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)

We investigated plasma levels of cytokines and endotoxin in septic shock to clarify the roles of various cytokines in this type of shock. Endotoxemia was observed in 16 of 22 septic shock patients. Plasma levels of tumor necrosis factor-alpha (TNF-alpha), interleukin 1 beta (IL-1 beta) IL-2, and IL-6 were significantly higher in septic shock than in sepsis without shock. Strong correlations were noted between TNF-alpha and IL-2 levels and between IL-1 beta and IL-6 levels. Patients with high TNF-alpha and IL-2 levels also showed endotoxemia. We defined two types of septic shock from these data, i.e., endotoxin+TNF-alpha + IL-2 shock and IL-beta + IL-6 shock. In the former type, high TNF-alpha and IL-2 levels were present before the onset of shock, and shock itself was associated with endotoxemia. The second type showed simultaneous elevation of IL-1 beta and IL-6 levels at the onset of septic shock, and endotoxin was detected in some of them. These results suggest that endotoxin and extremely high levels of TNF-alpha and IL-2, or the simultaneous elevation of IL-1 beta and IL-6, are related to the onset of septic shock.
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PMID:Two types of septic shock classified by the plasma levels of cytokines and endotoxin. 129 90

Several studies in human patients and in laboratory animals have revealed a correlation between serum interleukin (IL)-6 levels and outcome in clinical sepsis and in related animal models, respectively. In the present study, two monoclonal antibodies were used to investigate the contribution of IL-6 in the lethal action of tumor necrosis factor (TNF) and of lipopolysaccharide (LPS) in mice. We studied the potential protective properties of an anti-murine (m) IL-6 antibody and of an anti-mIL-6 receptor antibody. In controlled experiments, we observed that both monoclonal antibodies conferred a dose-dependent protection to a lethal dose of mTNF. Detailed studies with the monoclonal antibodies indicate, however, that protection was no longer observed when the mTNF dose was slightly higher than the lethal dose. Likewise, the anti-IL-6 monoclonal antibody protected against injections of LPS at a lethal-dose concentration, but here too failed to protect against higher doses of LPS. The anti-IL-6 monoclonal antibody was unable to protect against mTNF in mice sensitized by galactosamine, the corticoid receptor antagonist RU38486 or human (h) IL-1 beta. Protection did not correlate with the serum concentrations of IL-6. Finally, we demonstrate that hIL-6 injection did not change the sensitivity of mice towards mTNF. We conclude that, although IL-6 levels may be of value as a marker for the outcome in septic shock, this cytokine contributes only marginally in the pathogenesis leading to death. The small, but real, contribution of IL-6 in some situations might be due to its ability to up-regulate the level of TNF receptors.
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PMID:Limited involvement of interleukin-6 in the pathogenesis of lethal septic shock as revealed by the effect of monoclonal antibodies against interleukin-6 or its receptor in various murine models. 132

Interleukin-1 (IL-1) is a 17-kDa pro-inflammatory cytokine synthesized from a variety of cell types primarily in association with disease states or during host perturbation such as immune responses. At pM or even fM concentrations, IL-1 triggers various responses in nearly all cells. It appears that there is little or no major role for IL-1 in homoeostatic mechanisms. There are two IL-1's (alpha and beta) each with its distinct sequence; there are two IL-1 receptors. Disease states such as local and systemic infection, septic shock, degenerative arthritis and autoimmune diseases such as nephritis, vasculitis and inflammatory bowel disease appear to be mediated, in part, by IL-1. Organ failure, capillary leak and death occur in animals after a combination of tumour necrosis factor (TNF) and IL-1 which is more effective in inducing these changes than either cytokine alone. IL-1 is also a potent inducer of endothelial cell adhesion molecules, IL-6, and IL-8, a neutrophil chemotactic and activating factor. Strategies for reducing the effects of IL-1 have been based on suppression of transcription, translation, or secretion; more recently, receptor blockade has been a new approach. A naturally occurring IL-1-specific receptor antagonist (IL-1ra), which shares 40% conserved amino-acid homology with IL-1 beta, binds to IL-1 surface receptors with the same affinity as IL-1 but does not possess agonist activity and acts as a competitive inhibitor of IL-1. Studies using the IL-1ra to block endogenous IL-1 in a variety of animal disease models suggest that IL-1 plays a key role in triggering the cascade of inflammatory responses. In addition, the IL-1ra reduces the spontaneous production of growth factors and proliferation of leukaemic cells. The IL-1ra may be an advantageous therapy in patients with sepsis, diabetes, inflammatory bowel, arthritis and cancer.
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PMID:Reduction of inflammation by decreasing production of interleukin-1 or by specific receptor antagonism. 139 23

Cytokines are immunoregulatory molecules that are important mediators of the host response to stress and infection. Infants and children undergoing major surgery are particularly at risk of developing sepsis and have altered metabolic responses to surgical stress compared to adults. We have investigated the temporal sequence of cytokine responses in six infants (mean age, 11 +/- 7.5 months) undergoing pull-through operation for Hirschsprung's disease and correlated them with hemodynamic and biochemical parameters. Tumor necrosis factor (TNF-alpha), interleukin-1 beta (IL-1 beta), and interleukin-6 (IL-6) were measured by ELISA preoperatively, intraoperatively (hourly), and 24 and 48 hours postoperatively. IL-6 levels increased significantly in all cases within 2 hours of commencement of the operation (P less than .01) and were maximal 24 hours postoperatively. No significant changes in IL-1 beta levels (mean range, 70 to 110 pg/mL) were seen in these patients. TNF levels were undetectable (less than 20 pg/mL) throughout the study. Cortisol levels were increased in all patients during operation. Serum C-reactive protein levels were first detected 24 hours postoperatively and continued to increase 48 hours postoperatively. Hemodynamically, heart rate increased during the first 3 hours of operation and correlated with increase in IL-6 levels. Blood pressure and temperature changes did not correlate with cytokine levels. This study identifies IL-6 as the earliest detectable cytokine response associated with major surgery in infants. It also suggests that IL-6 can be unregulated, independently of other cytokines, in response to surgical stress.
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PMID:Early induction of IL-6 in infants undergoing major abdominal surgery. 140 30

IL-8, a cytokine known for its potent and specific neutrophil activation and chemoattractant properties, has been recently detected in the circulation during septic shock, endotoxemia, and after IL-1 alpha administration. Because of its observed in vitro actions, it has been hypothesized that IL-8 may contribute to the dynamics of circulating granulocytes and to the pathologic sequelae seen in sepsis. Here, human rIL-8 is administered to healthy nonhuman primates as a single i.v. injection or as a continuous 8-h i.v. infusion. We demonstrate that both methods of i.v. administration result in a rapid but transient, severe granulocytopenia, followed by a granulocytosis that persists as long as IL-8 levels are detectable in the circulation. There were no hemodynamic changes after IL-8 administration, and animals remained clinically stable during the 24-h observation period. No detectable circulating TNF-alpha, IL-1 beta, or IL-6 response was induced by either IL-8 administration regimen. Histopathologic examination revealed mild to moderate neutrophilic margination in lung, liver, and spleen, of greater severity in baboons receiving the 8-h infusion. There was no associated neutrophilic infiltration or tissue injury. Thus, IL-8 modulates circulating granulocyte dynamics and likely directs their actions, but when administered i.v. to healthy animals, either as a bolus dose or as a continuous infusion for up to 8 h, does not induce the hemodynamic and metabolic aberrations or the acute organ damage seen during sepsis.
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PMID:Effects of intravenous IL-8 administration in nonhuman primates. 154 15

Intrapulmonary activation of leukocytes and release of cellular mediators and enzymes are involved in the pathophysiology of the adult respiratory distress syndrome (ARDS). To investigate a possible role of local cytokines, we measured bronchoalveolar fluid (BALF) and plasma levels of tumor necrosis factor alpha (TNF-alpha) and its soluble inhibitors (sTNF-RI + RII), interleukin-1 beta (IL-1 beta), interferon-alpha (IFN-alpha), and granulocyte elastase in 14 patients at risk for ARDS and in 35 patients developing ARDS after trauma, sepsis, or shock. During clinical development of severe ARDS, BALF cytokines increased markedly: TNF-alpha from 116 +/- 36 to 10,731 +/- 5,048 pg/ml (mean +/- SEM), p = 0.001; sTNF-RI + RII from 3.7 +/- 1.4 to 24.6 +/- 2.6 ng/ml, p less than 0.05; and IL-1 beta from 7,746 +/- 5,551 to 42,255 +/- 19,176 pg/ml, p = 0.01. Plasma cytokines were not increased in most patients, nor were they correlated with the development or severity of ARDS. BALF elastase was higher in patients developing ARDS than in those at risk but not going into pulmonary failure (0.97 +/- 0.26 versus 0.28 +/- 0.13 U/ml, p = 0.026), and the highest values were observed in the early stages of severe ARDS (1.85 +/- 0.39 U/ml). BALF elastase levels correlated with IFN-alpha (r = 0.72, p less than 0.001). In conclusion, local release of TNF-alpha and IL-1 beta, possibly by pulmonary macrophages or other cells, and/or accumulation in the lung is associated with the development of ARDS.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:High bronchoalveolar levels of tumor necrosis factor and its inhibitors, interleukin-1, interferon, and elastase, in patients with adult respiratory distress syndrome after trauma, shock, or sepsis. 158 41

Despite antibiotic therapy intra-abdominal sepsis following major surgery is a significant cause of mortality. We sought to determine if interleukin-1 beta (IL-1) could improve survival in a murine model of intra-abdominal infection. Groups of 10 BDF1 mice received a single subcutaneous (sc) injection of recombinant human IL-1 beta 24 hr prior to cecal ligation and puncture (CLP) and were assessed twice daily for survival. Mice that received a single injection of IL-1 beta 24 hr prior to CLP had a dose-dependent improval in survival compared to controls. The beneficial effect of IL-1 treatment may have been related to its ability to stimulate myelopiesis. The addition of indomethacin, in an effort to limit possible toxicity of IL-1, did not further improve survival. Appropriate timing of specific immunomodulators may provide an additional strategy for the treatment of infections.
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PMID:Interleukin 1 beta improves survival following cecal ligation and puncture. 161 21

Leukocyte activation is a property of systemic infection. Animal experiments indicate interleukin-1 (IL-1) as a possible modulator, while contradictory results have been reported from in-vitro stimulation of isolated leukocytes. The purpose of the present study was to investigate the activation of isolated polymorphonuclear (PMN) leukocytes in vitro by preparations of recombinant human IL-1 beta and IL-1 receptor antagonist, which in earlier studies could elicit and abrogate, respectively, a sepsis-like syndrome in rabbits. They have also been shown to influence acute phase protein synthesis in mice and rats, and release of leukocyte cathepsin G in vivo. It was found that recombinant human IL-1 beta elicited a dose-dependent luminol-enhanced chemiluminescence response in isolated human PMN leukocytes in the dose range 8.8 x 10(-11)-8.8 x 10(-8) M. The effect could be blocked by prior treatment with the IL-1 receptor antagonist, indicating a direct effect on the specific IL-1 receptor. Preincubation by IL-1 beta enhanced the effect of a secondary challenge with phorbol 12-myristate 13-acetate or formyl-Met-Leu-Phe by 30-40%. The priming effect of rhIL-1 beta could also be blocked by the specific receptor antagonist. In this study, incubation of PMN leukocytes with rhIL-1 beta failed to induce degranulation of both azurophil (neutrophil proteinase 4/proteinase 3) and specific (lactoferrin) granules. rhIL-1 beta has been shown to induce degranulation in vivo, which is thus indicated as an indirect effect. We conclude that IL-1 beta is a direct and specific, but probably weak stimulator of the PMN leukocyte.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Stimulation of human polymorphonuclear leukocytes by recombinant human interleukin-1 beta. 162 64

Interleukin-1 (IL-1) has been implicated in the pathogenesis of sepsis. IL-1-receptor antagonist (IL-1ra) is a naturally occurring inhibitor of IL-1 activity that competes with IL-1 for occupancy of cell-surface receptors but possesses no agonist activity. We induced endotoxaemia in 9 healthy human volunteers by injection of Escherichia coli endotoxin, and measured plasma concentrations of IL-1 and IL-1ra by radioimmunoassay during the next 24 h. Peak plasma concentrations of IL-1ra were about a hundred-fold greater than those of IL-1 beta. No IL-1 or IL-1ra were detectable in the plasma of 4 volunteers injected with saline. Our results suggest that the predominant natural response to endotoxin in man is the production of antagonist rather than agonist.
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PMID:Production of interleukin-1-receptor antagonist during experimental endotoxaemia. 168 22

Aberrant immunologic host defenses associated with uremia may be a cause of the high incidence of sepsis in chronic hemodialysis (CHD) patients. This investigation determined the cytokine response of blood from five nondialyzed chronic renal failure (CRF) patients, five CHD patients, and five healthy controls (HC) after in vitro stimulation with 1 ng/ml Escherichia coli 0113 endotoxin. Concentrations of the cytokines TNF-alpha and IL-1 beta were determined by ELISA and were similar in all baseline and unspiked samples. TNF-alpha concentrations in CRF and CHD spiked samples were similar to each other but significantly greater (p less than 0.01) than in HC spiked samples. IL-1 beta concentrations in CRF, CHD, and HC-spiked samples were not significantly different. We conclude that CRF and CHD patients have enhanced TNF-alpha response, which may be related to uremia and not dialysis-related factors. Uremia does not potentiate IL-1 beta release.
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PMID:Enhanced release of TNF-alpha, but not IL-1 beta, from uremic blood after endotoxin stimulation. 176 36


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