The role of tumor necrosis factor in sepsis (original) (raw)
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Is TNF-α a prognostic factor in patients with sepsis?
Clinical Microbiology and Infection, 1997
To determine tumor necrosis factor-a (TNF-a) levels in a prospective study in 58 hospitalized patients in a department of internal medicine (63 episodes, 29 in immunocompromised patients) during a 7-month period.
LYMPHOTOXIN-α (TNF-β) DURING SEPSIS
Cytokine, 1996
T cell release of lymphotoxin-a (LT-a, or TNF-b) is stimulated by pyrogenic exotoxins of Gram-positive bacteria and mitogens. In contrast to TNF-a, it is unknown whether LT-a plays any role in the pathogenesis of sepsis and, in particular, the pathogenesis of Gram-positive sepsis. Sera from patients with sepsis were examined for LT-a and compared with normal volunteers and pregnant women. LT-a was detected in 33% of sepsis sera (mean 608.4 pg/ml SE 306), 16% of normal sera (mean 167 pg/ml SE 87) and 23% of sera from pregnant women (mean 714 pg/ml SE 191). These differences were not significant and there were no differences within sepsis sera when grouped by the type of causative organism, or disease severity. LT-a detected by immunoassay in serum was not bioactive, in contrast to that produced in cell culture. Recombinant soluble TNF receptors (rSTNFR) neutralized the bioactivity of recombinant LT-a at rSTNFR concentrations which did not interfere with immunoreactivity and which are known to prevail in vivo. Hence, LT-a is unlikely to have a critical role in the pathogenesis of sepsis. Much of the potential bioactivity of this lymphokine may be abrogated by TNFR in serum. + 5 $25.00/0 KEY WORDS: Lymphotoxin-a/tumour necrosis factor-b/sepsis syndrome/septic shock CYTOKINE
Is TNF-a a prognostic factor in patients with sepsis?
Clin Microbiol Infect, 1997
To determine tumor necrosis factor-a (TNF-a) levels in a prospective study in 58 hospitalized patients in a department of internal medicine (63 episodes, 29 in immunocompromised patients) during a 7-month period.
Journal of Cardiothoracic and Vascular Anesthesia, 1998
Despite the availability of potent antibiotics and intensive care, mortality rates from septic shock are 40-70%. We assessed the safety and efficacy of murine monoclonal antibody to human tumour necrosis factor alpha (TNF alpha MAb) in the treatment of septic shock. In a randomised, multicentre, double-blind, placebo-controlled clinical trial in 105 hospitals in the USA and Canada, we randomly assigned 1879 patients a single infusion of 7.5 mg/kg TNF alpha MAb (n=949) or placebo (0.25% human serum albumin n=930). Our main outcome measurement was the rate of all-cause mortality at 28 days. 382 (40.3%) of 948 patients who received TNF alpha MAb and 398 (42.8%) of 930 who received placebo had died at 28 days (95% CI -0.02 to 0.07, p=0.27). We found no association between therapy with TNF alpha MAb and increased rapidity in reversal of initial shock or prevention of subsequent shock. Similarly, baseline plasma interleukin-6 concentrations of more than 1000 pg/mL or detectable circulating TNF concentrations were not associated with improvement in survival after TNF alpha MAb therapy. Coagulopathy but not other organ or system failures, was significantly decreased in the TNF alpha MAb group compared with placebo (day 7, p<0.001; day 28, p=0.005). Serious adverse events were reported in 55.2% of patients given placebo and 54.1% in the TNF alpha MAb group. We did not find an improvement in survival after septic shock with TNF alpha MAb. Therapy not solely dependent on TNF alpha blockade may be required to improve survival.
umor necrosis factor related apoptosis inducing ligand (TRAIL) as a member of the TNF gene superfamily induces apoptosis primarily in tumor cells. TRAIL also plays an important role in the modulation of inflammatory responses, especially in the process of immune paralysis. The aim of the present study was to examine soluble TRAIL (sTRAIL) levels in septic patients in an attempt to explore the association between sTRAIL level and the risk of mortality. Plasma sTRAIL levels were detected by ELISA in 50 septic patients and 20 healthy volunteers. HLA-DR expression in monocytes was detected by flow cytometry. Selective biochemical parameters were recorded, and patients were monitored in a 28-day period for mortality. The mean plasma sTRAIL level in septic patients was significantly lower than that in healthy controls (16.9±8.3 vs. 68.3±8.6 pg/ml, P<0.01), and was significantly higher in 28-day survivors than those in non-survivors (19.4±9.8 vs. 13.9±4.7 pg/ml, P<0.05). Univariate analysis indicated that plasma sTRAIL level was positively correlated with monocyte and lymphocyte counts and HLA-DR expression level (r = 0.5, P<0.01; r = 0.3, P<0.05; r = 0.43, P<0.01, respectively). STRAIL level was negatively correlated with APACHE II score, BUN and age (r = -0.48, P<0.01; r = -0.29, P<0.05; r = -0.45, P<0.01, respectively). Multiple linear regression analysis indicated that the predictor of plasma soluble TRAIL level was HLA-DR expression (P<0.01). Low plasma sTRAIL levels were associated with immune paralysis and a high risk of mortality in patients with septic shock. sTRAIL may prove to be a potential biomarker of immune function and predict the survival of septic patients. Soluble Tumor Necrosis Factor Related Apoptosis Inducing Ligand Level as a Predictor of Severity of Sepsis and the Risk of Mortality in Septic Patients. Available from:
Antitumor Necrosis Factor Therapy Is Associated With Improved Survival in Clinical Sepsis Trials
Critical Care Medicine, 2013
Background-Sepsis is a lethal syndrome annually affecting ~900,000 patients in the United States alone. Despite their benefit in rheumatoid disease, selective anti-tumor necrosis factor (anti-TNF) agents failed to improve outcome in early sepsis trials in the 1990's. However, data from additional sepsis trials testing these agents is now available. Purpose-To determine the effect on survival of selective anti-TNF agents in randomized clinical sepsis trials. Data Sources-PubMed, Scopus, EMBASE, and Web of Science. Study Selection-Randomized human sepsis trials of selective anti-TNF agents reporting survival rates. Data Synthesis-Two investigators independently collected relevant data on study characteristics, treatment interventions, and patient from each study. Results-Anti-TNF agents in 15 sepsis trials (n=8,896 patients) meeting inclusion criteria had similar effects (I 2 =0, p=0.84) and compared to controls (placebo in 14 trials or a lower dose in 1 trial) overall decreased the relative risk (RR) of death (95% CI) [0.93 (0.88, 0.98), p=0.01]. In subgroup analysis, TNF monoclonal antibodies (10 trials, n=6,818) alone produced a significant survival benefit [0.93 (0.87, 0.99), p=0.02] (I 2 =0, p=0.83). TNF polyclonal antibodies (2 trials,
Inflammation Research, 2006
Background Negative results are frequent using anti-TNFα antibodies in sepsis models and clinical trials. Methods and Results Different prophylactic doses of anti-TNFα F(ab')2 antibody fragments were compared for the prevention of death by sepsis induced by cecal ligation and puncture (CLP) in mice. High (10 mg/kg) and very low (0.01 and 0.1 mg/kg) concentrations of anti-TNFα antibody fragments were not the most adequate for treating polymicrobial sepsis, since they did not significantly improve survival. To the contrary, intermediate doses (1 mg/kg) significantly protected the challenged animals. Protective activity was also observed when administration of the antibody fragments was initiated early (up to 30 min) after CLP. Conclusions These results suggest that in processes where excessive production of cytokines is involved, the aim should be to return them to their physiologically acting range but not to inhibit their production. The timing of initiating therapy should also be considered in order to maximize the possible benefits.
Journal of Clinical Medicine, 2020
Recent studies have suggested that TNF-related apoptosis-inducing ligand (TRAIL) is associated with mortality in sepsis, possibly through necroptosis. The objective of this study was to analyze the association between the plasma level of TRAIL and sepsis severity and outcomes. Furthermore, the plasma level of TRAIL was compared to that of receptor-interacting protein kinase-3 (RIPK3), a key executor of necroptosis, to identify any correlation between TRAIL and necroptosis. Plasma levels of TRAIL and RIPK3 from consecutively enrolled critically ill patients were measured by ELISA. Of 190 study patients, 59 (31.1%) and 84 (44.2%) patients were diagnosed with sepsis and septic shock, respectively. There was a trend of decreased plasma level of TRAIL across the control, sepsis, and septic shock groups. For 143 patients with sepsis, patients with low plasma TRAIL were more likely to have septic shock and higher SAPS3 and SOFA scores. However, no difference in 28-day and 90-day mortalitie...
Tumor Necrosis Factor gene polymorphism results in high TNF level in sepsis and septic shock
Cytokine, 2013
Introduction: Systemic sepsis releases several cytokines among which tumor necrosis factor alfa (TNFa) has emerged as key cytokine causing septic shock. Single Nucleotide Polymorphisms (SNPs) at positions À238, À308, À376 and +489 in the promoter region of TNF gene exhibit differential association to inflammation and increased TNF production in sepsis. Materials and Methods: This research work was carried out in 278 critically ill patients and 115 controls. The patients were divided into four groups: Healthy controls, SIRS, Sepsis and Septic shock. Plasma cytokine level was evaluated by ELISA. Specific sequences of TNF gene (À238, À308, À376, +489) were amplified using polychromase chain reaction (PCR). SNP detected by BamHiI, NcoI, FokI, TaiI restriction enzymes. Results: Mean plasma TNFa level in healthy Control group was 8.37 ± 2.23 pg/ml, in SIRS group, the mean plasma TNFa level was 77.99 ± 5.51 pg/ml, in Sepsis patients 187.1 ± 14.33 pg/ml and in septic shock 202.2 ± 14.85 pg/ml; range 56.17-417.1 pg/ml. SNP was studied among different patient groups, which showed a higher frequency of mutants among sepsis and shock patients as compared to control. Conclusion: Plasma TNF alpha level was significantly high in patients with sepsis and septic shock. SNP of TNF gene showed significant association between polymorphism and development of severe sepsis and septic shock, this would help us in evaluating patients at high risk for septic shock and such patients needed to obtain a rational basis for therapy.