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T van der Poll

Publications and source records attributed to T van der Poll.

At least 145 records · Page 8Linked to original sources
PubMed1994

Platelet-activating factor antagonist TCV-309 attenuates the induction of the cytokine network in experimental endotoxemia in chimpanzees.

Platelet-activating factor (PAF) has been postulated to play a role in the pathogenesis of sepsis. Additionally, in vitro studies have revealed tight interactions between PAF and the cytokine network, and PAF is considered to be an important stimulator of neutrophil functions. To assess the intermediate role of PAF in the induction of cytokines and neutrophil degranulation in endotoxemia in vivo, 12 healthy adult chimpanzees were i.v. injected with a bolus dose of Escherichia coli endotoxin (4 ng/kg); four animals received endotoxin alone, whereas the other chimpanzees were infused with the specific and potent PAF antagonist TCV-309 (bolus of 100 micrograms/kg, followed by either 100 micrograms/kg/h (n = 4) or 500 micrograms/kg/h (n = 4) for 5 h). At both doses TCV-309 significantly inhibited the endotoxin-induced rise in cytokine levels. Peak TNF concentrations after injection of endotoxin alone were 366 +/- 96 pg/ml, vs 105 +/- 47 and 115 +/- 56 pg/ml after administration of endotoxin together with the lower or higher dose of TCV-309, respectively (p < 0.05). TCV-309 also reduced the appearance of soluble TNFRs. Maximal levels of the type I soluble TNFR were diminished from 2.53 +/- 0.27 ng/ml (endotoxin alone) to 1.69 +/- 0.36 ng/ml (high dose TCV-309; p < 0.05); peak values of the type II soluble TNFR were diminished from 8.62 +/- 1.19 ng/ml to 5.76 +/- 0.92 ng/ml (p < 0.05). Furthermore, TCV-309 attenuated the endotoxin-induced release of IL-6 (160 +/- 82 pg/ml after endotoxin alone, vs 63 +/- 30 pg/ml in the low dose TCV-309 group (p < 0.05) and 65 +/- 29 pg/ml in the high dose group (p = 0.07) as well as that of IL-8 (279 +/- 168, vs 71 +/- 15 and 46 +/- 17 pg/ml, respectively; both p < 0.05). TCV-309 tended to reduce the endotoxin-provoked rise in serum IL-1R antagonist levels. In contrast, TCV-309 did not affect the neutrophilic leukocytosis elicited by endotoxin, nor did it inhibit endotoxin-induced neutrophil degranulation, as monitored by the plasma levels of elastase-alpha 1-antitrypsin complexes. We conclude that PAF plays a role, either directly or indirectly, in the stimulation of the cytokine network and in the shedding of soluble TNFR in endotoxemia. PAF does not seem to be an important intermediate factor in endotoxin-induced neutrophilia or neutrophil degranulation.

Animals↗
PubMed1994

Differential effects of anti-tumor necrosis factor monoclonal antibodies on systemic inflammatory responses in experimental endotoxemia in chimpanzees.

Tumor necrosis factor (TNF) is considered to be a pivotal mediator of endotoxin-induced lethality. To assess the intermediate role of TNF in specific systemic inflammatory responses known to contribute to tissue injury in endotoxemia, eight healthy adult chimpanzees were intravenously injected with Escherichia coli endotoxin (4 ng/kg). In four of these animals the administration of endotoxin was followed immediately by a bolus intravenous injection of an anti-TNF monoclonal antibody (15 mg/kg). Treatment with anti-TNF completely prevented the endotoxin-induced increase in serum TNF activity, and profoundly reduced the appearance of interleukin-6 and -8 (both P < .05). Neutrophilia and lymphopenia were not affected by anti-TNF, whereas neutrophil degranulation, as measured by the plasma concentrations of elastase-alpha 1-antitrypsin complexes, was only slightly reduced (peak levels after endotoxin alone 31.0 +/- 3.4 ng/mL, versus 25.5 +/- 3.4 ng/mL after endotoxin with anti-TNF; P < .05). Anti-TNF did not influence endotoxin-induced activation of the coagulation system, as reflected by unchanged increases in the plasma concentrations of the prothrombin fragment F1 + 2 and thrombin-antithrombin III complexes. In contrast, anti-TNF strongly attenuated the activation of the fibrinolytic system, ie, peak plasma levels of plasmin-alpha 2-antiplasmin were 33.8 +/- 11.1 nmol/L after endotoxin alone and 17.0 +/- 2.9 nmol/L after endotoxin with anti-TNF (P < .05). These results suggest that TNF is not the common mediator of systemic inflammatory changes in low-grade endotoxemia. Moreover, the finding that in this mild model anti-TNF specifically inhibited fibrinolysis suggests that treatment with anti-TNF potentially may enhance the tendency towards microvascular thrombosis in sepsis.

Animals↗
PubMed1994

Model for whole body production of tumour necrosis factor-alpha in experimental endotoxaemia in healthy subjects.

1. Tumour necrosis factor-alpha is considered an important mediator in the pathophysiology of several diseases. Although much information is available about the serum concentrations of this cytokine in these illnesses, little is known about the production of tumour necrosis factor-alpha in disease in vivo. 2. In the present study we aimed to estimate the extent and the kinetics of whole body tumour necrosis factor-alpha synthesis in experimental endotoxaemia in six healthy humans. For this purpose we first examined the pharmacokinetic behaviour of an intravenously injected bolus of recombinant human tumour necrosis factor-alpha (50 micrograms/m2) in another group of six normal subjects. We then calculated the total amount of tumour necrosis factor-alpha produced after intravenous injection of endotoxin (2 ng/kg) as the product of the systemic clearance of recombinant human tumour necrosis factor-alpha (9.5 +/- 5.0 ml min-1 kg-1) and the area under the tumour necrosis factor-alpha concentration-time curves in the endotoxaemic subjects. 3. Recombinant human tumour necrosis factor-alpha showed evident two-compartment kinetics with an initial rapid disappearance (t1/2 5.1 +/- 2.2 min) and a terminal slower elimination (t1/2 49 +/- 5 min). Tumour necrosis factor-alpha synthesis after endotoxin varied markedly between individuals, ranging from 11.8 to 114.1 micrograms (52.7 +/- 34.7 micrograms). The changes in time of the serum concentrations of tumour necrosis factor-alpha after administration of endotoxin could be accurately described with an adapted two-compartment open model that incorporated both rapid tumour necrosis factor-alpha production (74% of the total amount) and slow tumour necrosis factor-alpha production (26%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Activation of the cytokine network in a patient with AIDS and the recalcitrant erythematous desquamating disorder.

An AIDS patient with the recalcitrant erythematous desquamating (RED) disorder, a presumed variant of the Staphylococcus aureus toxic shock syndrome that is characterized by relapses, skin involvement, and variable multiple-organ involvement, is described. A strain of S. aureus producing toxic shock syndrome toxin 1 was isolated from the patient, but no antibodies to this exotoxin were detectable before and during the most severe episode of the RED disorder. Levels of cytokines were measured during episodes and at other times. Tumor necrosis factor and interleukin 6 were detectable only during the most severe exacerbation of the disorder; this finding suggests a pathogenetic role for these cytokines.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Tumor necrosis factor is involved in the appearance of interleukin-1 receptor antagonist in endotoxemia.

To assess the role of tumor necrosis factor (TNF) in the appearance of interleukin-1 receptor antagonist (IL-1RA) in endotoxemia, 4 healthy humans were studied after a bolus intravenous injection of recombinant human TNF (50 micrograms/m2). In addition, 8 healthy chimpanzees were investigated after a bolus intravenous injection of Escherichia coli endotoxin (4 ng/kg) with (n = 4) or without (n = 4) a simultaneous intravenous injection of a monoclonal anti-TNF antibody (15 mg/kg). TNF induced a pronounced rise in IL-1RA concentrations, becoming apparent after 1 h and peaking after 3 h (P < .05). The rise in IL-1RA after administration of endotoxin started 2 h later. Neutralization of the early endotoxin-induced TNF activity by anti-TNF caused a marked reduction in IL-1RA concentrations (P < .05). These results indicate that TNF is an intermediate factor in IL-1RA release in endotoxemia.

Adult↗
PubMed1994

Soluble receptors for tumor necrosis factor as predictors of progression to AIDS in asymptomatic human immunodeficiency virus type 1 infection.

Serum concentrations of soluble receptors for tumor necrosis factor-alpha (sTNF alpha R) types I and II, beta 2-microglobulin, and CD4 cell counts were determined at entry and 3-5 months before AIDS diagnosis in 20 untreated, asymptomatic human immunodeficiency virus type 1 (HIV-1)-seropositive subjects, who progressed to AIDS within 5.5 years of study entry, and in an equal number of HIV-seronegative and untreated seropositive controls, who remained asymptomatic. At entry, concentrations of sTNF alpha R type II and beta 2-microglobulin were elevated and increased further in progressors. The odds ratio (OR) for sTNF alpha R type II concentrations > or = 6.5 ng/mL was 18.4 and for beta 2-microglobulin concentrations > or = 3 mg/L was 6.6; CD4 cell counts were not predictive. Five months before diagnosis, the OR was 102.0 for sTNF alpha R type II concentrations > or = 7.5 ng/mL, 13.5 for beta 2-microglobulin concentrations > or = 4 mg/L, and 6.9 for CD4 cell counts < 250/mm3 (counts < 500/mm3 were not predictive). Of the three variables, sTNF alpha R type II was proved by bivariate analysis to be the strongest and earliest predictor of disease progression.

Acquired Immunodeficiency Syndrome↗
PubMed1994

A review of studies of the activation of the blood coagulation mechanism in chimpanzees (Pan troglodytes).

This paper reviews our recent studies of blood coagulation activation in the chimpanzee which were carried out employing sensitive immunoassays that measure activation markers of blood coagulation in plasma. Infused factor VIIa activated both factors IX and X in vivo; this reaction depended on the formation of the factor VIIa-tissue factor (TF) complex. The infusion of endotoxin also led to assembly of the factor VIIa-TF complex, enhancing fibrin formation. This process occurred through the intermediate action of specific cytokines.

Animals↗
PubMed1994

Noradrenaline inhibits lipopolysaccharide-induced tumor necrosis factor and interleukin 6 production in human whole blood.

Sepsis and lipopolysaccharide (LPS) trigger the systemic release of both cytokines and catecholamines. Cytokines are known to be capable of eliciting a stress hormone response in vivo. The present study sought insight into the effect of noradrenaline on LPS-induced release of tumor necrosis factor alpha (TNF) and interleukin 6 (IL-6) in human whole blood. Whole blood was incubated with LPS for 4 h at 37 degrees C in the presence and absence of noradrenaline and/or specific alpha and beta antagonists and agonists. Noradrenaline caused a dose-dependent inhibition of LPS-induced TNF and IL-6 production. This effect could be completely prevented by addition of the specific beta 1, antagonist metoprolol, while it was not affected by the alpha antagonist phentolamine. Specific beta-adrenergic stimulation by isoprenaline mimicked the inhibiting effect of noradrenaline on LPS-evoked cytokine production, whereas alpha-adrenergic stimulation by phenylephrine had no effect. Fluorescence-activated cell sorter analysis demonstrated that beta-adrenergic stimulation had no effect on LPS binding to and internalization into mononuclear cells or on the expression of CD14, the major receptor for LPS on mononuclear cells. In acute sepsis, enhanced release of noradrenaline may be part of a negative feedback mechanism meant to inhibit ongoing TNF and IL-6 production.

Adult↗
PubMed1994

Inhibition of endotoxin-induced activation of coagulation and fibrinolysis by pentoxifylline or by a monoclonal anti-tissue factor antibody in chimpanzees.

Knowledge of the pathogenetic mechanisms responsible for the activation of the coagulation system associated with endotoxemia is important for the development of improved modalities for prevention and treatment. We analyzed the appearance in plasma of TNF, IL-6, and indices of coagulation and fibrinolytic system activation in normal chimpanzees after intravenous infusion of endotoxin. Endotoxin infusion elicited reproducible and dose-dependent elevations in serum TNF and IL-6, as well as marked increases in thrombin generation in vivo as measured by immunoassays for prothrombin activation fragment F1 + 2, thrombin-antithrombin III complexes, and fibrinopeptide A. Activation of the fibrinolytic mechanism was monitored with assays for plasminogen activator activity and plasmin-alpha 2-antiplasmin complexes. To potentially intervene in the molecular pathways elicited by endotoxin, pentoxifylline, an agent that interrupts "immediate early" gene activation by monocytes, or a potent monoclonal antibody that neutralizes tissue factor-mediated initiation of coagulation, were infused shortly before endotoxin. Pentoxifylline markedly inhibited increases in the levels of TNF and IL-6, as well as the effects on coagulation and fibrinolysis. In contrast, the monoclonal antibody to tissue factor completely abrogated the augmentation in thrombin generation, but had no effect on cytokine levels or fibrinolysis. We conclude that the endotoxin-induced activation of coagulation appears to be mediated by the tissue factor-dependent pathway, the fibrinolytic response triggered by endotoxin is not dependent on the generation of thrombin, and that the release of cytokines may be important in mediating the activation of both the coagulation and the fibrinolytic mechanisms in vivo.

Animals↗
PubMed1994

Effects of acute and chronic interleukin-6 administration on thyroid hormone metabolism in humans.

Cytokines, such as tumor necrosis factor-alpha and interleukin-1 beta (IL-1 beta), alter thyroid hormone metabolism, and may be involved in the pathogenesis of the euthyroid sick syndrome. Both cytokines also induce the production of IL-6. To assess whether IL-6 itself modulates thyroid hormone metabolism, we studied the acute and chronic effects of recombinant human IL-6 (rhIL-6) on thyroid hormone concentrations in patients with renal cell cancer. In the first study protocol, plasma thyroid hormone concentrations were measured during a 4-h infusion of rhIL-6 (150 micrograms) or, on another day, during infusion of saline (control; n = 8). There were no effects of rhIL-6 infusion on T4, free T4, or thyroid hormone-binding index. However, rhIL-6 induced a significant decrease in the plasma concentrations of TSH (P < 0.001) and T3 (P < 0.001) compared with those in the control study, associated with an increase in rT3 concentrations (P < 0.001). In the second study, a dose of 150 micrograms rhIL-6 was administered sc for 42 consecutive days (n = 8). Weekly assessment of thyroid hormone and TSH concentrations showed a decrease in the T3 concentration (P < 0.001) and a transient increase in rT3 (P < 0.01) and free T4 concentrations (P < 0.01). There were no changes in T4 concentrations during chronic administration of rhIL-6. It is concluded that IL-6 induces major changes in thyroid hormone metabolism and may be another pathogenetic factor in the euthyroid sick syndrome.

Carcinoma, Renal Cell↗
PubMed1994

Increase of sTNF receptor levels in acute renal allograft rejection after treatment with OKT3.

The use of OKT3 is associated with severe clinical side-effects. Adverse reactions are partly attributed to release of tumour necrosis factor (TNF). TNF binds to two receptors on the outer membranes of most human cell lines. Shedding of these proteins (sTNFR-p55 and sTNFR-p75) may block biological effects of TNF. Here we show a fair correlation between serum levels of sTNFRs and renal function as measured by glomerular filtration rate (GFR). In addition we assessed levels of sTNFR-p55 and sTNFR-p75, corrected for reduced renal clearance, in renal allograft rejection and following treatment with OKT3. Corrected serum levels (CSL) of sTNFR-p55 and sTNFR-p75 were determined in 12 renal allograft patients treated for an acute rejection episode with either OKT3 or methylprednisolone (MPNS). Serum levels of CSLsTNFR-p55 and CSLsTNFR-p75 in both groups prior to anti-rejection treatment were not elevated. CSLsTNFRs peaked at 1 h after the administration of OKT3, whereas in the MPNS group CSLsTNFRs remained unchanged. We conclude that in acute renal transplant rejection CSLsTNFRs increase after treatment with OKT3. In spite of high circulating sTNFRs levels all OKT3-treated patients suffered from clinical side-effects.

Adult↗
PubMed1993

Pathogenesis of disseminated intravascular coagulation in sepsis.

OBJECTIVE: To review new insights in the pathogenetic mechanisms involved in the development of disseminated intravascular coagulation (DIC) in septic patients, in order to develop new directions for therapeutic intervention. DATA SOURCES: Articles and published peer-reviewed abstracts on the mechanism of the initiation of DIC in sepsis. STUDY SELECTION: Studies selected for detailed review were those reporting specifics about the mechanism of activation of coagulation and fibrinolysis in experimental human and animal models of sepsis. Data extraction guidelines for assessing data quality included validity of the model, quality of the laboratory assessment of activation of coagulation and fibrinolysis, and methodological considerations, such as the presence of control experiments and statistical analysis. DATA SYNTHESIS: After the presence of endotoxin in the circulation, significant coagulation activation can be detected. This activation is preceded by an increase in the serum levels of various cytokines, such as tumor necrosis factor and interleukins. Inhibition of the increase in tumor necrosis factor results in inhibition of coagulation activation. Measurement of molecular markers for the activation of coagulation proteins at various levels indicates that the activation of coagulation is mediated by the tissue factor-dependent pathway, which is further confirmed by experiments in which the inhibition of the tissue factor-dependent pathway resulted in complete inhibition of coagulation activation. The activation of coagulation seems to be amplified by impaired function of the protein C-protein S inhibitory pathway. An imbalance between coagulation and fibrinolysis, ultimately leading to plasminogen activator inhibitor type 1-mediated inhibition of fibrinolysis, may further promote the procoagulant state. CONCLUSION: The increased knowledge of the various pathogenetic mechanisms of coagulation activation and fibrinolysis in sepsis may have therapeutic implications; however, their efficacy needs to be assessed in appropriate clinical trials.

Animals↗
PubMed1993

Pentoxifylline attenuates neutrophil activation in experimental endotoxemia in chimpanzees.

Costimulation of neutrophils and cytokines may play an important role in organ injury in sepsis. Pentoxifylline inhibits various neutrophil functions in vitro, and attenuates endotoxin-induced production of TNF in both in vitro and in vivo models. To assess the effect of pentoxifylline on neutrophil activation in endotoxemia, nine adult chimpanzees (Pan troglodytes) were i.v. injected with saline (n = 2), Escherichia coli endotoxin (4 ng/kg; n = 4), or E. coli endotoxin (4 ng/kg) in combination with pentoxifylline (500 mg/3 h, starting 30 min before the endotoxin injection; n = 3). Serial blood samples were obtained for measurements of leukocyte counts and the granulocytic proteinases elastase complexed with alpha 1-antitrypsin and lactoferrin, and cytokines during the next 5 h. No changes were observed in the saline-treated chimpanzees. Endotoxin induced a marked leukocytosis and neutrophilia, which were slightly reduced by pentoxifylline. In contrast, pentoxifylline almost completely prevented endotoxin-induced neutrophil degranulation: peak elastase-alpha 1-antitrypsin was 164 +/- 21 ng/ml (mean +/- SE) after endotoxin alone, vs 71 +/- 7 ng/ml after endotoxin with pentoxifylline (t = 3 h; p < 0.05); peak lactoferrin was 329 +/- 15 and 182 +/- 5 ng/ml, respectively (t = 5 h; p < 0.05). Pentoxifylline also inhibited the endotoxin-induced release of TNF (271 +/- 26 vs 55 +/- 23 pg/ml at t = 1.5 h; p < 0.05) and IL-6 (225 +/- 42 vs 73 +/- 25 pg/ml at t = 2 h; p < 0.05). IL-8 release was not significantly inhibited by pentoxifylline. In none of the animals activation of the C system could be detected. We conclude that pentoxifylline attenuates neutrophil activation in endotoxemia in chimpanzees, probably in part by inhibiting the release of TNF.

Animals↗
PubMed1993

Effects of tumor necrosis factor on the hypothalamic-pituitary-testicular axis in healthy men.

Tumor necrosis factor (TNF) has been implicated as a mediator of many diseases associated with alterations in hypothalamic-pituitary-testicular (HPT) function. To assess the effects of TNF on the HPT axis, we performed a saline-controlled cross-over study in six healthy men, sequentially measuring serum concentrations of gonadotropins, testosterone, and sex hormone-binding globulin (SHBG) after a bolus intravenous injection of recombinant human TNF (50 micrograms/m2). TNF induced an early and transient increase in serum luteinizing hormone (LH) levels from 6.0 +/- 1.0 to a maximum of 8.0 +/- 1.0 U/L after 30 minutes (P < .005), whereas the concentrations of follicle-stimulating hormone (FSH) remained unchanged. The increase in LH concentrations was followed by a transient decrease in serum testosterone levels from 18.2 +/- 0.3 to 9.1 +/- 1.2 nmol/L after 4 hours (P < .0001). Remarkably, LH levels had returned to control values when the testosterone level reached its nadir. SHBG levels were not affected by TNF. Our results suggest that TNF affects the HPT axis at multiple levels and may be involved either directly or indirectly in the decrease in circulating testosterone concentrations in systemic illnesses.

Adult↗