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)

Due to intensive research in the field of cytokines during the last decade the knowledge of cytokine mediated processes has increased intensively. Modulation or even inhibition of the inflammatory cascade gave hope to effective therapeutic possibilities in sepsis or autoimmune diseases, particularly in rheumatoid arthritis (RA). Interestingly the application of biological immunomodulating substances could not increase the prognosis in sepsis, sometimes even deterioration occurred. However, in inflammatory bowel diseases and RA substantial efficacy could be revealed. Since blockade of II-1 or II-2 led to some beneficial results, but also sometimes to significant toxicity, TNF-alpha blockade gave hope to constitute a promising therapeutical target. Since the efficacy of a monoclonal anti-TNF-alpha antibody and a recombinant soluble TNF receptor p75 fusion protein had been demonstrated in animal studies and in vitro, these results could be confirmed in controlled multicenter trials, showing significant improvement of patients according to Paulus and/or ACR criteria. However, a final assessment of therapeutical TNF-alpha blockade in RA cannot be given yet, since the tolerability in long-term application, particularly with respect to the risk of infections and the induction of malignancies and antibodies (e.g. drug induced lupus erythematosus) has to be observed carefully for longer times. Also the cost effectiveness of this new therapeutic approach needs further investigations.
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PMID:[Anti-TNF-alpha therapy as a new option in treatment of rheumatoid arthritis?]. 1063 66

The dose-dependent increase in mortality in patients with sepsis who are treated with tumor necrosis factor (TNF) p75 soluble receptor Fc conjugate (p75-Fc) remains unexplained. In this study, neutralization of TNF-alpha-induced interleukin (IL)-8 by p75-Fc in whole human blood exhibited a U-shaped inhibition curve, whereas the TNF-soluble p55 receptor, linked to polyethylene glycol (p55-PEG), exhibited a dose-dependent inhibition. Native soluble p75 increased TNF-alpha-induced IL-8, versus a 61% reduction by native p55. Spontaneous IL-8 production was increased by p75-Fc or native p75 but not by p55-PEG or native p55. Unexpectedly, TNF-alpha-stimulated IL-1 receptor antagonist was suppressed by p75-Fc but not by p55-PEG. Studies of binding to TNF trimer revealed that p75-Fc has an affinity 40-fold lower than that of p55-PEG and a faster off rate. Native and p75-Fc pass TNF-alpha to membrane receptors more readily than does native or p55-PEG, which may partly explain the increased mortality in patients with sepsis who are treated with p75-Fc.
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PMID:Tumor necrosis factor (TNF)-alpha-induced interleukin-8 in human blood cultures discriminates neutralization by the p55 and p75 TNF soluble receptors. 1106 45

This study was to evaluate the levels of the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) and the cytokine inhibitors soluble TNF-alpha receptor (sTNFR) and interleukin (IL-1) receptor antagonist (IL-1ra), as well as the intensity of oxidative metabolism of peripheral blood polymorphonuclear leukocytes in the course of sepsis in newborns. An increase of TNF-alpha, sTNFR and IL-1ra concentrations was found in the blood serum of the patients at the time of diagnosis. This was further accompanied by polymorphonuclear leukocyte stimulation and, as a consequence of prolonged bacterial antigen stimulation, functional exhaustion of these cells and their diminished oxidative metabolism was observed. Within the same time period, an enhanced expression of p55 and p75 TNF-alpha receptors on polymorphonuclear leukocyte cell surfaces was found. It was indicated that the applied pharmacotherapy caused a decrease of the initially elevated concentrations of TNF-alpha and proinflammatory cytokine inhibitors (sTNFR, IL-1ra). The intensive therapy of sepsis was associated with the increased oxidative burst of polymorphonuclear leukocytes along with the decrease of p55 and p75 expression on their cell surfaces.
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PMID:Proinflammatory cytokine inhibitors, TNF-alpha and oxidative burst of polymorphonuclear leukocytes in the pathogenesis of sepsis in newborns. 1134 20

Tumor necrosis factor-alpha (TNF-alpha), a crucial mediator in sepsis, elicits multiple biologic effects, including intravascular thrombosis and circulatory shock. TNF-alpha exerts its biologic effects through two distinct cell surface receptors, TNF-R1 and TNF-R2. The pathophysiologic interaction between TNF-alpha and nitric oxide (NO) in glomerular thrombosis caused by endotoxemia in rats and wild-type mice (C57BL6) as well as in knockout mice that are deficient in TNF-R1 (R1 -/-), TNF-R2 (R2 -/-), or both receptors (R1R2 -/-) was studied. Administration of lipopolysaccharide (LPS; Escherichia coli endotoxin) resulted in increased NO and TNF-alpha production but failed to induce glomerular thrombosis. Concomitant administration of LPS + NG-nitro-L-arginine methyl ester (L-NAME; an NO synthesis inhibitor) resulted in glomerular thrombosis in rats and in wild-type mice. Intraperitoneal administration of pentoxifylline before LPS inhibited TNF-alpha synthesis and prevented glomerular thrombosis in rats given LPS + L-NAME. In contrast to the results observed in rats and wild-type mice, administration of LPS + L-NAME did not result in glomerular thrombosis in knockout mice with either single or double TNF-alpha receptor deletion. Thus, during endotoxemia, (1) TNF-alpha fosters glomerular thrombosis if there is deficiency of NO synthesis and (2) both TNF-alpha receptors are necessary for TNF-alpha's prothrombogenic action. Clinically, these novel studies suggest that in gram-negative endotoxemia, inhibition of NO synthesis and selective blockade of TNF-alpha receptors may provide unique therapeutic approaches for mitigation of glomerular thrombosis and restitution of vascular tone.
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PMID:Countervailing influence of tumor necrosis factor-alpha and nitric oxide in endotoxemia. 1137 43

We compared six inflammatory mediators (C-reactive protein (CRP), interleukin-6 (IL-6), soluble tumour necrosis factor receptors (p55 and p75) and soluble adhesion molecules (ICAM-1, E-selectin)) as early diagnostic tests for neonatal sepsis, and studied the possible benefit of combining parameters. Blood samples were obtained from 166 consecutively admitted neonates, who were suspected to suffer from infection within the first week of life. Neonates were retrospectively classified as infected (sepsis, clinical sepsis or pneumonia), possibly infected, or non-infected. Twenty-four infected neonates had higher serum levels of all six mediators (all P < 0.05), and 18 possibly infected neonates had higher levels of CRP, IL-6, ICAM-1 and E-selectin (all P < 0.05), than neonates without infection (n = 124). Receiver operator characteristic plots showed that CRP was the single best diagnostic test. Multiple logistic regression modelling, including various combinations of two to six mediators, consistently showed that IL-6, in addition to CRP, predicted sepsis. With infected and possibly infected neonates as the reference standard, a combined test of CRP > or = 10 mg/l and/or IL-6 > or = 20 pg/ml had a sensitivity of 85%, specificity of 62%, and negative likelihood ratio of 0.24. Using infected neonates as reference standard alone, and including possibly infected as controls, sensitivity increased to 96%, whereas specificity decreased to 58%; a negative test result (CRP < 10 mg/l and IL-6 < 20 pg/ml) ruled out sepsis with high certainty (likelihood ratio = 0.07). CRP performed best as a diagnostic test for neonatal sepsis. Diagnostic accuracy was further improved by combining CRP and IL-6, whereas the other parameters (p55, p75, ICAM-1 and E-selectin) added no further diagnostic information.
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PMID:Early diagnostic markers for neonatal sepsis: comparing C-reactive protein, interleukin-6, soluble tumour necrosis factor receptors and soluble adhesion molecules. 1175 Jan 94

The levels of the proinflammatory cytokines interleukin 6 (IL-6) and IL-8, and the anti-inflammatory cytokines IL-10 and IL-13 were studied in child patients with sepsis. The changes of the cytokine inhibitors soluble IL-6 receptor and soluble p75 TNF-alpha receptor were also investigated in the patients' sera. An increase of pro- and anti-inflammatory cytokine levels was demonstrated at the time of diagnosis. Pharmacotherapy was accompanied by a decrease of the elevated concentrations of both cytokines and their inhibitors. The time pattern of changes in cytokine and cytokine inhibitor serum concentrations along with the time course of acute phase indices, including procalcitonin and C-reactive protein, allows for an evaluation of the system inflammatory response and may support diagnostic and prognosis methods.
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PMID:Proinflammatory cytokines (IL-6, IL-8), cytokine inhibitors (IL-6sR, sTNFRII) and anti-inflammatory cytokines (IL-10, IL-13) in the pathogenesis of sepsis in newborns and infants. 1179 38

The ongoing evaluation of the cytokine-cascade and the steadily growing knowledge about cytokine mediated processes seem to open striking therapeutical options in the fields of sepsis, autoimmune and chronic inflammatory joint or bowel diseases via modulation or inhibition of the cytokine-cascade. There is no doubt about the efficacy of the various anticytokine-treatments in the therapy of chronic inflammatory rheumatic diseases. A large number of preclinical and clinical studies forms the scientific basis for these almost widely established therapies. These so-called "biologicals" are fully accepted as disease modifying antirheumatic drugs, equal to or even more potent than the classical substances. On the one hand, these agents are acting as tumor necrosis factor-alpha-blockers, like a chimeric (human/mouse) monoclonal anti-tumor-necrosis-factor-alpha-antibody (Infliximab), a recombinant soluble tumor necrosis factor-receptor p75 fusion protein (Etanercept), and a fully humanized anti-tumor-necrosis-factor-alpha-antibody (Adalimumab); on the other hand a recombinant human interleukin-1 receptor antagonist (Anakinra) is used in clinical practice. Generally these drugs are very well tolerated; the most common adverse events are higher infection rates (including tuberculosis) and injection-site reactions for the subcutaneously administered agents. Of course one should be aware of the possibly elevated risk for malignancies although there is no evidence for that so far, but the observation time since launching of these drugs is considerably short. To conclude, involved physicians should use these new "tools" very carefully and critically, because long-term tolerance and safety is a matter of ongoing investigation and last but not least because of the growing importance of cost effectiveness when using such expensive medications. Above all initiation and monitoring of those therapies should be restricted to rheumatologists
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PMID:[Biologicals in treatment of rheumatoid arthritis and other inflammatory arthropathies]. 1292 5

Interleukin (IL)-12 is a heterodimeric proinflammatory cytokine formed by a p35 and a p40 subunit. To determine the role of IL-12 in abdominal sepsis, p35 gene-deficient (IL-12 knockout, KO) mice and normal wild-type (WT) mice were injected intraperitoneally with Escherichia coli. Peritonitis was associated with a bacterial dose-dependent increase in IL-12 p40 and IL-12 p75 concentrations in peritoneal fluid and plasma. Whereas at 6 h postinfection, IL-12 KO and WT mice displayed similar bacterial counts, at 20 hours IL-12 KO mice had significantly more bacteria in liver homogenates and were more susceptible to progressing to systemic infection. In addition, IL-12 KO mice demonstrated higher levels of proinflammatory cytokines in peritoneal fluid and increased lung and liver injury. IL-12 deficiency did not influence the recruitment of cells to the site of the infection. These data suggest that endogenous IL-12 is involved in the early antibacterial host response during abdominal sepsis.
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PMID:Endogenous interleukin-12 improves the early antimicrobial host response to murine Escherichia coli peritonitis. 1561 32

Tumor necrosis factor-alpha (TNF) is a major mediator of apoptosis as well as immunity and inflammation. Inappropriate production of TNF or sustained activation of TNF signaling has been implicated in the pathogenesis of a wide spectrum of human diseases, including cancer, osteoporosis, sepsis, diabetes, and autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. TNF binds to two specific receptors, TNF-receptor type I (TNF-R1, CD120a, p55/60) and TNF-receptor type II (TNF-R2, CD120b, p75/80). Signaling through TNF-R1 is extremely complex, leading to both cell death and survival signals. Many findings suggest an important role of phosphorylation of the TNF-R1 by number of protein kinases. Role of TNF-R2 phosphorylation on its signaling properties is understood less than TNF-R1. Other cellular substrates as TRADD adaptor protein, TRAF protein family and RIP kinases are reviewed in relation to TNF receptor-mediated apoptosis or survival pathways and regulation of their actions by phosphorylation.
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PMID:TNF signaling: early events and phosphorylation. 1806 42

Tumor necrosis factor-alpha (TNF-alpha) is thought to play a major role in systemic inflammation associated with sepsis. A potent TNF antagonist, a recombinant fusion protein that consists of the soluble TNF receptor (p75) linked to the Fc portion of human IgG1 (sTNFR II/IgG1 Fc fusion protein, sTNFR:Fc), has been shown to provide rapid and sustained improvement in local inflammation diseases by binding TNF-alpha and preventing its proinflammatory activities. To explore the potential therapeutic efficacy for septic shock of sTNFR:Fc, we investigate the effect of this molecule on the survival rate, blood pressure, serum TNF-alpha bioactivity as well as the expression of TNF-alpha at mRNA level in the liver in a LPS-induced rat septic shock model. Blood pressure of the rats was monitored by multi-channel creature signal analysis system. Serum TNF-alpha level and bioactivity was assessed using an enzyme-linked immunoassay and a L929 cytotoxicity assay, respectively. The expression of TNF-alpha mRNA in liver was examined by semi-quantitative RT-PCR. sTNFR:Fc administered to rats 24h before LPS challenge ablated the rise in serum TNF-alpha bioactivity that occurs in response to LPS and protected against hypotension and death. These results indicate that TNF-alpha is a mediator of fatal septic shock, and suggest that sTNFR:Fc offer a potential therapy of systemic infection.
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PMID:Soluble TNFR II/IgG1 Fc fusion protein treatment in the LPS-mediated septic shock of rats. 1884 68


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