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)

Tumor necrosis factor (TNF), a macrophage product released in response to endotoxin and other stimuli, has been shown to be a central mediator of endotoxin or septic shock. However, its highly conserved and wide-ranging physiological effects suggest that it may also be an essential cytokine in the host defense against acute bacterial infection or sepsis. A single nontoxic dose of human recombinant TNF administered intravenously 24 h prior to a lethal infusion of Escherichia coli lipopolysaccharide (LPS) completely prevented acute LPS-induced hypotension, ameliorated tissue injury in the lungs and liver, and improved survival in male Fisher 344 rats. The protective effects of TNF were dose dependent and required a 24-h pretreatment interval. After the infusion of LPS, animals in both groups (TNF-treated animals and saline-pretreated controls) initially appeared acutely ill and had a similar severe metabolic acidosis, indicating that TNF did not inactivate or prevent the toxic effects of LPS. Twelve hours after the administration of TNF, the gene for manganous superoxide dismutase, a mitochondrial enzyme which scavenges toxic reactive oxygen species and is induced during conditions which generate a free radical stress, was expressed in liver tissue, suggesting that the induction of manganous superoxide dismutase may be an important in vivo protective mechanism against cellular injury during lethal endotoxemia.
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PMID:Single-dose tumor necrosis factor protection against endotoxin-induced shock and tissue injury in rats. 193 48

The production by monocytes of interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF alpha) in intensive care unit (ICU) patients with sepsis syndrome (n = 23) or noninfectious shock (n = 6) is reported. Plasma cytokines, cell-associated cytokines within freshly isolated monocytes and LPS-induced in vitro cytokine production were assessed at admission and at regular intervals during ICU stay. TNF alpha and IL-6 were the most frequently detected circulating cytokines. Despite the fact that IL-1 alpha is the main cytokine found within monocytes upon in vitro activation of cells from healthy individuals, it was very rarely detected within freshly isolated monocytes from septic patients, and levels of cell-associated IL-1 beta were lower than those of TNF alpha. Cell-associated IL-1 beta and TNF alpha were not correlated with corresponding levels in plasma. Upon LPS stimulation, we observed a profound decrease of in vitro IL-1 alpha production by monocytes in all patients, and of IL-1 beta, IL-6, and TNF alpha in septic patients. This reduced LPS-induced production of cytokines was most pronounced in patients with gram-negative infections. Finally, monocytes from survival patients, but not from nonsurvival ones recovered their capacity to produce normal amounts of cytokines upon LPS stimulation. In conclusion, our data indicate an in vivo activation of circulating monocytes during sepsis as well as in noninfectious shock and suggest that complex regulatory mechanisms can downregulate the production of cytokines by monocytes during severe infections.
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PMID:Dysregulation of in vitro cytokine production by monocytes during sepsis. 193 59

Endotoxin (lipopolysaccharide [LPS]) and tumor necrosis factor (TNF-alpha) have been implicated in the pathogenesis of sepsis-induced adult respiratory distress syndrome. To evaluate the possible interaction of the hepatic-pulmonary macrophage axis in the adult respiratory distress syndrome, we compared the kinetics of immunosuppressive prostaglandin E2, TNF-alpha, and interleukin 6 production in LPS-stimulated Kupffer cells and alveolar macrophages (AMs). Interleukin 6 production by Kupffer cells was significantly higher than for equal numbers of AMs. Kupffer cell TNF-alpha levels peaked early before decreasing as regulatory prostaglandin E2 levels rose. In contrast, AM TNF-alpha levels rose sharply and remained significantly higher than for Kupffer cells throughout culture coincident with negligible prostaglandin E2 production. Kupffer cell sequestration of LPS may normally invoke a coordinated cytokine response able to locally induce acute-phase hepatocytes. In hepatic failure, however, LPS spillover to the lung may promote adult respiratory distress syndrome by inducing unregulated AM TNF-alpha production within the pulmonary microenvironment.
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PMID:Organ interactions in sepsis. Host defense and the hepatic-pulmonary macrophage axis. 198 33

While the production of tumor necrosis factor (TNF) and interleukin-6 (IL-6) in septic shock and other inflammatory states is well established, the role of interleukin-8 (IL-8), a recently described neutrophil chemoattractant and activator, has yet to be fully elucidated. Using lipopolysaccharide (LPS)-stimulated human whole blood as an ex vivo model of sepsis, the kinetics of messenger RNA (mRNA) up-regulation and protein release of these cytokines were examined. Two waves of cytokine gene activation were documented. TNF and IL-6 were induced in the first wave with mRNA levels peaking between 2-4 hours and then rapidly declining. TNF and IL-6 protein peaked at 4-6 hours and then stabilized. IL-8 mRNA and protein were induced in the first wave, reached a plateau between 6-12 hours, and rose again in a second wave which continued to escalate until the end of the 24 hour study. These data demonstrate the complex patterns of cytokine gene expression and suggest that production of early mediators may augment continued expression of IL-8 to recruit and retain neutrophils at a site of inflammation.
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PMID:Kinetics of TNF, IL-6, and IL-8 gene expression in LPS-stimulated human whole blood. 198 98

Sepsis results in muscle catabolism and peripheral release of amino acids with a concomitant uptake of amino acids in liver and acute-phase protein synthesis. In addition, there appears to be a cytokine-induced process that blocks muscle amino acid uptake in sepsis, further diverting amino acids from the periphery to the liver. In this article, evidence that cytokines and glucocorticoids play an important role in the regulation of hepatic and muscle protein metabolism during sepsis is presented.
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PMID:Cytokines and glucocorticoids in the regulation of the "hepato-skeletal muscle axis" in sepsis. 199 Aug 81

Using a model of sepsis induced by parenteral challenge of mice with bacterial lipopolysaccharide (LPS), the authors analyzed the in vivo expression of interleukin-1 (IL-1) alpha,beta and tumor necrosis factor (TNF). Both TNF and IL-1 alpha,beta were detected in hepatic sinusoidal macrophages (Kupffer cells), immunohistochemically. Kinetic analysis showed a clear sequence of synthesis. Tumor necrosis factor was produced first, reaching maximal expression at 1 hour after LPS challenge, then rapidly disappeared. IL-1 beta followed, reaching maximal expression at 2 to 3 hours, then dropped off by 6 hours. Interleukin-1 alpha expression reached a peak at 6 hours and had disappeared by 18 hours. Analysis of serum bioactivity also revealed sequential expression that correlated with immunohistochemical findings. Tumor necrosis factor was maximal at 1 hour and IL-1 at 6 hours. The IL-1 bioactivity was not due to interleukin-6 (IL-6), as this was depleted from specimens by immunoabsorption. Also IL-6 bioactivity reached maximal levels at 3 hours, earlier than IL-1. Pretreatment with 4 mg/kg dexamethasone significantly decreased Kupffer cell expression of TNF and IL-1 alpha (about 80% and 60% suppression, respectively) but had less effect on IL-1 beta expression (about 30% suppression). Accordingly, serum levels of TNF were suppressed by 75% while serum IL-1 was decreased by 39%, indicating differential sensitivity of these cytokines to glucocorticoids. Endogenous corticosteroid levels increased as TNF levels decreased, supporting the contention that glucocorticoids regulate TNF synthesis. In contrast, IL-1 levels rose concurrently with corticosterone. These data indicate a sequential activation of cytokine gene expression in vivo, which may be critical to the cascade of events leading to septic shock, and provide evidence that Kupffer cells are a major source of cytokines in endotoxemia. Finally, the differential sensitivity of cytokine expression to glucocorticoids may in part explain the inadequacy of the latter in the treatment of sepsis.
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PMID:In vivo biologic and immunohistochemical analysis of interleukin-1 alpha, beta and tumor necrosis factor during experimental endotoxemia. Kinetics, Kupffer cell expression, and glucocorticoid effects. 199 64

The clinical and immune modulatory effects of interleukin-2 (IL-2) and interferon (INF) alfa-2a were examined in a phase II study in patients with metastatic renal cell carcinoma (six patients) and melanoma (eight patients). Treatment consisted in IL-2 3 MU/m2 continuous infusion days 1-4 and INF alfa-2a 6 MU/m2 subcutaneously day 1 and 4, both given on alternate weeks. Tumour response was assessed after four cycles of treatment or earlier, if necessary. Patients with stable disease or response were to be continued for another nine cycles or up to disease progression. The 14 patients received a total of 60 cycles of treatment. Major toxicities (WHO Grade III/IV) were fever, capillary leak syndrome with hypotension, nausea and vomiting, erythema with pruritus, leuco- and thrombopenia and sepsis with staphylococcus aureus. Five of 14 patients (36%) developed a self limiting autoimmune thyroiditis with HLA-DR expression on thyrocytes. Long term treatment toxicity was moderate with an average weight loss of 5% and an average fall in Karnofsky index of 10% compared to baseline. No responses were seen in renal cell carcinoma, two patients with melanoma had a partial and two a minor response with a duration of 1-7 months. Serial measurements of immune modulatory parameters showed a functional response to treatment with an increase of NK- and LAK-activity during the first two cycles, followed by a plateau and decrease during the third and fourth cycles. These findings were paralleled by a successive decline in treatment induced INF gamma response. These findings suggest, that alternative weekly treatment with IL-2 and INF alfa-2a results in an exhaustion of lytic capacity of NK- and LAK-cells and an attenuation of secondary cytokine release.
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PMID:Clinical and immune modulatory effects of alternative weekly interleukin-2 and interferon alfa-2a in patients with advanced renal cell carcinoma and melanoma. 199 8

The purpose of the study was to evaluate the role of tumor necrosis factor alpha (TNF alpha) in the pathogenesis of acute lung injury in critically ill patients. An immunoradiometric assay with an upper normal limit of 9 pg/ml was used to measure plasma TNF alpha levels (pl-TNF alpha) in 34 patients with adult respiratory distress syndrome (ARDS) and in 16 patients in whom, despite the presence of risk factors, ARDS did not develop. Pl-TNF alpha was elevated in 76% of the patients with ARDS (71 +/- 104 pg/ml) and in 48% of the at-risk patients (47 +/- 73 pg/ml); the difference between the two groups was not statistically significant. In 13 patients studied serially from the onset (Day 0) to the fifth day of ARDS, the peak pl-TNF alpha occurred later than Day 0 in seven subjects. Although the highest pl-TNF alpha levels were found in septic patients, moderately elevated values were also observed in 56% of nonseptic subjects. We conclude that plasma TNF alpha level is not a marker of ARDS but rather of shock and sepsis. These results do not exclude a pathogenic role of TNF alpha in acute lung injury since this cytokine could be produced and exert its effects within the lungs. The large incidence of abnormally high could be produced and exert its effects within the lungs. The large incidence of abnormally high plasma TNF alpha levels raises important questions on the role of this toxic cytokine in other disorders occurring in critically ill patients.
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PMID:Plasma levels of tumor necrosis factor in the adult respiratory distress syndrome. 200 Oct 71

Interleukin 8 (IL-8), a potent activator of neutrophils, may be important in the early host response to serious Gram-negative infections. IL-8 was measured with other acute phase cytokines (tumor necrosis factor alpha [TNF-alpha], IL-6 and IL-1 beta) in 25 normal humans randomized to receive either intravenous endotoxin alone or endotoxin after oral administration of ibuprofen or pentoxifylline, agents that alter some of the inflammatory responses induced by endotoxin in vitro. TNF immunoreactivity was maximum at 1.5 h, and total TNF (area under the curve) was 4.2- and 4.5-fold greater in subjects given endotoxin/ibuprofen compared to subjects given endotoxin alone (p = 0.026) or endotoxin/pentoxifylline (p = 0.004), respectively. IL-6 levels were maximum at 2-3 h and did not differ among the three groups. No IL-1 beta was detected in any subject. IL-8 levels peaked at 2 h in subjects given either endotoxin alone or endotoxin/pentoxifylline, falling towards baseline by 5 h. Subjects given endotoxin/ibuprofen had a more sustained rise in IL-8 with peak levels 2.8- and 2.5-fold higher at 3 h compared to endotoxin alone (p = 0.048) or endotoxin/pentoxifylline (p = 0.023), respectively. Differences in total IL-8 release among groups approached statistical significance (ANOVA, p = 0.07). This trend reflected the increased release of IL-8 by the subjects receiving ibuprofen compared to pentoxifylline (1.9-fold higher; p = 0.024). This suggests that cyclooxygenase products may provide important negative feedback loops for cytokine production in vivo. Increases in circulating IL-8 are part of the acute inflammatory response of humans to endotoxin. Altered cytokine responses caused by antiinflammatory therapy may have important implications for both host defense and injury during septicemia.
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PMID:Detection of interleukin 8 and tumor necrosis factor in normal humans after intravenous endotoxin: the effect of antiinflammatory agents. 200 51

To study the effect of plasma removal vs plasma administration on the appearance of tumor necrosis factor (TNF) and interleukin 1 in septic shock, 24 anesthetized piglets were inoculated with live Escherichia coli. Plasma exchange with albumin was performed in one group. Fresh-frozen plasma was administered to a second group. A third group served as nontreated controls. Following plasma exchange, a reduction in both TNF and interleukin 1 levels occurred, whereas plasma infusion was followed by a decrease in TNF levels only. No significant differences were observed between the two treated groups with respect to survival or cardiovascular performance, with both being significantly enhanced compared with the controls. High levels of TNF and interleukin 1 correlated with depressed cardiovascular performance in the early phase of the shock. Our results confirm the important role of TNF and interleukin 1 as early mediators of septic shock. However, the benefit of reducing cytokine activity in later stages of septicemia seems to be dubious.
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PMID:Tumor necrosis factor and interleukin 1 appearance in experimental gram-negative septic shock. The effects of plasma exchange with albumin and plasma infusion. 202 43


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