prolonged recovery phase (up to 30 days). Of 18 patients, 8 had detectable plasma IL-8 and all had raised plasma IL-6 concentrations. In patients who died median initial concentration of IL-8 (167 pg/ml; range, 97 to 362 pg/ml) and IL-6 (4,800 pg/ml; range, 60 to 9,245 pg/ml) in plasma were higher than those in survivors (P less than 0.008 and P = 0.007, respectively). Septic patients who survived and patients with localized disease had similar cytokine levels. Plasma IL-8 and IL-6 concentrations were elevated throughout the inpatient period of recovery. Circulating leukocytes contained mRNA for IL-8 but not for IL-6 and TNF, and they may secrete IL-8. An elevated plasma IL-6 concentration (greater than 1,000 pg/ml) had 75% mortality) was the best predictor of mortality in P. pseudomallei sepsis. Fifty percent of patients with detectable plasma IL-8 concentrations died. In contrast, plasma TNF bioactivity did not relate to outcome; 75% of patients who did never had detectable plasma TNF activity.
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PMID:Prolonged elevation of interleukin-8 and interleukin-6 concentrations in plasma and of leukocyte interleukin-8 mRNA levels during septicemic and localized Pseudomonas pseudomallei infection. 137 98

Interleukin-1 (IL-1) is a 17-kDa pro-inflammatory cytokine synthesized from a variety of cell types primarily in association with disease states or during host perturbation such as immune responses. At pM or even fM concentrations, IL-1 triggers various responses in nearly all cells. It appears that there is little or no major role for IL-1 in homoeostatic mechanisms. There are two IL-1's (alpha and beta) each with its distinct sequence; there are two IL-1 receptors. Disease states such as local and systemic infection, septic shock, degenerative arthritis and autoimmune diseases such as nephritis, vasculitis and inflammatory bowel disease appear to be mediated, in part, by IL-1. Organ failure, capillary leak and death occur in animals after a combination of tumour necrosis factor (TNF) and IL-1 which is more effective in inducing these changes than either cytokine alone. IL-1 is also a potent inducer of endothelial cell adhesion molecules, IL-6, and IL-8, a neutrophil chemotactic and activating factor. Strategies for reducing the effects of IL-1 have been based on suppression of transcription, translation, or secretion; more recently, receptor blockade has been a new approach. A naturally occurring IL-1-specific receptor antagonist (IL-1ra), which shares 40% conserved amino-acid homology with IL-1 beta, binds to IL-1 surface receptors with the same affinity as IL-1 but does not possess agonist activity and acts as a competitive inhibitor of IL-1. Studies using the IL-1ra to block endogenous IL-1 in a variety of animal disease models suggest that IL-1 plays a key role in triggering the cascade of inflammatory responses. In addition, the IL-1ra reduces the spontaneous production of growth factors and proliferation of leukaemic cells. The IL-1ra may be an advantageous therapy in patients with sepsis, diabetes, inflammatory bowel, arthritis and cancer.
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PMID:Reduction of inflammation by decreasing production of interleukin-1 or by specific receptor antagonism. 139 23

Tumor necrosis factor alpha (TNF) has been described as a primary mediator of the pathophysiology associated with bacterial sepsis/endotoxemia. We tested the efficacy and possible mechanisms of protection of a monoclonal antibody against TNF (TNF Mab) in a low mortality (29%), endotoxemic baboon model. A number of parameters were monitored at days 0, 1, 2 and 5-7 after challenge with 2 mg E. coli endotoxin/kg. TNF Mab pretreatment (15 mg/kg) prevented the increase in detectable serum TNF and the early perturbations in cardiovascular function which occurred in the control group. Early metabolic dysfunction was delayed in the TNF MAb group and was attenuated thereafter. Dysfunction of the kidney, liver, and coagulation systems and the increased IL-6 levels were significantly attenuated in the TNF MAb group; neutrophil activation was not affected by TNF MAb. No deaths occurred in the TNF MAb group. These results support the hypothesis that TNF plays a central role in the pathophysiology of endotoxic shock.
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PMID:Efficacy of monoclonal antibody against tumor necrosis factor alpha in an endotoxemic baboon model. 142 24

The appearance of the "streptococcal toxic shock-like syndrome" led to a growing interest in infections caused by Streptococcus pyogenes (group-A-streptococci). Since 1987 some 800 cases with a lethality of 20% or more were observed. Contrary to toxic scarlet fever the site of primary infection are the lower respiratory tract or soft tissue infections. Erythrogenic toxins and low molecular weight mitogens, inducing cytokines (IL-2, IL-3, IL-6, TNF-alpha, IFN-gamma) seem to be involved in the pathogenesis of these severe infections. Morphologically and culturally the strains isolated from cases of toxic shock-like syndrome cannot be differentiated from isolates of epidemic scarlet fever or sporadic cases. At the same time, when in Scandinavia an epidemic by S.pyogenes type 1 with many cases of toxic shock was observed, the same type caused a scarlet fever epidemic without complications in eastern Germany. Erythrogenic toxin type A or its toxoid, respectively, can be used for successful immunizations of rabbits. Another--antibacterial-immunization can be done with the M-protein of S.pyogenes, which is limited by its type-specificity. Streptococcal vaccination is required especially for developing countries with a high incidence of rheumatic fever. Infections due to Streptococcus agalactiae (group-B streptococci) are often underestimated though they have a first position in septicemia and meningitis of newborns. Taxonomy and nomenclature of streptococci are often changing; a list of the presently known species is presented in table I.
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PMID:[Epidemiology and pathogenesis of streptococcal infection]. 150 78

Previous studies have shown that hepatocellular function is significantly depressed early during sepsis and that this is associated with a marked increase in the circulating levels of the hepatocellular stimulatory factor (IL-6). It remains unknown, however, whether or not Kupffer cells (KC) are activated during sepsis and whether these cells are the major contributors to the increased circulating levels of this cytokine. The objectives of this study were, therefore, to determine whether or not during sepsis: (1) KC are stimulated in vivo to release IL-6, as compared to other cytokines; (2) KC differ from splenic macrophages (SM phi) in their ability to release cytokines; and (3) there is a difference in macrophage (M phi) cytokine release between endotoxin (ET)-tolerant (C3H/HeJ) and ET-intolerant (C3H/HeN) mice. To assess this, KC and SM phi were harvested at 1 or 24 hr from mice which had been subjected to polymicrobial sepsis by cecal ligation and puncture (CLP) or sham-operation. Following depletion of the nonadherent cells, KC and SM phi cultures were incubated for 24 hr in the presence or absence of 10 micrograms of ET/ml, and the levels of interleukin (IL)-1, IL-6, and TNF release were determined by bioassays. Sepsis induced an early (at 1 hr) in vivo stimulation of KC but not SM phi IL-6 release, irrespective of ET-tolerance/intolerance. However, the release of IL-1 or TNF was not markedly different for either CLP or sham KC.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Sepsis induces an early increased spontaneous release of hepatocellular stimulatory factor (interleukin-6) by Kupffer cells in both endotoxin tolerant and intolerant mice. 152 41

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