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 severe sepsis, a network of proinflammatory cytokines (TNF, IL-1 beta, IL-6, IL-8) is activated and blood levels of these cytokines are elevated, albeit inconsistently and with large individual variations. In addition, elevated blood levels of anti-inflammatory cytokines (IL-10), as well as of soluble cytokine receptors (sTNF-RI and II, IL-1ra), have been found. They seem to have a regulatory function in the host response. Levels of TNF and IL-6 are usually highest at the time of admission, whereas the time course of IL-1 beta levels (when detectable) can vary considerably. Limited data on IL-8 levels suggest that they may remain elevated for longer periods. Elevated levels of sTNFR and IL-1ra may also persist for a prolonged period of time. The pathogenetic significance of these observations is still unclear, but persistingly high levels of proinflammatory cytokines may be associated with organ failure and mortality.
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PMID:Time course of cytokine levels in sepsis. 863 33

The complement activation fragment C5a was recently shown to induce interleukin (IL)-6 synthesis by peripheral blood mononuclear cells. To understand better the role of C5a in cytokine regulation in vivo, we investigated the effects of complement depletion by cobra venom factor (CVF) or of anti-C5a monoclonal antibodies (mAb) on IL-6 generation in an animal model of septic shock. Complement-depleted pigs which were subsequently challenged with Escherichia coli generated significantly (p < 0.05) less IL-6 during the 6-h observation period than complement-sufficient controls. To address specifically the role of C5a in IL-6 regulation, we produced a C5a(57-74) peptide-specific mAb (T13/9) which neutralizes the bioactivity of porcine C5a. The mAb T13/9 does not cross-react with the precursor protein C5. The pretreatment of pigs with anti-C5a mAb T13/9 prior to the induction of sepsis resulted in a decrease of over 75% in serum IL-6 bioactivity compared to control animals (p < 0.0001). These results indicate a role for C5a in the modulation of IL-6 synthesis in Gram-negative bacteremia.
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PMID:Inhibition of interleukin-6 synthesis in an animal model of septic shock by anti-C5a monoclonal antibodies. 864 74

Microbial products released during bacterial infection induce cytokine-mediated inflammatory responses that can be protective, but excessive release of inflammatory cytokines may promote development of the sepsis syndrome. We examined the ability of bacterial DNA to induce in vivo cytokine release and to potentiate the toxicity of LPS. Intravenous treatment of mice with Escherichia coli (EC) DNA, but not calf thymus (CT) DNA, induced a rapid (within 4 h) dose-dependent increase in serum IFN-gamma and splenic IFN-gamma-forming cells. Over 90% of splenic IFN-gamma-producing cells were identified by surface phenotype as NK cells. Mice also mounted an IFN-gamma response following challenge with 20-base oligonucleotide that contained an internal CG motif (but did not respond to a control oligonucleotide). Treatment of mice with EC DNA followed by a sublethal LPS challenge resulted in a 3-fold increase in the peak serum level of TNF-alpha and a 10-fold increase in the peak level of IL-6 compared with mice that received CT DNA followed by LPS. Mice treated with EC DNA followed by LPS showed 75% mortality, compared with no deaths in mice treated with CT DNA followed by LPS. EC DNA/LPS treatment of mice with disrupted IFN-gamma genes resulted in a 5% mortality while 59% of similarly treated +/+ mice died. Thus, bacterial DNA induces in vivo release of IFN-gamma which, in turn, is associated with an increase in LPS-induced TNF-alpha and IL-6 release, and with increased sensitivity to the toxic effects of LPS.
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PMID:Bacterial DNA induces NK cells to produce IFN-gamma in vivo and increases the toxicity of lipopolysaccharides. 864 98

Acute inflammatory illnesses, including the sepsis syndrome, often include a component of coagulation. A human whole blood culture system was developed so that the relationship between coagulation activation and cytokine responses in the presence or absence of lipopolysaccharide (LPS) could be evaluated. In the absence of LPS stimulation, coagulation activation resulted in a novel pattern of cytokine production. During a 4-hour culture of coagulating blood, significant production of interleukin-8 (IL-8; >2,000 pg/mL) was observed, whereas other proinflammatory cytokines including IL-1 beta, IL-6, or tumor necrosis factor a were undetectable or less than 35 pg/mL. The cytokine profile was distinct from that of fully anticoagulated, LPS-stimulated blood, which showed levels of all the indicated proinflammatory cytokines > or = 2,000 pg/mL over the same time period. Over 24 to 48 hours, the coagulation-induced cytokine response was characterized by marked and sustained IL-8 production, limited IL-6 generation (with kinetics delayed relative to IL-8), and minimal or undetectable tumor necrosis factor alpha levels. The magnitude of the whole blood IL-8 response correlated with the level of coagulation activation as determined by measurement of thrombin-antithrombin III complex formation. The combined stimuli of coagulation activation and LPS challenge induced a synergistic enhancement of IL-8 production but not of IL-6. Coagulation-induced cytokine production and the synergistic production of IL-8 by coagulation and LPS could be attenuated by hirudin or tissue factor pathway inhibitor (TFPI). Studies to elucidate mechanisms implicated (1) the TFPI third Kunitz and carboxy-terminus as important structural components for TFPI regulation of coagulation activation and (2) thrombin as a candidate mediator of the mononuclear cell cytokine response to coagulation activation. In summary, a unique aspect of the crosstalk between the coagulation and cytokine cascades in whole blood is shown with the identification of IL-8 as a key proinflammatory participant.
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PMID:The proinflammatory cytokine response to coagulation and endotoxin in whole blood. 865 18

Interleukin (IL)-12 is thought to be a key factor for the induction of interferon gamma (IFN-gamma), a cytokine essential for the lethal effects of endotoxin. We report here on the release of the nonfunctional subunit of IL-12, p40, as well as biologically active heterodimeric IL-12, p70, after administration of a lethal (n = 5) or sublethal (n = 8) dose of live Escherichia coli to baboons. Remarkably, on lethal challenge, peak levels of p40 were observed at 3 hours that were about twofold lower than those elicited after sublethal challenge (2,813 +/- 515 pg/mL v 4,972 +/- 732 pg/mL, P < .05). This disparity was also observed, although to a lesser extent, for IL-12 p70 antigen, of which maximum levels of 91 +/- 47 pg/mL and 151 +/- 41 pg/mL were measured 6 hours after a lethal or sublethal dose of E coli, respectively. Circulating p70 antigen correlated with IL-12 biologic activity (r = 0.869; P < .001). When comparing lethal to sublethal conditions, lower peak levels of IL-12 on lethal E coli sharply contrasted with higher levels of other proinflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, IL-1beta, IL-6, and IL-8 observed in these animals. Lower IL-12 concentrations in the lethal group may have resulted in part from the enhanced production of IL-10, a known inhibitor of IL-12 synthesis in vitro, as peak levels of this cytokine 3 hours postchallenge inversely correlated with peak levels of IL-12, in particular p40 (r = -0.802; P < .01). Contrary to what might be expected if IFN-gamma were solely induced by IL-12, lethally challenged baboons generated threefold more IFN-gamma at 6 hours than those receiving a sublethal dose (P < .05). Moreover, higher levels of IFN-gamma were associated with lower p40/p70 ratios, suggesting that, in agreement with observations in vitro, IFN-gamma may have preferentially upregulated the release of p70 over p40. These data show that IL-12 is released in experimental septic shock in nonhuman primates and suggest that IL-10 and IFN-gamma are involved in the regulation of this release. Furthermore, this study indicates that the systemic release of IL-12 might be essential, but is not likely sufficient, to promote lethal production of IFN-gamma in sepsis.
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PMID:Release of interleukin-12 in experimental Escherichia coli septic shock in baboons: relation to plasma levels of interleukin-10 and interferon-gamma. 865 27

In a prospective study of 65 patients with S. aureus septicemia, the clinical value of measuring serum IL-6 and lactoferrin levels was assessed and compared with CRP levels and WBC count. 20/65 (31%) patients had a CRP value < or = 100 mg/l on admission and 10 (50%) and 11 (55%) of these had serum levels of IL-6 > 100 pg/ml or lactoferrin > 2.0 mg/l, respectively. 41/64 (64%) patients had a WBC count < or = 15.0 x 10(9)/l and the corresponding figures for increased IL-6 and lactoferrin values were 29 (71%) and 21 (51%) patients, respectively. The high concentrations of IL-6 and lactoferrin on admission decreased rapidly during the hospital stay, better reflecting the clinical course than CRP and WBC count. Patients with endocarditis showed higher IL-6 levels and body temperatures both on admission and during the first days of hospitalization compared with patients without endocarditis.
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PMID:Interleukin-6, C-reactive protein, lactoferrin and white blood cell count in patients with S. aureus septicemia. 865 73

"Septic autocannabalism" been coined to describe the metabolic response that follows severe sepsis in humans. The normal protein- and energy-conserving mechanisms evoked during simple starvation are not observed following the onset of sepsis. The metabolic response to sepsis entails rapid breakdown of the body's reserves of protein, carbohydrate, and fat. Hyperglycemia with insulin resistance, profound negative nitrogen balance, and diversion of protein from skeletal muscle to splanchnic tissues are prominent features. These responses are believed to be mediated in large part by inflammatory cytokines such as tumor necrosis factor alpha (TNFalpha), interleukin 1beta (IL-1beta), and IL-6. Secondary induction of catecholamines, cortisol, and glucagon by cytokines is likely to be another important effector mechanism. Infection and inflammation elicit a complex network of interwoven responses, and no single mediator alone accounts for the responses observed. Sepsis also commonly involves alterations in cardiovascular function with altered flow to key metabolic sites, hypoxia, damage to the gut's mucosal barrier, secondary organ failure, and alterations in capillary permeability. These structural and functional alterations also strongly influence the metabolic profile during infection. If these catabolic responses persist for more than a few days, severe malnutrition results and is likely to be an important risk factor for mortality in these patients. The altered metabolic milieu during sepsis prevents effective use of exogeneously delivered glucose and protein; at best, administration of these agents ameliorates but does not prevent the persistence of catabolism. Delivery of agents that antagonize cytokines and other moieties such as glutamine and growth hormone may, in the future, help to restore nitrogen balance during sepsis.
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PMID:Metabolism of sepsis and multiple organ failure. 866 35

A relationship between physiological parameters of severe sepsis and immunological function has not been established. In ten severely ill patients with sepsis physiological risk was assessed by the Acute Physiology and Chronic Health Evaluation (APACHE) III score, while one component of immunological function was evaluated using peripheral blood mononuclear cell (PBMC) cytokine production after stimulation with lipopolysaccharide (LPS) in vitro. Five of the ten patients died. Mean (s.e.m.) APACHE III scores at admission were not significantly different between survivors and non-survivors (82(13) versus 95(13)) but after 72 h they were lower in survivors (51(13) versus 111(15), P < 0.05). Downregulation of cytokine production by PBMC on LPS stimulation was a transient event in survivors. Survivors had a three-fold increase in tumour necrosis factor alpha bioactivity within 72 h, but there was no increase in non-survivors. A similar pattern was demonstrated for interleukin (IL) 1 beta (P < 0.05 between survivors and non-survivors) and IL-6 (P = 0.06) immunoactivity. Physiological as well as immunological parameters in critically ill patients with sepsis independently predicted hospital survival (r2 = 0.2). These data demonstrate a relationship between the pattern of cytokine production in vitro and survival.
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PMID:Correlation between Acute Physiology and Chronic Health Evaluation (APACHE) III score and immunological parameters in critically ill patients with sepsis. 898 40

Leukemia inhibitory factor (LIF), a pleiotropic cytokine with many biologic effects overlapping with those of IL-6, has been implicated in the pathogenesis of sepsis. We here analyzed the kinetics of LIF in 13 baboons challenged with a lethal (n=6) or sublethal (n=7) dose of Escherichia coli. In addition, to assess the role of TNF-alpha in the induction of LIF in vivo, seven baboons were studied that had either received a bolus injection of recombinant human TNF-alpha (100 micrograms/kg, n=3), or to whom 15 mg/kg of an anti-TNF mAB before lethal E. coli challenge was administered (n=4). LIF levels increased 2 h after E coli challenge, and reached maximum values at 4 and 8 h after a sublethal (4.4 +/- 1.6 ng/ml) or lethal (40.9 +/- 3.8 ng/ml) dose, respectively. TNF-alpha injection induced a modest rise in LIF concentrations, peaking after 6 h (228 +/- 46 pg/ml). Circulating LIF correlated with plasma levels of IL-6, both after E. coli challenge (Spearman Rank coefficient of correlation (r) = 0.849, p<0.001), as well as upon TNF-alpha injection (r=0.863, p<0.001). Moreover, the E. coli-induced release of either cytokine was reduced 6- to 10-fold after pretreatment with anti-TNF mAb, except in one nonsurviving animal, which exhibited a progressive increase of LIF and IL-6 levels despite the absence of TNF immunoreactivity. These results show that TNF-alpha is an intermediate factor in concerted release of LIF and IL-6 in vivo, and indicate that the enhanced elaboration of these cytokines may predict disease outcome in severe sepsis.
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PMID:Release of leukemia inhibitory factor in primate sepsis. Analysis of the role of TNF-alpha. 866 13

Acute-phase reactants (APRs) are proteins synthesized in the liver following induction by interleukin-1 (IL-1), IL-6, and glucocorticoids, involving transcriptional gene activation. Lipopolysaccharide-binding protein (LBP) is a recently identified hepatic secretory protein potentially involved in the pathogenesis of sepsis, capable of binding the bacterial cell wall product endotoxin and directing it to its cellular receptor, CD14. In order to examine the transcriptional induction mechanisms by which the LBP gene is activated, we have investigated the regulation of expression of its mRNA in vitro and in vivo as well as the organization of 5' upstream regulatory DNA sequences. We show that induction of LBP expression is transcriptionally regulated and is dependent on stimulation with IL-1beta, IL-6, and dexamethasone. By definition, LBP thus has to be viewed as a class 1 acute-phase protein and represents the first APR identified which is capable of detecting pathogenic bacteria. Furthermore, cloning of the LBP promoter revealed the presence of regulatory elements, including the common APR promoter motif APRE/STAT-3 (acute-phase response element/signal transducer and activator of transcription 3). Luciferase reporter gene assays utilizing LBP promoter truncation and point mutation variants indicated that transcriptional activation of the LBP gene required a functional APRE/STAT-3 binding site downstream of the transcription start site, as well as an AP-1 and a C/EBP (CCAAT enhancer-binding protein) binding site. Gel retardation and supershift assays confirmed that upon cytokine stimulation APRF/STAT-3 binds to its recognition site, leading to strong activation of the LBP gene. Unraveling of the mechanism of transcriptional activation of the LBP gene, involving three known transcription factors, may contribute to our understanding of the acute-phase response and the pathophysiology of sepsis and septic shock.
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PMID:The lipopolysaccharide-binding protein is a secretory class 1 acute-phase protein whose gene is transcriptionally activated by APRF/STAT/3 and other cytokine-inducible nuclear proteins. 866 65

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