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)

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

Apoptosis (A O) is a pathological process by which cells undergo a form of inducible nonnecrotic cellular suicide. In vitro studies suggest that changes in the rate of macrophage (Mo) A O may be associated with elevated proinflammatory cytokine secretory capacity, such as interleukin-1 beta (IL-1 beta) (via IL-1 converting enzyme activation). Furthermore, it has been reported that Mo are activated during early (0-4 hours) experimental septic insult to act as sources of proinflammatory cytokines, such as IL-1. However, with the progression of sepsis, these same cells become refractory to further stimulation (appearing dysfunctional). Nonetheless, it remains unknown if this acquired immunosuppression (dysfunction) is associated with an acceleration in macrophage A O. To determine this, male C3H/HeN mice were subjected to sepsis (cecal ligation and puncture, CLP) or sham-CLP and 4 or 24 hours thereafter Mo were isolated from the peritoneum (PMo) and liver (KMo). Macrophage monolayers were lysed either after stimulation with lipopolysaccharide (LPS) (10 microgram/mL, 24 hours) in vitro or immediately (ex vivo) before LPS stimulation and the cytoplasmic cell fraction was retained. The extent of A O was determined using a cell-death enzyme-linked immunosorbent assay, which detects the presence of cytoplasmic oligonucleosomes and changes in the propidium iodide staining intensity. The results indicate that, early after CLP (4 hours) only PMo stimulated with LPS in vitro showed evidence of increasing A O. At 24 hours (late) after the onset of sepsis, the ex vivo extent of A O in PMo was increased but it was decreased in KMo. However, the addition of LPS in vitro results in a marked increase in both septic PMo and KMo A O. This latter result suggests that the inability of Mo to release cytokines in response to stiumulants, such as LPS during late sesis (24 hours), may be because of induciton of accelerated A O in these Mo populations.
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PMID:Is sepsis-induced apoptosis associated with macrophage dysfunction? 861 34

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

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

The paper presents the molecular biology and biological activity of IL-1 alpha, IL-1 beta and IL-1 receptor antagonist. The role of IL-1 family in pathogenesis of a various disease including myeloid leukemias and other neoplastic diseases, diabetes mellitus, inflammatory diseases, sepsis syndrome and atherosclerosis is presented. Potential therapeutic value of IL-1 and IL-1 receptor antagonist is also discussed.
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PMID:[Biological properties and clinical importance of interleukin 1]. 865 31

Proinflammatory cytokines are important mediators during endotoxemia. In experimental models, injection of lipopolysaccharide (LPS) activates macrophages leading to excessive secretion of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta and IL-6; infusion of high dose of these mediators results in organ failure and death. Natural infection may be different, because it persists over days or even weeks, with repeated endotoxin challenge to macrophages. Little is known about the capacity of peripheral blood mononuclear cells (PBMCs) to release proinflammatory cytokines under these conditions. Therefore, as an ex vivo model of sepsis, the expression of proinflammatory cytokines after stimulation of whole blood with LPS was studied. A high LPS dose (1 microgram/ml) maximally increased TNF-alpha, IL-1 beta and IL-6 secretion in controls, but a marked depression was observed in septic patients (p < 0.01; 15 patients with severe sepsis versus 20 control patients without infection). This reduction persisted for up to 10 days after diagnosis of sepsis. The release of TNF-alpha, IL-1 beta and IL-6 was markedly decreased in the septic group even when a lower and physiologically more relevant LPS concentration (1 ng/ml) was used. IL-1 beta mRNA was similar to controls, but a down-regulation was observed in TNF-alpha and IL-6 transcript levels in PBMCs from the blood of septic patients. This was at least in part due to a marked reduction in TNF and IL-6 mRNA half-life. These results indicate that different mechanisms down-regulate proinflammatory cytokine release in the whole blood of septic patients. Although excessive secretion is known to be deleterious, low concentrations of these cytokines are involved in regulating essential cellular and humoral immune functions. Thus, the reduced capacity to express and release adequate amounts of proinflammatory cytokines after exposure to endotoxin, as observed in whole-blood PBMCs from septic patients, may contribute to the development of immunodeficiency.
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PMID:Interleukin-1, -6 and tumor necrosis factor-alpha release is down-regulated in whole blood from septic patients. 867 54

Fusion proteins of the human 55-kDa TNF receptor extracellular domain with hinge and C2/C3 constant domains of human IgG1 or IgG3 heavy chains were tested in a primate sepsis model. Twenty-four baboons received 4.6, or 0.2 mg/kg of TNFR5-G1,3, or placebo, before the administration of a lethal dose of live Escherichia coli. Treatment with TNFR5-G1,3 decreased 5-day mortality from 88% in the placebo group to 12% in the TNFR5-G1,3-treated animals (p < 0.01 by Fisher's exact test). Treatments with TNR5-G1 and TNFR5-G3 in doses from 0.2 to 4.6 mg/kg were efficacious. Free plasma TNF was neutralized by all treatments, but inactive TNF/TNFR5-G1,3 complexes remained in circulation for prolonged periods. TNFR5-1,3 treatments attenuated the hemodynamic disturbances, reduced fluid requirements, and decreased the systemic IL-1 beta, IL-6, and IL-8 responses. In addition, TNFR5-G1,3 treatment shortened the granulocytopenia and reduced the loss of cellular TNF receptors from granulocytes. The decrease in fibrinogen concentrations and increase in prothrombin and partial thromboplastin times were significantly attenuated by TNFR5-G1,3 treatment. TNFR5-G1,3 treatment markedly attenuated the rise in plasma lactate concentration. Histologic studies of TNFR5-G1,3 revealed dose-dependent protection against tissue injury by Escherichia coli administration.
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PMID:Protection against lethal Escherichia coli bacteremia in baboons (Papio anubis) by pretreatment with a 55-kDa TNF receptor (CD120a)-Ig fusion protein, Ro 45-2081. 869 Sep 12

Serum levels of interleukin-1 beta (IL-1 beta) in newborn infants with septicaemia were measured and possible relationships between the clinical course of the infants, causative micro-organisms and IL-1 beta levels were investigated in a prospective study. The study groups comprised 49 newborn infants (25 mature, 24 premature) with proven sepsis and 40 healthy newborn infants (20 mature, 20 premature). Serum IL-1 beta levels were measured using the IL-1 beta immunoradiometric assay. The levels were found to be lower in neonates with sepsis (median 0.1 pg/ml) than in healthy controls (median 27.9 pg/ml) (p < 0.001). Non-significant trends towards lower levels were observed in children with shock and in non-survivors. No correlation was found between IL-1 beta and postnatal age, gestational age or the study weight of the patients. There was no significant difference in the serum IL-1 beta level in septic patients infected with Gram-positive bacteria and those infected with Gram-negative bacteria. The results show that the concentration of IL-1 beta is significantly decreased in preterm and term neonates with sepsis.
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PMID:Serum interleukin-1 beta in neonatal sepsis. 869 99

Sepsis is a constellation of clinical signs and symptoms resulting from excessive systemic host inflammatory response to infection. This inflammatory response is largely mediated by cytokines, which are released into the systemic circulation. Plasma concentrations of specific cytokines, TNF alpha, IL-1 beta, IL-6 and IL-8 are frequently elevated in human sepsis and cytokine concentrations correlate with severity and outcome of sepsis. In addition to pro-inflammatory cytokines, soluble cytokine receptors, cytokine receptor antagonists and counter-inflammatory cytokines are also produced in large quantities in patients with sepsis; however, the specific role of these molecules in sepsis remains undefined. A complex interaction of cytokines and cytokine-neutralizing molecules probably determines the clinical presentation and course of sepsis. Intervening in this sequence of events to modify the host inflammatory responses may prove to be a beneficial treatment strategy for sepsis, but currently tested anticytokine therapies have been largely unsuccessful.
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PMID:Sepsis and cytokines: current status. 870 20

Circulatory secretory non-pancreatic phospholipase A2 (snp-PLA2) was measured prospectively at the onset (day 0) of severe sepsis in 52 patients as well as on day 1 and 2 in 25 patients, in order to answer two questions: 1) does the snp-PLA2 plasma concentration differ according to the type and severity of infection? 2) what is the relation between snp-PLA2 and other mediators involved in severe sepsis, such as endotoxin, cytokines (TNF alpha, IL-1 beta, IL-6) and thromboxane B2 (the stable metabolite of thromboxane A2)? On day 0, the snp-PLA2 circulatory level was 78 +/- 17 nmol/min/ml in patients with severe sepsis as compared to 3.5 +/- 2 nmol/min/ml in 40 healthy volunteers. There was no statistical difference according to the outcome, the presence of shock, or the type of infection on day 0. However, snp-PLA2 remained elevated or even increased in patients who ultimately died, while it decreased in survivors (p = 0.01 by ANOVA). The cytokine profiles during the 2-day follow-up were similar to that of snp-PLA2, but the differences were not statistically significant between survivors and non-survivors. No correlation was found between snp-PLA2 and other mediators for either initial or peak values.
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PMID:Secretory non-pancreatic phopholipase A2 in severe sepsis: relation to endotoxin, cytokines and thromboxane B2. 874 Jan


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