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)

Group B streptococcus (GBS), a common neonatal gram-positive pathogen, causes similar pathophysiologic features in human newborns and neonatal animal models of sepsis. Previous reports suggest that mediators in addition to TxA2 and PGI2 contribute to the late effects of GBS infusion (2 to 4 h), which include persistent increases in Ppa, hypoxemia, systemic hypotension, and a progressive fall in CO. Tumor necrosis factor (TNF) infusion in animals produces several of the late GBS effects. We hypothesized that GBS causes increased serum TNF levels 2 to 4 h into infusion in neonatal piglets. We also postulated that the TNF inhibitor, pentoxifylline (PTF), would attenuate both GBS-induced TNF production and late GBS effects. In piglets infused with 1.25 x 10(9) cfu/kg/h of GBS, serum TNF levels (pg/ml, ELISA assay) significantly increased at 2 h (231 +/- 41) and at 4 h (1,047 +/- 290, n = 9). In piglets infused with concomitant GBS + PTF, serum TNF levels at 4 h (208 +/- 39, n = 8) were reduced compared to GBS alone piglets (p less than 0.02). Control piglets infused with 0.9% saline or PTF alone for 4 h had no detectable serum TNF (less than 35). GBS alone and GBS + PTF infusion caused similar increases in serum TxB2 levels at 1, 2, and 4 h. Serum 6-keto-PGF1 alpha levels (pg/0.1 ml) significantly increased at 4 h (85 +/- 18) with GBS alone, and were more elevated at 4 h (306 +/- 75) with GBS + PTF infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Group B streptococcus induces tumor necrosis factor in neonatal piglets. Effect of the tumor necrosis factor inhibitor pentoxifylline on hemodynamics and gas exchange. 200 Oct 73

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

Tumor necrosis factor (TNF) facilitates superoxide production, and spin traps may detoxify superoxide by acting as superoxide dismutase mimics. We investigated the ability of a stable nitroxide spin trap, TEMPOL, to protect TNF-sensitive cells from exogenously added TNF. WEHI or L929 cells were incubated with TNF (500 units/ml) for 18 hr either simultaneously with 0 to 8 mM TEMPOL or with the TEMPOL added at varying intervals after TNF exposure. A dose-dependent increase in survival was noted in the TEMPOL-treated cells, with 92 +/- 2% survival of WEHIs treated with 4 mM TEMPOL compared to 26 +/- 1% survival for non-TEMPOL-exposed cells (P2 less than 0.01). Significant increases in survival could be accomplished with as late as 15-hr delayed addition of the compound. The mechanism of protection does not seem to involve newly synthesized protein, and Northern blot analysis revealed that TEMPOL does not induce the genes for MnSOD or Cu-ZnSOD. The ability of TEMPOL to protect against TNF injury, even when exposure is delayed, may prove useful in conditions thought to be associated with free radical-lymphokine interactions such as ischemia-reperfusion, oxygen toxicity, or sepsis.
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PMID:Spin trap protection from tumor necrosis factor cytotoxicity. 203 86

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

Tumor necrosis factor-alpha (TNF alpha) and interleukin-1 alpha (IL-1 alpha) are pluripotent cytokines mediating the host response to sepsis, injury, and cancer. Animals can be protected from the lethal effects of TNF alpha by repeated administration of sublethal doses, but the mechanism of this effect is not known. Human foreskin fibroblasts (FS4 cells), which rapidly elaborate interleukin-6 (IL-6) when stimulated with TNF alpha or IL-1 alpha, were grown in culture as confluent monolayers and their secretion of IL-6 was quantitated using the murine B9-hybridoma bioassay against an external reference of human recombinant IL-6 (Genetics Institute). When FS4 cells were incubated with human recombinant TNF alpha (50 ng/ml; Cetus) or recombinant IL-1 alpha (30 pg/ml; Genzyme) a rapid increase in IL-6 production was measured over control, rising to IL-6 levels of 71.7 +/- 5.9 units/ml with TNF alpha and 54.0 +/- 1.2 units/ml with IL-1 alpha after 7.5 hr incubation. FS4 cells which were exposed to cytokine, rinsed, and then reexposed to cytokine 24 hr later produced significantly less IL-6 [38.1 +/- 2.8 units/ml with second exposure to TNF alpha (P less than 0.05), and 18.3 +/- 1.9 units/ml with second exposure to IL-1 alpha (P less than 0.01)]. Successive daily exposure to TNF alpha or IL-1 alpha caused a further stepwise diminution of IL-6 secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Decreased IL-6 secretion by fibroblasts following repeated doses of TNF alpha or IL-1 alpha: post-transcriptional gene regulation. 206 55

Tumor necrosis factor (TNF) is a cytokine that mediates many of the metabolic responses after endotoxemia, septicemia, and tissue injury. The effect of TNF on testicular function was determined in a series of studies in which rhTNF (0, 2, and 4 X 10(5) units/kg/24 hours) was administered by continuous infusion to male Wistar rats maintained on total parenteral nutrition adequate for growing rats. Testicular weight and histology, and plasma luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels were determined at 1, 3, and 6 days. Testicular weight decreased within 24 hours and this was associated with a fall in plasma testosterone and increased LH and FSH levels. These changes persisted for 6 days, indicating a loss of testosterone-mediated negative feedback on gonadotropin release. Histologic examination demonstrated significant damage to the germ cells in the adluminal compartment of the seminiferous epithelium; extensive exfoliation of spermatocytes and spermatids occurred at day six. However the primary spermatogonia in the basal compartment were relatively spared. Damage to the seminiferous epithelium at earlier times was noted in some tubules. The decrease in testosterone concentration and increase in gonadotropin levels suggest that TNF interferes with Leydig cell function. Germ cell damage may be a direct effect of TNF on these cells or may occur through secondary mechanisms involving Leydig or Sertoli cell dysfunction.
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PMID:The testicular effects of tumor necrosis factor. 210 22

Tumor necrosis factor has been implicated in the activation of blood coagulation in septicemia, a condition commonly associated with intravascular coagulation and disturbances of hemostasis. To evaluate the early dynamics and the route of the in vivo coagulative response to tumor necrosis factor, we performed a controlled study in six healthy men, monitoring the activation of the common and intrinsic pathways of coagulation with highly sensitive and specific radioimmunoassays. Recombinant human tumor necrosis factor, administered as an intravenous bolus injection (50 micrograms per square meter of body-surface area), induced an early and short-lived rise in circulating levels of the activation peptide of factor X, reaching maximal values after 30 to 45 minutes (mean +/- SEM increase after 45 minutes, 34.2 +/- 18.2 percent; tumor necrosis factor vs. saline, P = 0.015). This was followed by a gradual and prolonged increase in the plasma concentration of the prothrombin fragment F1+2, peaking after four to five hours (mean increase after five hours, 348.0 +/- 144.8 percent; tumor necrosis factor vs. saline, P less than 0.0001). These findings signify the formation of factor Xa (activated factor X) and the activation of prothrombin. Activation of the intrinsic pathway could not be detected by a series of measurements of the plasma levels of factor XII, prekallikrein, factor XIIa-C1 inhibitor complexes, kallikrein-C1 inhibitor complexes, and the activation peptide of factor IX. The delay between the maximal activation of factor X and that of prothrombin amounted to several hours, indicating that neutralization of factor Xa activity was slow. We conclude that a single injection of tumor necrosis factor elicits a rapid and sustained activation of the common pathway of coagulation, probably induced through the extrinsic route. Our results suggest that tumor necrosis factor could play an important part in the early activation of the hemostatic mechanism in septicemia.
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PMID:Activation of coagulation after administration of tumor necrosis factor to normal subjects. 221 25

Tumor necrosis factor (TNF) released by lipopolysaccharide (LPS)-stimulated mononuclear phagocytes is a critical mediator of sepsis. We examined the capacities of rough mutant Salmonella typhimurium LPS (Rc) and LPS partial structures lipid A, monophosphoryl lipid A (MPLA), lipid IVA, and lipid X to induce production of TNF in whole blood. Rc LPS (0.0001-10 ng/ml) produced a dose-dependent release of TNF as determined by cytotoxicity of actinomycin D-sensitized L929 murine fibroblasts. Lipid A, MPLA, lipid IVA, and lipid X exhibited decreasing capacities to stimulate production of TNF in whole blood, respectively. Fractional deacylation of LPS by incubation with acyloxyacyl hydrolase isolated from human leukocytes produced a reduction in the capacity of LPS to induce TNF release in whole blood. Maximal enzymatic deacylation reduced activity of LPS by greater than 100-fold. Coincubation with lipid IVA inhibited TNF release induced by Rc LPS or lipid A, but not by phorbol ester. In contrast, MPLA, lipid X, and deacylated LPS failed to inhibit LPS-stimulated release of TNF. Corresponding to the inhibition of the release of TNF protein, lipid IVA also inhibited the accumulation of TNF mRNA in LPS-stimulated mononuclear cells. These results suggest that lipid IVA may act as a competitive antagonist of LPS, perhaps at the receptor level.
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PMID:Lipid IVA inhibits synthesis and release of tumor necrosis factor induced by lipopolysaccharide in human whole blood ex vivo. 219 1

Tumor necrosis factor, a mononuclear phagocyte-derived peptide produced in response to lipopolysaccharide, has been shown to mediate certain aspects of septic shock and multiple organ failure resulting from gram-negative septicemia. In the present investigation, pretreatment of animals with pentoxifylline inhibited lipopolysaccharide-induced serum tumor necrosis factor in a dose-dependent fashion. Pentoxifylline prevented the sequestration of neutrophils seen in animals given intravenous lipopolysaccharide. Furthermore, pentoxifylline protected animals from the lethal effects of an intravenous challenge with lipopolysaccharide. These data indicate that pentoxifylline inhibits lipopolysaccharide-induced tumor necrosis factor and may be an effective agent in mitigating the lethal consequences of sepsis and other disease processes mediated by this cytokine.
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PMID:Pentoxifylline inhibits lipopolysaccharide-induced serum tumor necrosis factor and mortality. 223 23

Tumor necrosis factor (TNF), a polypeptide produced predominantly by activated macrophages, is an important mediator of sepsis. We analyzed the specific metabolic changes that occur in the gut following TNF administration. Following general anesthesia, hemodynamic and metabolic indices were measured serially in control dogs (n = 7) and animals receiving a continuous sublethal intravenous infusion of TNF (0.57.10(5) IU/kg/6 hours, n = 7). During TNF infusion mean arterial pressure gradually decreased despite fluid administration, which maintained wedge pressure and cardiac index, which were similar to control animals. While TNF significantly reduced intestinal blood flow to 12 +/- 3 mL/min/kg compared to 28 +/- 3 mL/min/kg (p less than 0.01) in controls, intestinal oxygen consumption was maintained due to an increased extraction rate. Despite hypoperfusion the intestinal exchange of metabolic substrate (glucose, lactate, pyruvate, alanine, glutamine, glutamate, and ammonia) was comparable between the control and TNF-infused animals. However, when substrate carbon balance across the intestinal tract was calculated, it appeared that there was a limitation in fuel availability in the TNF animals. This may be due to competition for fuel between the gut and other major organs. Fuel limitation may jeopardize rapid cell proliferation and mucosal repair and with regional hypoperfusion these processes may account for the mucosal ulcerations observed at the termination of the study.
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PMID:The effects of tumor necrosis factor on intestinal structure and metabolism. 225 57


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