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)

Tumor necrosis factor (TNF) mRNA was detected by Northern blotting in whole-organ homogenates of the spleen, liver, kidney, lung, and small bowel in naive and saline-injected control rats, supporting the hypothesis that TNF mRNA is present in vivo in a preformed intracellular pool. TNF mRNA in endotoxin-treated rats as quantitated by densitometry of the ratio of TNF mRNA to actin mRNA in Northern blots was present in increased quantity in the liver, kidney, and lung (1.6-2.9 times over time zero levels) at 15 minutes and increased quantity in the spleen, liver, and kidney (1.3-1.9 times over time zero levels) at 30 minutes. The kinetics of endotoxin-induced TNF gene expression are consistent with the relatively transient peak of serum TNF protein levels reported by previous investigators to occur approximately 1 hour after injection of endotoxin. Because TNF mRNA appeared ubiquitous in the organs of control rats examined and because the endotoxin-induced increase in TNF mRNA was relatively small, endotoxin may induce the expression of the TNF protein in serum not only by increasing TNF mRNA levels but perhaps more importantly by a posttranscriptional mechanism. The presence of a preformed pool of TNF mRNA may teleologically be viewed as a mechanism to increase the rapidity of the host's response to sepsis.
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PMID:Endotoxin-induced cytokine gene expression in vivo. I. Expression of tumor necrosis factor mRNA in visceral organs under physiologic conditions and during endotoxemia. 264 83

Tumor necrosis factor (TNF) is a macrophage product released in response to endotoxin that has been implicated as a cause of the toxicity and lethality seen in septic shock. Previous work suggests that tolerance to nutritional and lethal effects of TNF occur after repeated exposure to recombinant tumor necrosis factor (rTNF). In this study pretreatment of rats with a single low intravenous dose of rTNF prevented subsequent death when a lethal dose of rTNF was administered 24 hours later (tolerance or tachyphylaxis). Pretreatment with rTNF also afforded protection against the lethal effects of either endotoxin or cecal ligation and puncture when rats were challenged 24 hours later. Recombinant TNF injected 6 hours after cecal ligation and puncture initially resulted in a significant survival advantage for treated animals. When this experiment was repeated with a different lot of rTNF, however, the therapeutic benefit of rTNF was not obtained until the dose was decreased by a factor of 10. Protection against the lethal effects of cecal ligation and puncture did not occur when rTNF was given 24 hours after the insult. A single low dose of rTNF can result in tolerance or tachyphylaxis to the lethal effects of TNF. The results suggest that the early administration of low-dose rTNF may be useful in the prevention and treatment of the lethality of sepsis.
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PMID:Prevention and treatment of endotoxin and sepsis lethality with recombinant human tumor necrosis factor. 266 93

Tumor necrosis factor (TNF) cachectin has been implicated as an important host mediator responsible for shock and multiple organ failure (MOF) observed during sepsis. Using a sensitive enzyme-linked immunosorbent assay, we measured plasma TNF levels in 43 septic patients suffering from a broad range of diseases. Measurements were taken on the day that sepsis was diagnosed. Eleven patients had detectable TNF plasma levels ranging from 10 to 100 pg/ml (TNF-positive group); in 32 patients circulating TNF could not be detected (TNF-negative group). The groups did not differ significantly as to age, underlying disease, percentage positive bacteremia and bacteriologic profile, sepsis score, and extent of MOF. Eight (73%) of 11 TNF-positive patients died from sepsis during ICU stay, vs. 11 (34%) of 32 TNF-negative patients (p less than .05). This study demonstrates that sepsis is accompanied by detectable circulating TNF in 25% of the cases, and for these patients mortality is twice that for comparable TNF-negative patients.
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PMID:Plasma tumor necrosis factor and mortality in critically ill septic patients. 272 Dec 8

Using an enzyme-linked immunosorbent assay, we measured plasma levels of tumor necrosis factor (TNF) in 38 patients who were treated with either antilipid A antibody or a placebo for presumed gram-negative bacteremia. Sixteen of the 38 patients had positive blood cultures: 14 with gram-negative rods and 2 with Streptococcus pneumoniae. Initial serum samples for TNF determinations were obtained within 2 to 72 hours (mean, 18.8 hours) after the onset of clinical signs of sepsis. Six (16%) of 38 patients had detectable TNF levels: 4 of 14 with positive blood cultures for gram-negative rods but only 2 of 22 with negative blood cultures (odds ratio, 4; 95% confidence limits, 0.5 and 24.3). Of the 6 patients, 4 had received the placebo and 2 had received the antibody. Tumor necrosis factor levels did not predict adult respiratory distress syndrome, shock, disseminated intravascular coagulation, renal failure, or mortality. The highest TNF levels (500 and 250 pg/mL) were observed in 2 patients with Enterobacter cloacae bacteremia who had received the placebo and antilipid A antibody, respectively. The other 2 patients with bacteremia and detectable TNF levels had positive blood cultures for Haemophilus influenzae (50 pg/mL) and Bacteroides fragilis (120 pg/mL), respectively. Despite negative blood cultures, the remaining 2 patients repeatedly had detectable TNF levels and a clinical picture consistent with gram-negative sepsis.
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PMID:Plasma tumor necrosis factor levels in patients with presumed sepsis. Results in those treated with antilipid A antibody vs placebo. 230 78

Tumor necrosis factor/cachectin (TNF) is a mediator of the septic shock state, which can modulate hemostatic properties of the vessel wall. The interaction of TNF with endothelium is not cytotoxic, rather it is receptor mediated and results in a change in receptor expression on the endothelial cell surface, enabling endothelium to actively promote coagulation. Anticoagulant mechanisms, including the protein C/protein S system and fibrinolysis are suppressed, whereas the initiation and propagation of procoagulant activity is enhanced. This unidirectional shift in vessel wall coagulant activity favoring clot formation could contribute to the coagulopathy associated with sepsis and indicates a mechanism through which the coagulation system serves as an integral part of the host response.
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PMID:Tumor necrosis factor/cachectin-induced modulation of endothelial cell hemostatic properties. 282

Tumor necrosis factor (TNF) has been implicated in the toxic manifestations of overwhelming bacterial infection and in the tissue wasting that often accompanies prolonged infections and malignancy. We have examined a possible role of TNF in the early metabolic alterations following acute tissue injury or sepsis. Recombinant human TNF stimulated rat liver amino acid uptake up to 5-fold in vivo and there was a concomitant increase in plasma glucagon. In vitro TNF had no direct effect on hepatocyte amino acid uptake, but it markedly enhanced the stimulation of amino acid transport by glucagon, without an alteration in binding of glucagon to hepatocytes. This permissive effect of TNF on glucagon action represents an interrelationship between the immune and endocrine systems, and it may help to explain the mechanism of hormonal regulation of both the anabolic and catabolic responses to acute injury.
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PMID:Modulation of endogenous hormone action by recombinant human tumor necrosis factor. 282 98

Tumor necrosis factor (TNF) is a macrophage-derived peptide mediator released during endotoxemia and sepsis. We examined the systemic and visceral hemodynamic response to low doses of human recombinant TNF in rats. Each animal received a 30-minute intravenous infusion of either saline solution (n = 8) or TNF (n = 8) in a dose of 0.25 mg/kg or 1.0 mg/kg. Thermodilution cardiac output, blood pressure, pulse, vascular resistance, effective hepatic blood flow (galactose clearance), and effective renal plasma flow (p-aminohippurate clearance) were determined at time = 2 hours. The 0.25-mg/kg dose had no apparent effect on systemic hemodynamics. The 1.0-mg/kg dose produced a hyperdynamic systemic circulatory response with an elevated cardiac output, tachycardia, and a diminished systemic vascular resistance. Effective hepatic blood flow was exquisitely sensitive to even the lowest dose of TNF, with a 29% reduction despite the normal cardiac output. Renal flow was unaffected by either dose. Tumor necrosis factor-induced systemic and visceral hemodynamic changes are remarkably similar to those seen in gram-negative sepsis, suggesting that TNF may occupy a proximal position in the pathogenesis of overwhelming infection.
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PMID:Recombinant human tumor necrosis factor produces hemodynamic changes characteristic of sepsis and endotoxemia. 293 Mar 53

Tumor necrosis factor/cachectin (TNF) has been implicated as a mediator of the host response in sepsis and neoplasia. Recent work has shown that TNF can modulate endothelial cell hemostatic properties, suggesting that endothelium is a target tissue for TNF. This led us to examine whether endothelial cells have specific binding sites for TNF and augment the biological response to TNF by elaborating the inflammatory mediator, IL-1. Incubation of 125I-recombinant human TNF with confluent, cultured human umbilical vein endothelial cells resulted in time-dependent, reversible, and saturable binding. Binding was half-maximal at a TNF concentration of 105 +/- 40 pM, and at saturation 1,500 molecules were bound per cell. Heat-treated TNF, which is biologically inactive, did not bind to endothelium. In addition to surface binding, TNF induced the elaboration of IL-1 activity by endothelial cells in a time-dependent manner. Generation of IL-1 activity required protein synthesis and was half-maximal at a TNF concentration of 50 +/- 20 pM. IL-1 activity from TNF-treated endothelium could be adsorbed by an immobilized antibody to IL-1. Heat-treated TNF was ineffective in eliciting endothelial cell IL-1. These data indicate that TNF can bind specifically to endothelium and initiate a cascade of inflammatory and coagulant events on the vessel surface potentially central to the host response to neoplasia and sepsis.
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PMID:Tumor necrosis factor/cachectin interacts with endothelial cell receptors to induce release of interleukin 1. 301 46

Tumor necrosis factor (TNF; cachectin) has been implicated as a mediator of the toxic manifestations of overwhelming bacterial infection as well as the chronic catabolic state of cancer cachexia. We have examined the acute metabolic and hormonal response after administration of recombinant human TNF in the rat. TNF given by intraperitoneal injection produced dose- and time-related increases in hepatic amino acid uptake, decreases in serum trace metal concentrations, and a pattern of endocrine hormone alterations characteristic of the acute phase response to tissue injury. In vitro zinc transport studies by rat hepatocytes cultured in the presence of TNF alone, or in combination with recombinant human interleukin 1, another mediator of the acute phase response, demonstrated that neither monokine was capable of directly stimulating zinc transport into cells. These findings suggest that TNF may function as an endogenous mediator of the early metabolic response to sepsis and that the trace metal changes induced by TNF in vivo may occur through a secondary mechanism.
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PMID:Hormonal and metabolic response to recombinant human tumor necrosis factor in rat: in vitro and in vivo. 304 39

Tumor necrosis factor (TNF), a macrophage secretory protein produced by peripheral blood monocytes from patients with cancer, has been shown to possess cytotoxicity toward tumor cells in vitro. TNF in the blood of individuals with cancer is usually not detectable except with extremely sensitive radioimmunoassay or enzyme-linked immunosorbent assay (ELISA) methods. We have encountered two patients with the rare syndrome of extensive bone marrow necrosis in association with cancer. The first patient presented with marrow failure secondary to necrosis and was found to have adenocarcinoma in thoracic lymph nodes, lung, and marrow lymphatics at autopsy. Plasma tested at two dilutions (1:200 and 1:2,000) contained TNF at a concentration of 8.3 ng/ml, or 80 U/ml by a cytotoxicity assay using LM cells. The presence of TNF was confirmed with immunoblotting. The second patient had a poorly differentiated lymphoid tumor involving bone marrow, pancytopenia, and marrow necrosis. The plasma cytotoxicity assay indicated the presence of 0.7 ng/ml or 7 U/ml TNF. TNF was not detectable in plasma from six other patients with untreated cancer involving bone or bone marrow using either of our methods. The levels of TNF in the two patients with marrow necrosis were greater than those previously measured by others in patients with cancer but were comparable to those noted in patients with lethal sepsis. Since large doses of TNF have been shown to cause organ necrosis in animals, the data presented here are consistent with TNF involvement in mediating the observed marrow necrosis in our patients.
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PMID:Extensive bone marrow necrosis in patients with cancer and tumor necrosis factor activity in plasma. 318 18


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