Tumour necrosis factor-alpha: its role in the metabolic response to sepsis.
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Energy Metabolism↗
Biomedical subjects
T van der Poll
Publications and source records attributed to T van der Poll.
Endotoxin and tumor necrosis factor-alpha-induced interleukin-8 release in humans.
Neutrophil recruitment and activation are thought to play an important role in tissue damage observed in septicemia. Interleukin-8 (IL-8) is a small cytokine with important neutrophil-activating and chemoattractant properties. IL-8 release was studied after injection of human volunteers with low doses of either endotoxin (2 ng/kg of body weight) or tumor necrosis factor-alpha (TNF alpha) (50 micrograms/m2). After TNF-alpha injection, IL-8 appeared at 30 min, whereas increased levels were first observed after 90 min in endotoxin-challenged volunteers. Peak levels were measured at 120 min after both endotoxin (192 +/- 193 ng/L) and TNF alpha (500 +/- 236 ng/L) injection. These data indicate that IL-8 is released in humans after injection of endotoxin and TNF alpha and suggest that endotoxin-induced IL-8 release is mediated by TNF alpha.
Adult↗
Release of soluble receptors for tumor necrosis factor in clinical sepsis and experimental endotoxemia.
To assess the role of tumor necrosis factor (TNF) in the appearance of soluble TNF receptors (sTNFRs), 20 consecutive patients with a clinical diagnosis of sepsis were studied as were 7 chimpanzees after administration of endotoxin (4 ng/kg) with or without pentoxifylline. The patients had markedly elevated serum levels of sTNFR-p55 and sTNFR-p75 compared with healthy controls (P < .0001 for both receptors). The levels of both soluble receptors correlated with simultaneously measured immunoreactive TNF concentrations (p55: r = .63, P < .01; p75: r = .69, P < .001). In the chimpanzees, endotoxin induced subsequent rises in the serum concentrations of TNF and sTNFRs. Although pentoxifylline reduced the TNF response to intravenous endotoxin to 20% (P < .05), the appearance of sTNFRs was only moderately inhibited (sTNFR-p55 to 79% on average, P < .05; sTNFR-p75 to 77%, P = .12). These results indicate that TNF either does not play an important role in the appearance of sTNFRs in systemic infection or that a small amount of TNF remaining in the circulation after some bacterial challenges is sufficient to preserve the secretion of its soluble receptors.
Adult↗
Soluble receptors for tumour necrosis factor: a putative marker of disease progression in HIV infection.
OBJECTIVE: To assess the value of concentrations of soluble receptors for tumour necrosis factor (sTNFR) as markers for disease progression in HIV infection. DESIGN: We measured concentrations of sTNFR in the serum of 32 HIV-infected male patients in various stages of disease and in 12 healthy male control subjects. Correlations between the levels of sTNFR and CD4+ lymphocyte counts were calculated. RESULTS: Serum levels of sTNFR p55 and p75 were elevated in parallel with severity of clinical stage. sTNFR p55 levels were higher at later stages of HIV infection (Centers for Disease Control stage IV) with or without concurrent illness, whereas sTNFR p75 was already elevated in asymptomatic carriers, compared with controls. There was an inverse correlation between sTNFR concentrations and CD4+ lymphocyte counts. CONCLUSIONS: Our results suggest that sTNFR concentrations could be potential markers for disease progression in HIV infection.
Acquired Immunodeficiency Syndrome↗
Tumor necrosis factor induces von Willebrand factor release in healthy humans.
Tumor necrosis factor (TNF) is an important mediator of the host responses to systemic infection. To investigate the effect of TNF on the release of von Willebrand factor (vWF) into the circulation, we performed a controlled study in six healthy men, sequentially measuring the plasma concentrations of vWF antigen after a bolus intravenous injection of recombinant human TNF (50 micrograms/m2). TNF induced a marked increase in vWF antigen plasma levels, becoming significant after 45 min and peaking after 4 h (percentage increase from base line: 351 +/- 46; p less than 0.0001, TNF versus saline). The multimeric organization of circulating vWF was not affected by TNF. We conclude that TNF may be an early mediator of increased vWF secretion in systemic infection.
Adult↗
Effects on leukocytes after injection of tumor necrosis factor into healthy humans.
Tumor necrosis factor (TNF) has been implicated as a proximal mediator of the septic syndrome. To evaluate the possible role of TNF in leukocyte activation in septicemia, we performed a cross-over saline-controlled study in six healthy men who were intravenously injected with recombinant human TNF (50 micrograms/m2), and analyzed changes in circulating white blood cells and parameters for neutrophil and monocyte activation. TNF elicited a very rapid neutropenia, reaching a nadir after 15 minutes, followed by a neutrophilia. Lymphocytes showed a sustained decrease, whereas monocytes declined transiently. TNF injection was also associated with neutrophil activation, as reflected by a mean fivefold increase in the plasma concentrations of elastase-alpha 1-antitrypsin complexes and a mean sevenfold increase in plasma lactoferrin levels. Serum neopterin, a marker of monocyte activation, was significantly increased 24 hours after the administration of TNF. These changes occurred in the absence of detectable complement activation, as indicated by unchanged C3a-desarg plasma values. Serum interleukin-6 showed a nearly 40-fold increase after TNF injection, whereas interleukin-1 remained undetectable throughout. We conclude that the systemic release of TNF, triggered early after invasive infection, may be involved in the alterations in circulating leukocyte numbers and in the activation of leukocytes, during the development of the septic syndrome.
Adult↗
Fibrinolytic response to tumor necrosis factor in healthy subjects.
Tumor necrosis factor (TNF) may be involved in the disturbance of the procoagulant-fibrinolytic balance in septicemia, leading to microvascular thrombosis. To assess the dynamics of the fibrinolytic response to TNF in humans, we performed a crossover saline-controlled study in six healthy men, investigating the effects of a bolus intravenous injection of recombinant human TNF (50 micrograms/m2) on the stimulation and inhibition of plasminogen activation as well as on plasmin activity and inhibition. TNF induced a brief fourfold increase in the overall plasma plasminogen activator (PA) activity peaking after 1 h (p less than 0.0001), which was associated with rises in the antigenic levels of urokinase-type plasminogen activator (p less than 0.0001) and tissue-type plasminogen activator (p less than 0.0001). Plasminogen activator inhibitor type I antigen remained unchanged in the first hour, but showed a rapid eightfold increase thereafter (p less than 0.0001), which coincided with the decrease in PA activity. Generation of plasmin activity in the first hour was signified by an 11-fold rise in D-dimer levels (p less than 0.0001); inhibition of plasmin was reflected by a 36-fold rise in plasmin-alpha 2 antiplasmin complexes (p less than 0.0001), as well as by a transient 16% decrease in alpha 2-antiplasmin activity (p less than 0.01). In conclusion, TNF induced an early activation of the fibrinolytic system becoming maximal in 1 h, with a rapid inhibition thereafter. Earlier observations in the same subjects showed sustained coagulation activation for 6-12 h. The observed disbalance between the procoagulant and fibrinolytic mechanisms after TNF injection confirms the in vivo relevance of the effects of TNF on vascular endothelium in vitro and may explain the tendency towards microvascular thrombosis in septicemia.
Adult↗
Comparison of the early dynamics of systemic prostacyclin release after administration of tumor necrosis factor and endotoxin to healthy humans.
Excessive production of prostaglandins may be of importance for the development of organ damage in generalized infection. To investigate the role of tumor necrosis factor (TNF) in systemic prostacyclin release in gram-negative septicemia, the plasma concentrations of its stable metabolite 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) were sequentially measured after intravenous bolus injections of recombinant human TNF (50 micrograms/m2; n = 6) and Escherichia coli endotoxin (2 ng/kg; n = 3) in healthy men. TNF induced a rapid increase in plasma 6-keto-PGF1 alpha from 0.11 +/- 0.01 to 0.44 +/- 0.15 ng/ml after 30 min (P less than .001). Endotoxin also elicited a rise in plasma 6-keto-PGF1 alpha, but peak values were reached only after 90 min (from 0.07 +/- 0.01 to 0.19 +/- 0.04 ng/ml; P less than .002). These results indicate that TNF may serve as an intermediate factor in systemic elaboration of prostacyclin in endotoxemia and gram-negative septicemia.
6-Ketoprostaglandin F1 alpha↗
Comparison of the early dynamics of coagulation activation after injection of endotoxin and tumor necrosis factor in healthy humans.
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Adult↗
Activation of coagulation after administration of tumor necrosis factor to normal subjects.
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.
Adult↗
Tumor necrosis factor: a putative mediator of the sick euthyroid syndrome in man.
Tumor necrosis factor-alpha (TNF) is believed to be an important mediator in many diseases that are associated with the sick euthyroid syndrome. To investigate the effect of TNF on thyroid hormone metabolism, we performed a controlled study in six healthy postabsorptive males, in whom plasma thyroid hormones and TSH were sequentially measured after iv bolus injections of recombinant human TNF (50 micrograms/m2) and isotonic saline. During the 10.5-h study TNF produced the characteristic changes in circulating thyroid hormones and TSH observed in the sick euthyroid syndrome. Compared with the control experiment, TNF induced significant decreases in T3 (-36 +/- 2%; saline, -20 +/- 3%; P less than 0.05) and TSH levels (-68 +/- 3%; saline, -44 +/- 8%; P less than 0.05) and a significant increase in rT3 values (+48 +/- 11%; saline, -12 +/- 7%; P less than 0.05). T4 and free T4 index were not affected by TNF. Free T4 showed a mean transient increase of 18% in five subjects (nonsignificant), which occurred synchronically with a transient 3.5-fold rise in circulating FFA levels. Our results suggest that TNF is involved, either directly or indirectly, in the pathogenesis of the sick euthyroid syndrome.
Adult↗
Low levels of specific T cell activation marker CD27 accompanied by elevated levels of markers for non-specific immune activation in the cerebrospinal fluid of patients with AIDS dementia complex.
Concentrations of soluble receptors for tumor necrosis factor (sTNFR-p55 and sTNFR-p75) and soluble T cell antigens CD25 and CD27 (sCD25 and sCD27) were measured in paired serum/cerebrospinal fluid (CSF) samples of 15 patients with AIDS dementia complex (ADC) and 15 HIV-infected control subjects (11 with other central nervous system (CNS) infections and four without CNS infection). In this study levels of sTNFR-p55, sTNFR-p75 and sCD25 were elevated in the CSF of ADC patients and of the 11 patients with other CNS infections, whereas CSF-levels of the specific T cell marker sCD27 were lower in patients with ADC as compared to the control subjects with and without other CNS infections. This pattern suggests a relative failure of eliciting a T cell-mediated immune response intrathecally in patients with ADC.
AIDS Dementia Complex↗