UMLS:C0036690 - FACTA Search

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

We report our investigations of circulating interleukin (IL) 1 beta, IL 6 and tumor necrosis factor (TNF)-alpha, as well as cell-associated IL 1 alpha, IL 1 beta and TNF-alpha in plasma and monocytes of 21 patients with sepsis syndrome and 6 patients with non-septic shock. Longitudinal studies reveal that (a) the most frequent detectable plasma cytokines were TNF-alpha and IL 6, (b) the presence and the kinetics of circulating cytokines were independent of one other, (c) detectable levels of cytokines could be found for a long period of time, and (d) significantly higher levels of IL 6 were found for non-surviving patients. Because of the in vivo half-life of cytokines and of the existence of numerous specific high-affinity receptors, it is quite probable that detectable plasma cytokines represent the excess of produced mediators which have not been trapped by the target cells. TNF-alpha (410 +/- 65 pg/10(6) monocytes) and IL 1 beta (153 +/- 60 pg/10(6) monocytes) were frequently found associated to monocyte lysates (88% and 50%, respectively). Despite the fact that IL 1 alpha is the most abundant cytokine found associated to monocytes following in vitro activation, IL 1 alpha was rarely found in monocytes of intensive care unit patients (29%). No correlation was found to exist between the levels of plasma cytokines and cell-associated cytokines. Some patients had plasma TNF-alpha or IL 1 beta in the absence of the corresponding monocyte-associated cytokine. This observation suggests that cells other than monocytes can participate in the production of circulating cytokines. At the end of the longitudinal study (day 14 +/- 2), only 2/12 surviving patients still had plasma TNF-alpha, whereas 8/12 had monocyte-associated TNF-alpha. These results indicate that activation of monocytes still occurs in patients for whom no plasma cytokines can be detected. Thus, in addition to the measurement of plasma cytokine, measurement of cell-associated cytokine appears useful to assess cytokine production and monocyte activation in vivo.
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PMID:Dissociation between plasma and monocyte-associated cytokines during sepsis. 188 62

The regulation of type 1 plasminogen activator inhibitor (PAI-1) gene expression was studied in vivo employing a murine model system. Nuclease protection analysis revealed relatively high concentrations of PAI-1 mRNA in the aorta, adipose tissue, heart, and lungs of untreated CB6 (BalbC X C57B16) mice. Treatment of CB6 mice with LPS, TNF-alpha, or transforming growth factor-beta (TGF-beta) increased the steady-state levels of PAI-1 mRNA within 3 h in all tissues examined. However, the greatest responses to TGF-beta were observed in adipose tissue and the kidney, while LPS and TNF-alpha strongly stimulated PAI-1 gene expression in the liver, kidney, lung, and adrenals. In C3H/HeJ mice, which exhibit defective TNF-alpha release in response to LPS, the response of the PAI-1 gene to LPS was severely attenuated. However, injection of these mice with TNF-alpha increased PAI-1 mRNA in a tissue-specific pattern strikingly similar to that observed in LPS-treated CB6 mice. These results demonstrate that the PAI-1 gene is regulated in a complex and tissue-specific manner in vivo, and suggest a role for TNF-alpha in the response of the PAI-1 gene to sepsis.
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PMID:Regulation of murine type 1 plasminogen activator inhibitor gene expression in vivo. Tissue specificity and induction by lipopolysaccharide, tumor necrosis factor-alpha, and transforming growth factor-beta. 191 85

Endotoxin (lipopolysaccharide [LPS]) and tumor necrosis factor (TNF-alpha) have been implicated in the pathogenesis of sepsis-induced adult respiratory distress syndrome. To evaluate the possible interaction of the hepatic-pulmonary macrophage axis in the adult respiratory distress syndrome, we compared the kinetics of immunosuppressive prostaglandin E2, TNF-alpha, and interleukin 6 production in LPS-stimulated Kupffer cells and alveolar macrophages (AMs). Interleukin 6 production by Kupffer cells was significantly higher than for equal numbers of AMs. Kupffer cell TNF-alpha levels peaked early before decreasing as regulatory prostaglandin E2 levels rose. In contrast, AM TNF-alpha levels rose sharply and remained significantly higher than for Kupffer cells throughout culture coincident with negligible prostaglandin E2 production. Kupffer cell sequestration of LPS may normally invoke a coordinated cytokine response able to locally induce acute-phase hepatocytes. In hepatic failure, however, LPS spillover to the lung may promote adult respiratory distress syndrome by inducing unregulated AM TNF-alpha production within the pulmonary microenvironment.
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PMID:Organ interactions in sepsis. Host defense and the hepatic-pulmonary macrophage axis. 198 33

Interleukin 8 (IL-8), a potent activator of neutrophils, may be important in the early host response to serious Gram-negative infections. IL-8 was measured with other acute phase cytokines (tumor necrosis factor alpha [TNF-alpha], IL-6 and IL-1 beta) in 25 normal humans randomized to receive either intravenous endotoxin alone or endotoxin after oral administration of ibuprofen or pentoxifylline, agents that alter some of the inflammatory responses induced by endotoxin in vitro. TNF immunoreactivity was maximum at 1.5 h, and total TNF (area under the curve) was 4.2- and 4.5-fold greater in subjects given endotoxin/ibuprofen compared to subjects given endotoxin alone (p = 0.026) or endotoxin/pentoxifylline (p = 0.004), respectively. IL-6 levels were maximum at 2-3 h and did not differ among the three groups. No IL-1 beta was detected in any subject. IL-8 levels peaked at 2 h in subjects given either endotoxin alone or endotoxin/pentoxifylline, falling towards baseline by 5 h. Subjects given endotoxin/ibuprofen had a more sustained rise in IL-8 with peak levels 2.8- and 2.5-fold higher at 3 h compared to endotoxin alone (p = 0.048) or endotoxin/pentoxifylline (p = 0.023), respectively. Differences in total IL-8 release among groups approached statistical significance (ANOVA, p = 0.07). This trend reflected the increased release of IL-8 by the subjects receiving ibuprofen compared to pentoxifylline (1.9-fold higher; p = 0.024). This suggests that cyclooxygenase products may provide important negative feedback loops for cytokine production in vivo. Increases in circulating IL-8 are part of the acute inflammatory response of humans to endotoxin. Altered cytokine responses caused by antiinflammatory therapy may have important implications for both host defense and injury during septicemia.
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PMID:Detection of interleukin 8 and tumor necrosis factor in normal humans after intravenous endotoxin: the effect of antiinflammatory agents. 200 51

Tumor necrosis factor (TNF) may be involved in the pathogenesis of acute lung injury (ALI) associated with septicemia. Therefore, we measured plasma TNF activity during sepsis and development of lung injury in a porcine model of ALI. Plasma samples were obtained from anesthetized saline-infused control pigs (n = 10) and those infused for 1 h with live Pseudomonas aeruginosa (10(8) organisms/ml, 0.3 ml/20 kg/min) (n = 16). TNF activity was measured in plasma using the L929 fibroblast cytolytic assay. L929 cytotoxicity caused by TNF-alpha or TNF-beta was determined in plasma by measuring the cytotoxicity neutralized by TNF antisera. No significant TNF activity was detected in control pig plasma. In septic pigs, TNF activity appeared in plasma 15 min after onset of septicemia and remained elevated throughout the experiment (6.1 +/- 10.2% to 80.0 +/- 5.0%, 15 and 300 min, respectively). The appearance of pulmonary arterial hypertension, increased lung water, decreased lung compliance, and deteriorating gas exchange was correlated with the rise in plasma TNF activity, which reached a peak at 90 to 120 min in septic pigs. Our results provide evidence that both TNF subtypes are present in plasma during septicemia. Anti-TNF-alpha and anti-TNF-beta neutralized TNF activity in whole septic plasma at 15, 30, and 45 min after onset of septicemia, and the antibodies blocked TNF activity in serially diluted septic plasma at all time points up to 210 min of sepsis. TNF activity in septic plasma at 210 to 300 min was not neutralized entirely by TNF antisera.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tumor necrosis factor. Alpha and beta subtypes appear in circulation during onset of sepsis-induced lung injury. 202 17

Much effort has been directed toward elucidating the host response to sepsis and inflammation, resulting in the definition of a cascade of endogenous mediators that direct metabolic and immunological responses. Here we report that IL-8, a novel cytokine produced by a variety of cells in vitro in response to stimulation with bacterial LPS and the proinflammatory cytokines, appears in the circulation of primates in vivo during septic shock, sublethal endotoxemia, and after the administration of IL-1 alpha. The magnitude of the IL-8 response correlates with the severity of the insult, and levels of IL-8 peak relatively late, after those of TNF-alpha and IL-1 beta, and simultaneously with those of IL-6. IL-8 has been primarily defined as a selective activator and chemoattractant of neutrophils, and we demonstrate that after LPS or IL-1 alpha infusion, circulating neutrophil numbers rapidly recover from an initial neutropenia while IL-8 concentrations are maximal, supporting the hypothesis that IL-8 influences circulating leukocyte populations in vivo. We conclude that IL-8 is another participant in the cytokine cascade elicited by sepsis and inflammation and, as such, may play a significant role in host defense and disease.
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PMID:IL-8 in septic shock, endotoxemia, and after IL-1 administration. 202 76

Tumor necrosis factor (TNF) is a peptide secreted by macrophages in response to endotoxin that can produce many of the changes seen in septic shock. After cecal ligation and puncture (CLP) rats gradually develop tachycardia, hypotension, tachypnea, and hypothermia. At 5 h post-CLP, rats have a peak in serum levels of endotoxin and 60% of rats have blood cultures that grow Gram-negative rods (Escherichia coli and Klebsiella pneumonia). At 20 h post-CLP all rats develop positive blood cultures. Serum levels of TNF are not reproducibly measurable in rats following CLP. Rats undergoing CLP have a 50-80% mortality with deaths usually occurring 24-72 h postinjury. Repetitive (twice daily x 6 d) i.p. injection of sublethal doses of recombinant human TNF-alpha (100 micrograms/kg) to rats undergoing CLP 1 d after the treatment period resulted in a significant reduction in mortality compared to control rats previously unexposed to rTNF (P less than 0.03). Animals treated with rTNF had no hypotension or hypothermia after CLP and regained normal food intake faster than control rats. 12 h after CLP the gene expression for manganous superoxide dismutase (MnSOD), an inducible mitochondrial metalloenzyme responsible for cellular resistance to injury from toxic reactive oxygen species, was higher in livers of rats treated with rTNF suggesting that the TNF treatment augmented expression of this protective enzyme. Unlike MnSOD, expression of the gene for copper-zinc SOD was not affected by CLP or rTNF treatment. The results suggest that prior treatment with recombinant TNF can ameliorate the lethality, hypotension, hypothermia, and anorexia of Gram-negative sepsis in rats and that the mechanism may be related to enhanced hepatic expression of the gene for MnSOD. Repeated administration of recombinant TNF may be a strategy to minimize mortality and morbidity of Gram-negative sepsis.
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PMID:Treatment with recombinant human tumor necrosis factor-alpha protects rats against the lethality, hypotension, and hypothermia of gram-negative sepsis. 205 27

Peripheral blood mononuclear cells (PBMC) from patients with severe forms of inherited epidermolysis bullosa (EB) are deficient in functions governing cellular immunity. Very low levels of interferon-gamma (IFN-gamma), interleukin-1 (IL-1), and interleukin-2 (IL-2) were produced in vitro by PBMC from patients with severe forms of EB (recessive dystrophic and dominant dystrophic) as compared to sex- and age-matched controls. Lymphokine production by PBMC from patients with junctional EB was somewhat greater than that from patients with dystrophic forms of EB but was significantly less than that from controls. The production of interferon-alpha was not found to be altered in the severe forms of EB. The PBMC from dystrophic types of EB were also deficient in production of tumor necrosis factors (TNF-alpha and TNF-beta). The degree of the reduction in immune functions was directly related to the severity of skin involvement, with recessive dystrophic EB having the lowest level of cytokine production. This reduced production of monokines and lymphokines may be partially responsible for the progression of cutaneous infections to septicemia and for the metastasis of cutaneous squamous cell carcinomas in patients with severe forms of dystrophic EB.
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PMID:Patients with severe forms of inherited epidermolysis bullosa exhibit decreased lymphokine and monokine production. 212 88

We have determined the plasma concentrations of types 1 and 2 of plasminogen activator inhibitor (PAI-1 and PAI-2), tumor necrosis factor (TNF-alpha) and endotoxin in 47 patients with bacterial infection (22 patients presented with positive blood cultures). Results were compared with those observed in 30 healthy subjects. There was a significant increase in PAI-1 and TNF-alpha in patients as compared to controls (p less than 0.0001), whereas no differences for PAI-2 were observed. PAI-1 and TNF-alpha were significantly higher in 18 patients with gram-negative bacteremia as compared to all other patients (p less than 0.0001). However, no correlation between the analyzed parameters and either endotoxin or clinical outcome was observed. We conclude that there is an increase of PAI-1 and TNF-alpha in patients with sepsis, which is not related to the endotoxin concentration. Our results suggest that PAI-1, but not PAI-2, is the main plasminogen activator inhibitor in human sepsis.
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PMID:Types 1 and 2 plasminogen activator inhibitor and tumor necrosis factor alpha in patients with sepsis. 227 26

Mortality of the septic syndrome is around 40-60% and can rise to 100% if multiple organ failure (MOF) develops. It is generally assumed that the high mortality of sepsis can only be reduced by early diagnosis and prevention of subsequent MOF. The aim of our study was to investigate the validity of routine TNF-alpha determination for the diagnosis of septicemia and, in combination with clinical scoring systems [MOF score and Acute Physiological and Therapeutic Intervention Score (APATIS)], to define a "therapeutic window" during which an anti-TNF-alpha agent could be applied with the greatest chance of success. METHODS. TNF-alpha serum levels were measured and APATIS and MOF scores were calculated daily in 87 ICU patients. TNF-alpha serum levels were determined by means of an immunoradiometric assay (TNF-alpha IRMA, Medgenix, Belgium). Sepsis was diagnosed in 24 patients according to clinical criteria. To quantify the severity of sepsis, we set up the APATIS. The MOF score was used to assess the severity of MOF. Data were analyzed using the SAS software package (SAS Institute, Cary, N.C.) and are expressed as mean +/- SEM. RESULTS. The mean values of all sequential TNF-alpha determinations were significantly higher in the septic patients compared to the nonseptic patients (73.2 +/- 4.3 vs 8.5 +/- 0.4 pg/ml; P less than 0.01). Similarly, the maximum TNF-alpha values were significantly higher in the septic group (156.9 +/- 26.5 vs 20.1 +/- 1.3 pg/ml; P less than 0.01). To differentiate between sepsis and nonsepsis we set the cut-off point at a TNF-alpha serum level of 40 pg/ml and calculated a sensitivity of 70.8%, a specificity of 98%, and a diagnostic accuracy of 91.3%. None of the patients with a maximum TNF-alpha level above 250 pg/ml survived. Mortality was 80% above a maximum TNF-alpha serum concentration of 200 pg/ml, whereas only 40% of patients with a TNF-alpha maximum below 150 pg/ml died. The mean APATIS and MOF scores were significantly higher for septic than for nonseptic patients (APATIS: 20.3 +/- 0.5 vs 8.1 +/- 0.2 and MOF: 9.8 +/- 0.1 vs 4.6 +/- 0.1). To differentiate between survival and nonsurvival, we set the cut-off point at 25 for APATIS and calculated a sensitivity of 79% and a specificity of 93%. At a MOF score of 8, the sensitivity was 89% and the specificity 82%. In our series cumulative mortality at a maximum MOF of less than 8 was 4% and at MOF greater than 10, 68%. We found an interval of 2.9 +/- 0.9 days between the time TNF-alpha serum levels first exceeded 40 pg/ml and the development of severe MOF (MOF greater than 10) in 13 patients. CONCLUSION. Sequential TNF-alpha serum level determinations are useful for the diagnosis and prognosis of septicemia. We found an interval of 3 days between rising TNF-alpha serum levels and the development of severe MOF. This latency may represent the "therapeutic window" during which an anti-TNF-alpha-agent, e.g., a monoclonal anti-TNF-alpha-antibody, could be applied as a therapeutic consequence.
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PMID:[Is TNF-alpha "ripe" for routine diagnosis in sepsis?]. 227 76

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