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)

We previously reported that injection of anti-IL-6 monoclonal antibody (mAb) in a patient with multiple myeloma (MM) induced the circulation of high amounts of IL-6 in the form of IL-6/anti-IL-6 monomeric complexes. This made it possible to estimate overall daily IL-6 production in patients in vivo, which had not been achieved in animals or humans before. In this study, estimations are given for a patient with MM who developed Escherichia coli sepsis during anti-IL-6 mAb. During the first 12 days, the overall IL-6 production was estimated at 1.5 to 2.0 micrograms/day. On day 13, serum IL-6 concentration, in the form of IL-6/anti-IL-6 complexes, increased 1000-fold and was 1.7 x 10(6) pg/ml, in relation with the development of E. coli sepsis. Overall IL-6 production was estimated to be greater than 7 mg/day, i.e. 3500 times higher than before sepsis. Serum IL-6 levels in the form of monomeric immune complexes remained very high for 20 days after sepsis indicating the persistence of very high overall IL-6 production (100 to 3500-fold greater than pre-sepsis production). This study demonstrates a considerable and persistent potential for IL-6 production in this patient during and after sepsis.
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PMID:Overall interleukin-6 production exceeds 7 mg/day in multiple myeloma complicated by sepsis. 818 69

Adenosine exhibits potent anti-inflammatory activities but its therapeutic use is limited by cardiovascular side effects. Inhibitors of an enzyme involved in adenosine metabolism, adenosine kinase (EC 2.7.1.20), were evaluated for their ability to enhance endogenous adenosine production. One novel adenosine kinase inhibitor, GP-1-515, was studied in two models of septic shock to assess its protective effects. GP-1-515 significantly decreased mortality in mice that received a lethal i.v. injection of endotoxin. The beneficial effect was accompanied by decreased neutrophil accumulation in the lungs and was reversed by an adenosine receptor antagonist, implying that the effects were mediated by endogenous adenosine. Plasma levels of TNF-alpha, but not IL-1 alpha or IL-6, were lower in the GP-1-515-treated animals. In a second model of sepsis, GP-1-515 increased survival in bacterial peritonitis in rats. The mechanism of action in both models was likely multifactorial, including adenosine-mediated inhibition of neutrophil adhesion, cytokine production, and oxygen radical generation. Adenosine kinase inhibitors have potent anti-inflammatory effects in vitro and in vivo and represent a novel therapeutic approach to the treatment of inflammatory diseases.
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PMID:Protective effect of an adenosine kinase inhibitor in septic shock. 820 12

It is believed that induction of cytokine expression by bacterial cell wall components plays a role in the development and course of sepsis. However, most attention has been focused on lipopolysaccharide (LPS). We studied the ability of N-acetylglucosaminyl-1,6-anhydro-N-acetylmuramyl-L-alanyl-D- isoglutamyl-m-diaminopimelyl-D-alanine (G(Anh)MTetra), a naturally occurring breakdown product of peptidoglycan that is produced by soluble lytic transglycosylase of Escherichia coli, to induce cytokine expression in human monocytes. G(Anh)MTetra was found to strongly induce interleukin (IL)-1 beta and IL-6 mRNA expression after 2 h and IL-1 beta and IL-6 protein secretion after 48 h of activation. The increase in mRNA accumulation was at least partly due to an increase in the transcription rates of the respective genes and was accompanied by a strong induction of nuclear factor-kappa B and activator protein-1 transcription factor expression. Experiments using inhibitors of protein kinase C, protein kinase A, and tyrosine kinase-dependent pathways revealed that G(Anh)MTetra-induced IL-1 beta and IL-6 mRNA expression involves activation of an H7-inhibitable pathway. By using the protein synthesis inhibitor cycloheximide, it was shown that G(Anh)MTetra-induced IL-6 mRNA expression depends on the synthesis of new protein, whereas G(Anh)MTetra-induced IL-1 beta mRNA accumulation does not. When responses to G(Anh)MTetra were compared with those to LPS and muramyldipeptide (MDP), it was found that the optimal response to G(Anh)MTetra induction was similar to that of LPS but significantly higher than the response to MDP. Furthermore, maximal G(Anh)MTetra-induced IL-1 beta and IL-6 mRNA expression could be enhanced by co-stimulation with LPS or MDP, suggesting that different receptors and/or transduction pathways were involved. These results indicate that G(Anh)MTetra induces IL-1 beta and IL-6 expression in human monocytes suggesting a possible role for G(Anh)MTetra in the release of cytokines during sepsis.
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PMID:G(Anh)MTetra, a natural bacterial cell wall breakdown product, induces interleukin-1 beta and interleukin-6 expression in human monocytes. A study of the molecular mechanisms involved in inflammatory cytokine expression. 830 82

In severe infections two factors play a part: the infectious agent and the response of the host. The response of the host involves production of a large number of endogenous mediators including a number of cytokines that are currently the focus of many studies: tumor necrosis factor (TNF alpha), interleukins (IL-1 and IL-6), and interferon gamma (IGN gamma). These cytokines are part of the body's normal defense mechanisms but can have toxic effects when produced in excessive amounts. Although levels of these cytokines are often high in the blood of patients with sepsis, persistence of these elevations is the main indicator of severe infection. Experimentally, injections of TNF alpha and IL-1 reproduce the manifestations of severe sepsis. Mice that are genetically unable to produce TNF alpha are resistant to the injection of endotoxin. Severe sepsis can be prevented by pretreatment of animals with anticytokine agents (polyclonal and monoclonal antibodies and anti-receptor agents ...). Many issues remain unresolved: for instance, the experimental results obtained with an intravenous bolus of endotoxin or bacteria have not been confirmed in some animal models of subacute infection. These models may more closely resemble human infections. The interrelations between these cytokines are extremely complex. Synergistic effects do occur, but the effects of combinations of cytokines can be different from those of each cytokine given alone... It follows that therapeutic use in humans of anti-cytokine molecules is still an approach of uncertain outcome that will perhaps be clarified by ongoing multicenter clinical trials.
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PMID:[Cytokines and severe infections]. 830 25

Interleukin-1 (IL-1) is a mediator of endotoxin shock and IL-1 receptor blockade has been shown to have therapeutic efficacy against endotoxic shock and sepsis in laboratory models. The current studies were designed to characterize the efficacy of a murine monoclonal IL-1 receptor antibody (IL-1rab) against endotoxin (LPS) lethality and to investigate whether combined anticytokine therapy using the IL-1rab and a highly specific polyclonal rabbit anti-mouse TNF antibody (TNF Ab) could provide additive or synergistic efficacy against LPS lethality in C57B1/6 female mice. A single intraperitoneal (ip) dose of IL-1rab, 0.1 or 0.2 mg, significantly reduced lethality from LPS, 30 to 40 mg/kg ip, compared to nonimmune IgG, 0.1 or 0.2 mg, in control mice (P2 < 0.05). Treatment with IL-1rab was effective when administered from 6 hr before to 1 hr after LPS. After LPS, circulating levels of IL-6 were significantly lower in IL-1rab-treated mice [IL-6 (ng/ml) 2 h after LPS: IgG, 100 +/- 25, IL-1rab, 41 +/- 8; 4 h after LPS: IgG, 46 +/- 13, IL-1rab, 8 +/- 1; P2 < 0.05 and 0.03, respectively]. Northern blot analysis showed that IL-1rab markedly lowered IL-6 gene expression after LPS. Combined treatment with IL-1rab and TNF Ab did not result in any improvement in survival after LPS compared to either agent alone. These results indicate that an IL-1 receptor antibody has therapeutic efficacy against LPS and significantly decreases IL-6 production.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interleukin-1 receptor antibody (IL-1rab) protection and treatment against lethal endotoxemia in mice. 833 25

In this study we have investigated the ability of lipopolysaccharide (LPS) to suppress binding and phagocytosis of erythrocytes via various receptors on mouse macrophages. Thioglycollate-elicited peritoneal macrophages were treated in vitro with LPS and the ability to bind and phagocytose radiolabeled sheep red blood cells was determined. We show that LPS can directly suppress phagocytosis of immunoglobulin G-opsonized and nonopsonized sheep red blood cells (SRBCs) by inflammatory macrophages. Suppression was dose dependent and was observed after 4 h of exposure. This effect lasted for at least 24 h following the removal of LPS. LPS suppressed the binding, rate, and absolute level of phagocytosis via Fc receptors. Phagocytosis via all Fc receptors (Fc gamma RI, Fc gamma RII, and Fc gamma RIII) was suppressed by LPS. Furthermore, suppression was not limited to Fc receptor-mediated phagocytosis because binding and uptake of C3bi-opsonized SRBCs to CR3 receptors was also decreased following LPS treatment. LPS did not exert its effects via the production of interleukin-1 (IL-1), IL-6, tumor necrosis factor alpha, or interferon alpha/beta, because antibodies to these cytokines did not abrogate the effect. The ability of LPS to suppress binding and phagocytosis of microorganisms may contribute to the toxic effects of LPS during gram-negative sepsis by preventing or delaying elimination of bacteria by host macrophages.
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PMID:Lipopolysaccharide-induced suppression of erythrocyte binding and phagocytosis via Fc gamma RI, Fc gamma RII, Fc gamma RIII, and CR3 receptors in murine macrophages. 833 82

Costimulation of neutrophils and cytokines may play an important role in organ injury in sepsis. Pentoxifylline inhibits various neutrophil functions in vitro, and attenuates endotoxin-induced production of TNF in both in vitro and in vivo models. To assess the effect of pentoxifylline on neutrophil activation in endotoxemia, nine adult chimpanzees (Pan troglodytes) were i.v. injected with saline (n = 2), Escherichia coli endotoxin (4 ng/kg; n = 4), or E. coli endotoxin (4 ng/kg) in combination with pentoxifylline (500 mg/3 h, starting 30 min before the endotoxin injection; n = 3). Serial blood samples were obtained for measurements of leukocyte counts and the granulocytic proteinases elastase complexed with alpha 1-antitrypsin and lactoferrin, and cytokines during the next 5 h. No changes were observed in the saline-treated chimpanzees. Endotoxin induced a marked leukocytosis and neutrophilia, which were slightly reduced by pentoxifylline. In contrast, pentoxifylline almost completely prevented endotoxin-induced neutrophil degranulation: peak elastase-alpha 1-antitrypsin was 164 +/- 21 ng/ml (mean +/- SE) after endotoxin alone, vs 71 +/- 7 ng/ml after endotoxin with pentoxifylline (t = 3 h; p < 0.05); peak lactoferrin was 329 +/- 15 and 182 +/- 5 ng/ml, respectively (t = 5 h; p < 0.05). Pentoxifylline also inhibited the endotoxin-induced release of TNF (271 +/- 26 vs 55 +/- 23 pg/ml at t = 1.5 h; p < 0.05) and IL-6 (225 +/- 42 vs 73 +/- 25 pg/ml at t = 2 h; p < 0.05). IL-8 release was not significantly inhibited by pentoxifylline. In none of the animals activation of the C system could be detected. We conclude that pentoxifylline attenuates neutrophil activation in endotoxemia in chimpanzees, probably in part by inhibiting the release of TNF.
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PMID:Pentoxifylline attenuates neutrophil activation in experimental endotoxemia in chimpanzees. 834 9

Experimental acute pyelonephritis in monkeys led to death in some of the animals following renal E. coli inoculation. It was found that both the inflammatory response and cytokine activation were much more severe in these monkeys as compared with others that survived. IL-1 was decreased just before death, and there were early increases in IL-2 and IL-6 serum concentrations, but no significant increase in TNF values. The data suggest that death in sepsis is due in part to excessive cytokine release because of a decrease in the protective activity of IL-1.
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PMID:Events leading to septic death from experimental acute pyelonephritis in the monkey. 834 80

The use of monoclonal antibodies (mAbs) directed to lipid A for the therapy of gram-negative sepsis is controversial. In an attempt to understand their biologic basis of action, we used a fluid-phase radioimmunoassay to measure binding between bacterial lipopolysaccharide (LPS) and two IgM mAbs directed to lipid A that are being evaluated for the treatment of gram-negative bacterial sepsis. Both antibodies bound 3H-LPS prepared from multiple strains of gram-negative bacteria when large excesses of antibody were used, although binding was modest and only slightly greater than control preparations. We also studied the ability of each anti-lipid A antibody to neutralize some of the biological effects of LPS in vitro. Despite large molar excesses, neither antibody neutralized LPS as assessed by the limulus lysate test, by a mitogenic assay for murine splenocytes, or by the production of cytokines interleukin (IL)-1, IL-6, or tumor necrosis factor from human monocytes in culture medium or in whole blood. Our experiments do not support the hypothesis that either of these anti-lipid A mAbs function by neutralizing the toxic effects of LPS.
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PMID:Assessment of ability of murine and human anti-lipid A monoclonal antibodies to bind and neutralize lipopolysaccharide. 841 11

Klebsiella pneumoniae, a worldwide cause of nosocomial infections, is one of the most common causes of death in newborns in nurseries. In this study, we investigated the role of interleukin-1 (IL-1) in an experimental animal model of neonatal sepsis, using a natural antagonist of IL-1 receptors, the IL-1 receptor antagonist (IL-1Ra), to block IL-1's effects in neonatal Klebsiella sepsis in the absence of antibiotic treatment. Newborn Wistar-Kyoto rats were injected intraperitoneally with a single dose (10 mg/kg) of either IL-1Ra (n = 43) or human serum albumin as a control (n = 40). At the same time, a 50% lethal dose of K. pneumoniae was injected subcutaneously. No antibiotics were given at any time. After 10 days, survival was 60% for the albumin group and 80% for the IL-1Ra group (P < 0.01). IL-1Ra treatment also afforded protection when the dose of bacteria was increased sixfold (P < 0.01). There were two episodes of leukopenia in the control group, which were suppressed by IL-1Ra (P < 0.01 and P < 0.001). IL-1 and IL-6 levels were lower in the IL-1Ra-treated group (P < 0.05 and P < 0.001, respectively). No differences between the two groups were observed in the number of bacteria in cultures of the blood, lungs, liver, or spleen. When IL-1Ra (10 mg/kg) was given both at time zero and 24 h after bacterial challenge, lethality was significantly increased (P < 0.01). Single doses of IL-1Ra of from 20 to 40 mg/kg progressively increased lethality compared with controls (P < 0.01) in both Wistar-Kyoto and Sprague-Dawley strain rats. In the same model, low doses of IL-1 itself (0.4 ng per rat), given 24 h prior to bacterial challenge, afforded protection (P < 0.001). These studies suggest that, in the absence of antibiotics, partial blockade of IL-1 receptors improves survival, whereas a longer or greater blockade increases lethality in newborn rats infected with K. pneumoniae.
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PMID:The interleukin-1 receptor antagonist can either reduce or enhance the lethality of Klebsiella pneumoniae sepsis in newborn rats. 843 13


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