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)

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

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

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

The role of tumor necrosis factor (TNF-alpha) in the pathogenesis of septic shock has been assessed by daily measurements of serum TNF-alpha levels in 60 patients admitted to the medical intensive care unit. All patients in the study had infectious disease and were at risk for the development of sepsis and septic shock. Sepsis was diagnosed in 34 patients, 24 of whom died (six within the first 24 hours). The 26 patients who did not evolve toward sepsis served as a control group. The clinical condition of all patients was monitored by daily APACHE II scoring. Blood was drawn once a day and additional samples were taken in patients whose clinical condition underwent sudden deterioration. TNF-alpha levels were measured with a commercially available immunoradiometric assay. At time of patient admission, TNF-alpha levels were higher in the group with sepsis than in the control group (median 79 iqr 329 vs median 0.5 iqr 5; p less than 0.001). In the group with sepsis, extremely high TNF-alpha levels were found in patients who died within 24 hours. These patients had TNF-alpha levels of 917 iqr 755 pg/ml, whereas the patients who died more than 24 hours after admission had TNF-alpha levels of 58 iqr 59 pg/ml. Survivors had lower TNF-alpha levels (26 iqr 347 pg/ml). APACHE II scores correlated with TNF-alpha levels in the total sepsis group (Spearman rank correlation coefficient 0.477; p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Serum tumor necrosis factor levels in patients with infectious disease and septic shock. 237 91

Glucose utilization of different tissues was investigated in vivo by the 2-deoxyglucose tracer technique. After infusion of a non-lethal dose of recombinant human TNF-alpha (150 micrograms/kg) to rats, glucose utilization was increased by 80-100% in spleen, liver, kidney, by 60% in skin and by 30-40% in lung and ileum. The largest increase (150%) was observed in the diaphragm. There was no significant change in glucose utilization by skeletal muscles, testis and brain. These data show that TNF exerts metabolic effects on macrophage-rich tissues, and suggest that enhanced secretion of TNF may be one of the important factors in eliciting the metabolic changes in sepsis and endotoxicosis.
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PMID:Tumor necrosis factor increases in vivo glucose utilization of macrophage-rich tissues. 368 7

Cytokine-inducible nitric oxide (NO) production has been implicated in the pathogenesis of septic shock. The present study was designed to determine which cytokines induce expression of the NO synthase gene in rat aortic vascular smooth muscle cells (VSMC) in vitro and whether NO synthase gene expression is inducible in vivo. NO synthase mRNA appeared after 4-h exposure to interleukin-1 beta (IL-1 beta), and levels continued to increase up to 24 h. Levels of NO synthase transcripts were greatest in VSMC treated with IL-1 beta (1 nM), lower in VSMC treated with Escherichia coli lipopolysaccharide (LPS; 100 micrograms/ml), and just detectable in VSMC treated with tumor necrosis factor-alpha (TNF-alpha; 1 nM). IL-1 beta, TNF-alpha, and LPS each induced NO synthase activity, assessed by release of nitrite, conversion of L-arginine to L-citrulline, and increased levels of guanosine 3',5'-cyclic monophosphate, whereas IL-2, IL-6, and interferon-gamma were ineffective. IL-1 beta was more potent and effective than TNF-alpha; however, submaximal concentrations of TNF-alpha acted synergistically with IL-1 beta to induce NO synthase gene expression and activity. Inducible NO synthase mRNA was present in aorta from rats 6 h after treatment with LPS (5 mg/kg), but not at 24 h. Synergistic activation of NO synthase gene expression in VSMC by IL-1 beta and TNF-alpha may contribute to hypotension in sepsis.
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PMID:Interleukin-1 beta and tumor necrosis factor-alpha synergistically induce NO synthase in rat vascular smooth muscle cells. 751 63


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