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S J van Deventer

Publications and source records attributed to S J van Deventer.

At least 19 recordsLinked to original sources
PubMed1992

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↗
PubMed1992

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↗
PubMed1992

Effectiveness of a human monoclonal anti-endotoxin antibody (HA-1A) in gram-negative sepsis: relationship to endotoxin and cytokine levels.

Gram-negative sepsis is caused by endotoxin-induced release of tumor necrosis factor (TNF) and other cytokines. HA-1A is a human monoclonal antibody that binds specifically to endotoxin. HA-1A should prevent death in endotoxemic patients and reduce serum levels of TNF and interleukin-6 (IL-6). This hypothesis was tested in 82 septic patients who were randomly allocated to receive a single intravenous 100-mg dose of HA-1A or placebo. Pretreatment endotoxemia was detected in 27 patients (33%). Death occurred within 28 days of treatment in 8 (73%) of 11 placebo recipients and in 5 (31%) of 16 HA-1A recipients (P = .02). The median decrease in serum TNF level 24 h after treatment was 12 ng/L in patients given HA-1A and 0 ng/L in placebo recipients (n = 65; P = .04). For IL-6, this was 204 ng/L in patients given HA-1A and 44 ng/L in placebo recipients (n = 67; P = .4). Thus, HA-1A reduces mortality in septic patients with endotoxemia and lowers serum TNF levels.

Adult↗
PubMed1992

CD4 antibody treatment in Crohn's disease.

Immunologic changes may play a role in the pathogenesis of Crohn's disease. Whether these changes are the primary cause of the disease or secondary to the inflammatory response remains unknown. Activated T helper cells probably play a pivotal role in Crohn's disease, although no causative antigen has been identified. Possible targets for immunomodulating therapy should include neutralization of the antigens, deletion of reactive activated T cells or, less specifically, interference with the antigen-presenting process. New, humanized, monoclonal antibodies that interfere with the antigen-presenting process are now available for clinical investigation. In particular, CD4 antibody treatment seems of interest, in view of the predominant role of T cells in Crohn's disease. Finally, because tumor necrosis factor is necessary for granuloma formation, inhibition of this factor may be expected to improve disease activity in Crohn's disease.

Antibodies, Monoclonal↗
PubMed1991

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↗
PubMed1991

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↗
PubMed1991

Interleukin 1 beta is expressed predominantly by enterocytes in experimental colitis.

The cytokine interleukin 1 beta is an important mediator of inflammatory processes capable of inducing eicosanoid production, T-cell activation, and increased vascular permeability. In this study, in situ hybridization techniques were used to delineate the kinetics and cellular source of induced interleukin 1 beta in acute experimental colitis. The induction of interleukin 1 beta messenger RNA was an early phenomenon and occurred predominantly in undifferentiated cells located in the basal part of the mucosal crypts but not in differentiated enterocytes. The undifferentiated enterocytes retained the messenger RNA during differentiation and migration to more apical parts of the crypts. These results suggest that induction of interleukin 1 beta messenger RNA in enterocytes is causally related to the subsequent inflammatory changes seen in acute experimental colitis.

Animals↗
PubMed1990

Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways.

Endotoxemia was evoked by bolus injection of Escherichia coli endotoxin (2 ng/kg body weight) in six healthy subjects to investigate the early kinetics of cytokine release in relation to the development of clinical and hematologic abnormalities frequently seen in gram-negative septicemia. The plasma concentration of tumor necrosis factor (TNF) increased markedly after 30 to 45 minutes, and reached a maximal level after 60 to 90 minutes. In each volunteer, the initial increase of plasma interleukin 6 (IL-6) concentrations occurred 15 minutes after the initial TNF increase, and maximal IL-6 concentrations were reached at 120 to 150 minutes. A transient increase in body temperature and pulse rate occurred simultaneously with the initial TNF and IL-6 increases, whereas a significant decrease in blood pressure occurred after 120 minutes. These changes were proportional to the changes in TNF and IL-6 concentrations. Coagulation activation, as assessed by a rise of prothrombin fragments and thrombin-antithrombin III complexes, was noted after 120 minutes, in the absence of activation of the contact system. A two- to sixfold increase in the concentrations of tissue plasminogen activator (t-PA) and von Willebrand factor antigen indicated endothelial cell activation. This increase started at 120 and 90 minutes, respectively. The release of t-PA coincided with activation of the fibrinolytic pathway, as measured by plasmin-alpha 2-antiplasmin complexes. The fibrinolytic activity of t-PA was subsequently offset by release of plasminogen activator inhibitor, observed 150 minutes after the endotoxin injection, and reaching a peak at 240 minutes. No complement activation was detected. These results show that in humans endotoxin induces an early, rapidly counteracted fibrinolytic response, and a more long-lasting activation of thrombin by a mechanism other than contact system activation. In addition, our data suggest that endotoxin-induced leukopenia and endothelial cell activation are mediated by TNF.

Adult↗
PubMed1990

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↗
PubMed1990

Detection and clinical relevance of human endotoxemia.

An optimized chromogenic assay for the detection of endotoxins in human blood is described. The assay comprises the removal of the inhibitory activity of plasma components by a dilution plus heating procedure, endotoxin-dependent activation of Limulus amebocyte lysate, and chromogenic measurement of the activated lysate. The assay has a detection limit of 3 ng endotoxin/L plasma. At the 10 ng/L level within-assay CV and between-assay CV of 14 and 21% were obtained respectively. In a prospective clinical trial including 473 consecutive febrile patients the assay has previously been demonstrated to have positive and negative predictive values of 48% and 99% for impending Gram-negative sepsis, respectively. In a similar study in 76 consecutive patients with Gram-negative infection of the urinary tract, these values were 73% and 95%, respectively. We conclude that this assay may provide the means to select those patients who are most likely to benefit from anti-endotoxin treatment. To facilitate endotoxin testing in other laboratories, a preliminary evaluation of a commercial endotoxin assay versus our own method was performed with 108 duplicate blood samples obtained from septic patients. With this assay detection limits of 2-3 ng endotoxin/L plasma could be obtained, as well as a good correlation (r = 0.94) and level of consensus to establish endotoxemia (93%) as compared to the house method. The commercial assay may therefore facilitate the introduction of endotoxin testing in other laboratories.

Bacterial Infections↗