Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

During severe sepsis syndromes, almost every gene coding for cytokines may be activated. The primary purpose of this activation is to defend the organism against infection, but sometimes these inflammatory mediators go out of control. The reasons why this may occur is unclear because the regulation of cytokines production is still poorly understood. Metabolic effects, production of endothelial adhesion molecules and triggering of neutrophils are some important consequences of cytokine overstimulation which may lead to the clinical picture of septic shock. The major cytokines involved in septic shock are tumor necrosis factor alpha (TNF) and interleukin-1 (IL-1). Both may induce lethal shock in experimental models. The effects of these 2 cytokines are difficult to differentiate from one another because they share many similar biological effects, one can induce the synthesis of the other, and they are strikingly synergistic with each other. gamma-interferon may amplify the inflammatory response by stimulating the cells of monocytic lineage and by increasing TNF-receptor expression, thus participating in the pathogenesis of the septic syndrome. The role of other cytokines is still poorly known. Clinical studies with anti-TNF monoclonal antibodies or with an IL-1 receptor antagonist are under way.
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PMID:[Cytokines and severe sepsis]. 834 26

Cytokines are suspected of playing an important role in the pathophysiology of septic shock. This study was undertaken to determine whether tumor necrosis factor alpha (TNF-alpha) induces the production of other cytokines and mediates mortality in a neonatal rat model of sepsis caused by group B streptococci (GBS). We have measured TNF-alpha, interleukin-1 alpha (IL-1 alpha), interleukin-6 (IL-6), and gamma interferon (IFN-gamma) levels in neonatal rats infected with different strains (H738, 259, and 90) and doses (1 50% lethal dose [LD50] and 5 90% lethal doses [LD90]) of type III GBS. TNF-alpha and IL-6 were detected by the L929 cytotoxicity and the B9 proliferation assays, respectively, in serial plasma samples. IL-1 alpha and IFN-gamma were measured in spleen homogenates by enzyme-linked immunosorbent assay kits by using antibodies raised against the corresponding mouse cytokines. Plasma TNF-alpha levels significantly rose above baseline values within 12 h after intraperitoneal challenge with 5 LD90 of GBS strain H738, corresponding to 3 x 10(3) CFU. A mean peak TNF-alpha concentration of 232 +/- 124 U/ml was reached at 20 h. Peak IL-1 alpha and IL-6 levels of 766 +/- 404 U/g and 1,033 +/- 520 U/ml, respectively, were reached at 24 h after bacterial challenge. Maximal spleen concentrations of IFN-gamma (449 +/- 283 U/g) were measured at 36 h. Concentrations of TNF-alpha, but not other cytokines, remained significantly elevated at 72 h, a time when mortality approached 100%. Significant correlations were found between concentrations of each of the cytokines tested and the logs of CFU concentrations in the blood. In order to ascertain whether TNF-alpha influenced the production of other cytokines, rat pups received two injections of anti-murine TNF-alpha or normal rabbit serum at 2 h before and at 26 h after challenge with live GBS. Plasma TNF-alpha bioactivity was undetectable in anti-TNF-alpha-treated animals, while IL-6 and IFN-gamma, but not IL-1 alpha, levels were significantly reduced, compared with normal serum controls. Rat pups pretreated with anti-TNF-alpha serum and infected with 1 and 5 LD90 of strains H738 and 259 showed enhanced early (48 to 72 h) survival. However, by 96 h this protection was no longer apparent.
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PMID:Cytokine appearance and effects of anti-tumor necrosis factor alpha antibodies in a neonatal rat model of group B streptococcal infection. 841 44

Interleukin 10 (IL-10) decreases production of IL-1, IL-6, and tumor necrosis factor alpha (TNF-alpha) in vitro, and neutralization of IL-10 in mice leads to elevation of the same monokines. We test here whether this monokine-suppressing property of IL-10 confers on it the capacity to protect mice from lipopolysaccharide-induced shock, a monokine-mediated inflammatory reaction. A single injection of 0.5-1 microgram of recombinant murine IL-10 reproducibly protected BALB/c mice from a lethal intraperitoneal injection of endotoxin. This result was obtained whether the IL-10 was administered concurrently with, or 30 min after the injection of endotoxin. The protective effect of IL-10 was reversed by prior injection of neutralizing anti-IL-10 antibodies, and correlated with a substantial decrease in endotoxin-induced TNF-alpha release. These data implicate IL-10 as a candidate for treatment of bacterial sepsis, and more generally as an effective antiinflammatory reagent.
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PMID:Interleukin 10 protects mice from lethal endotoxemia. 845 15

The production of tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and IL-6 and their pharmacomodulation were evaluated in a model of polymicrobial sepsis induced in mice by cecal ligation and puncture (CLP) and were compared with the effects of endotoxin (lipopolysaccharide [LPS]) treatment. LPS levels rose as early as 1 h after CLP and increased further after 2 and 21 h. TNF-alpha was detectable in serum, spleen, liver, and lungs during the first 4 h, with a peak 2 h after CLP. IL-1 beta was measurable in serum after 24 h, and levels increased significantly in spleen and liver 4 and 8 h after CLP. IL-6 levels increased significantly in serum throughout the first 16 h after CLP. These cytokines were detectable after LPS injection, with kinetics similar to those after CLP but at a significantly higher level. To cast more light on the differences between these two animal models of septic shock, we studied the effects of different reference drugs. Pretreatment with dexamethasone (DEX); ibuprofen (IBU), an inhibitor of cyclooxygenase; and NG-nitro-L-arginine, an inhibitor of nitric oxide synthase, significantly reduced survival, while chlorpromazine (CPZ) and TNF did not affect it. Only the antibiotics and pentoxifylline significantly increased survival in mice with CLP. However, CPZ and DEX protected the mice from LPS mortality. On inhibiting TNF-alpha with DEX, CPZ, or pentoxifylline, survival was reduced, unchanged, and increased, respectively, and on increasing TNF-alpha with IBU and TNF, survival was decreased or unchanged, respectively, suggesting that the modulation of this cytokine does not play a significant role in sepsis induced by CLP, unlike treatment with LPS. The negative effects of IBU and N(G)-nitro-L-arginine suggest a protective role by prostaglandins and nitric oxide in sepsis induced by CLP.
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PMID:Pattern of cytokines and pharmacomodulation in sepsis induced by cecal ligation and puncture compared with that induced by endotoxin. 854 33

The purpose of this was to study evaluate the effects of interleukin-1 (IL-1) inhibition by human recombinant IL-1 receptor antagonist (IL-1ra) on plasma prostaglandin, leukotriene, and cytokine levels in sepsis syndrome. As part of a multisite, prospective, randomized, double-blind, placebo-controlled clinical trial, 19 septic patients received IL-1ra in a 100 mg bolus followed by 2.0 mg/kg/h i.v. for 72 h (n = 10) or placebo (n = 9). Plasma thromboxane B2 (TXB2), prostaglandin 6-keto-F1 alpha (PGI), leukotriene B4 (LTB4), leukotrienes C4D4E4 (LTC4D4E4), IL-1 beta, IL-6, and tumor necrosis factor alpha (TNF) were measured by ELISA before study drug infusion (baseline) and at 24, 48, 72, and 96 h after the beginning of the study drug infusion. Differences between placebo and IL-1-ra for plasma LTB4 and TNF were not significant. Plasma TXB2, PGI, LTC4D4E4, and IL-6, expressed as % baseline, were significantly lower in patients receiving IL-1ra than in the placebo group (p < .05), while plasma IL-1 was increased significantly. IL-1 may be a necessary mediator of increased circulating PGI, TXB2, LTC4D4E4, and IL-6 levels in patients with sepsis syndrome. Plasma IL-1 is increased with infusion of IL-1ra. The clinical significance of IL-1 in modifying circulating eicosanoid and cytokine concentrations in clinical sepsis is not clear from the data.
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PMID:Interleukin-1 mediates increased plasma levels of eicosanoids and cytokines in patients with sepsis syndrome. 859 17

The existence of interleukin-12-mediated innate immune responses to group B streptococci (GBS) was tested by examining T-lymphocyte-independent gamma interferon (IFN) production in cultured splenocytes from severe combined immunodeficiency mice. Splenocytes were cultured with killed or living GBS for 48 h, and then IFN was measured by enzyme-linked immunosorbent assay. Type III GBS as well as other extracellular bacterial agents of neonatal sepsis (staphylococci and enterococci) induced IFN production, which was enhanced by interleukin-2 and was inhibited by neutralizing antibodies to tumor necrosis factor alpha and to mouse interleukin-12. Interleukin-12 bioactivity was present in conditioned medium from GBS-treated adherent macrophages. Adherent peritoneal macrophages and bone marrow-derived natural killer cells from severe combined immunodeficiency mice cultured separately with GBS did not produce IFN, whereas cocultures did produce IFN. Functional macrophage activation was evident by nitric oxide production in GBS-treated splenocyte cultures. The results show that extracellular pathogens such as GBS, similarly to intracellular microbes, induce macrophage interleukin-12 and tumor necrosis factor alpha, which promote natural killer cell secretion of IFN, which then enhances innate phagocyte resistance mechanisms.
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PMID:Interleukin-12 and tumor necrosis factor alpha mediate innate production of gamma interferon by group B Streptococcus-treated splenocytes of severe combined immunodeficiency mice. 860 95

The proinflammatory cytokines interleukin 1 alpha (IL-1 alpha), tumor necrosis factor alpha (TNF alpha) and interleukin 6 (IL-6) modulate the synthesis of complement factors B and C3 by endothelial cells (EC), and are considered to play an important role in the development of sepsis. By using agarose beads activating the alternative pathway of complement, we wanted to study the net effect of these cytokines on EC synthesis of the alternative and terminal pathways, measured by binding of anti-C3c and anti-TCC (terminal complement complex) antibodies to beads kept with the EC. Addition of IL-1 alpha and TNF alpha at concentrations of 50 and 100 U/ml resulted in a significant increase in binding of these antibodies to co-incubated beads, most pronounced for anti-C3c. IL-6 from 50-200 U/ml resulted in a stronger (two to fourfold) binding for both antibodies compared to experiments with IL-1 alpha and TNF. However, increased concentrations of IL-1 alpha (200 U/ml) and IL-6 (400 U/ml) resulted in a strong reduction in binding of anti-C3c and anti-TCC antibodies to the co-cultured beads. This study indicates that proinflammatory cytokines upregulate the synthesis by EC of the functional alternative and terminal pathways of complement.
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PMID:Interleukin-1 alpha, interleukin 6 and tumor necrosis factor alpha increase the synthesis and expression of the functional alternative and terminal complement pathways by human umbilical vein endothelial cells in vitro. 861 Nov 96

We have investigated the influence of the cytokine tumor necrosis factor alpha (TNF alpha), an important mediator of sepsis, on in vitro hamster diaphragm contractility. Costal diaphragm strips were excised and mounted on an experimental apparatus consisting of a force transducer and servomotor. Preparations were randomized to incubation in one of the following solutions: (1) indomethacin 10(-6) M (n = 5); (2) TNF alpha (0.1 ng/ml) (n = 5); (3) TNF alpha (500 ng/ml) (n = 5); and (4) TNF alpha (500 ng/ml) plus indomethacin (10(-6)) (n = 5). Baseline contractile parameters measured at optimal length included twitch and tetanic tension, half relaxation time, time to peak tension, force frequency response (10-80 Hz), and fatigability to response to repetitive stimulation. After 90-min incubation in one of the solutions, an identical stimulation protocol was repeated. Initial twitch and tetanus parameters were similar between groups. Maximal twitch tension and tetanic tension decreased significantly, as did tetanic stimulations at 10-80 Hz in the TNF group (500 ng/ml) (p < 0.05). Coincubation with indomethacin decreased but did not completely abolish changes in diaphragm function caused by the higher dose of TNF. There were no significant changes in twitch or tetanus parameters, or in response to repetitive stimulation after incubation in the lower dose TNF group (0.1 ng/ml). We conclude that TNF causes impairment of in vitro diaphragm contractility at high incubation concentrations of TNF and that this effect can be partially blocked by prostaglandin synthetase inhibition. No significant deleterious effect on in vitro contractility was detected at concentrations of TNF similar to serum levels in human sepsis.
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PMID:High-dose tumor necrosis factor alpha produces an impairment of hamster diaphragm contractility. Attenuation with a prostaglandin inhibitor. 863 Jun 10

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

"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


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