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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activation of endothelial and phagocytic cells, with concomitant formation of a range of adhesive molecules and inflammatory mediators, are integral parts of the host response to injurious agents (trauma, infection, altered antigens, toxins, chemicals etc.). The excessive mediator responses are associated with increased morbidity and lethality. Cytokines, soluble mediators secreted by cells, play an integral role in the metabolic and immune responses to the injurious agents. Widespread tissue damage, when associated with fulminant sepsis may induce massive release of cytokines (TNF, IL-1, IL-6), triggering certain steps of reactions involving multiple organs and culminating in the systemic inflammatory response syndrome, sepsis syndrome or multiple organ failure syndrome. (Fig. 2, Ref. 21.)
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PMID:[Inflammation, immunity and surgery]. 755 89

Tumor necrosis factor-alpha (TNF alpha), a cytokine that is produced in a variety of inflammatory diseases associated with cholestasis, is believed to be the primary mediator of the systemic effects of endotoxin. Thus, we have investigated the role of TNF alpha in the pathogenesis of endotoxin-induced cholestasis in intact animals, and in the uptake of taurocholate by cultured hepatocytes. Male Sprague-Dawley rats received either intravenous (IV) endotoxin (7.5 mg/kg) or monoclonal anti-TNF alpha antibody followed by endotoxin. Basal bile flow and bile salt excretion were measured for a 2-hour period, after which all animals received an IV bolus of taurocholate (10 mumol/100 g body weight). Endotoxin decreased basal bile flow by 41% and bile salt stimulated bile flow by 38% (n = 12; P < .01). Basal bile salt excretion was decreased 86% after endotoxin administration. Passive immunization with anti-TNF alpha antibody blocked this endotoxin-associated cholestasis. In addition, rat hepatocytes were isolated and cultured in the presence of either endotoxin (10 micrograms/mL) or TNF alpha (100 ng/mL) for 24 hours. These primary hepatocyte cultures exhibited a dose- and time-dependent, noncompetitive, inhibition of taurocholate uptake. We postulate that TNF alpha is an important mediator of the cholestasis of sepsis.
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PMID:Tumor necrosis factor-alpha decreases hepatocyte bile salt uptake and mediates endotoxin-induced cholestasis. 755 81

Postsplenectomy bacterial sepsis may be fatal, due to defects in both cellular and humoral immune responses. The objective of this study was to assess the efficacy of peritoneal macrophage antibacterial function in the early postsplenectomy period. Murine models of splenectomy and sham operation were characterized and peritoneal macrophages were harvested 24 h to 1 wk after surgery. Cells from splenectomized animals demonstrated a nonsignificant delay in phagocytosis of Escherichia coli at 24 h with, however, significantly impaired killing of intracellular organisms at 24 h and 1 wk compared to the sham group. Paradoxically, the production of the macrophage antibacterial product superoxide anion was not impaired at either time point in the splenectomy group compared with sham-operated and control mice. Nitric oxide release was significantly lower in the splenectomized group (p = 0.006), a possible explanation for reduced bacterial killing. Mortality from bacterial peritonitis was significantly higher with concomitant splenectomy than in the sham splenectomy group at 24 h (p < 0.02). The production of TNF from macrophages was up-regulated immediately following splenectomy, a cytokine which may contribute to mortality from bacteremic shock. Local defects in macrophage antimicrobial function may contribute significantly to bacteremia and to subsequent mortality in the early postsplenectomy period.
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PMID:Characterization of the defects in murine peritoneal macrophage function in the early postsplenectomy period. 760 13

Septic shock following gram-negative infection is a leading cause of mortality in critically ill patients, accounting for nearly 200,000 deaths a year. The exaggerated production of tumor necrosis factor-alpha (TNF alpha) is known to contribute to hemodynamic collapse and the hematological dyscrasia associated with gram-negative sepsis. Although previous studies have shown TNF alpha antibodies and TNF immunoadhesins to be effective in experimental gram-negative sepsis, we postulated that administration of a novel construct of two modified soluble p55 receptors linked to polyethylene glycol (PEG-BP-30) would also attenuate the hemodynamic and hematologic alterations to lethal Escherichia coli septic shock in non-human primates. Nine adult female and male baboons (Papio anubis), weighing 10-17 kg, were anesthetized and invasively monitored. The nine animals were randomized to receive either 0.2 mg/kg body wt PEG-BP-30 (n = 3), 5.0 mg/kg body wt PEG-BP-30 (n = 3), or placebo (n = 3). One hour after pretreatment, animals were infused with 5-10 x 10(10) CFU/kg of live E. coli iv and vital signs were recorded for the next 8 hr. Arterial blood was drawn for baseline parameters and throughout the study to obtain total and differential white blood cell and platelet counts and cytokine levels (TNF alpha, IL-1 beta, IL-6, IL-8). E. coli bacteremic baboons receiving only placebo demonstrated a significant fall in mean blood pressure and leukopenia. Two of the three animals expired. In contrast, five of the six baboons receiving the PEG-BP-30 survived and these animals exhibited markedly attenuated declines in blood pressure and leukocyte numbers.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:PEG-BP-30 monotherapy attenuates the cytokine-mediated inflammatory cascade in baboon Escherichia coli septic shock. 763 Jan 20

An increase in gluconeogenesis contributes to the cachexia seen in severe injury, sepsis, and malignancy by converting amino acids from skeletal muscle to glucose. Since tumor necrosis factor alpha (TNF alpha) may mediate this cachexia, we examined the effect of this cytokine on gluconeogenesis. Twenty-eight male Fischer rats were injected intraperitoneally with TNF alpha (250 micrograms/kg) or saline, and after 4 hours, isolated hepatocytes were obtained by in situ collagenase liver perfusion. Hepatocytes were incubated with alanine (10 mM), and rates of gluconeogenesis were determined. Plasma lactate, glucose, insulin, glucagon, cortisol, and amino acids were measured. TNF alpha administration resulted in a 50% increase in gluconeogenesis from alanine (P < 0.05) and a three-fold increase in plasma glucagon (P = 0.01). Total and glucogenic plasma amino acids decreased with TNF alpha injection (P < 0.05). In vivo TNF alpha causes an increase in hepatic gluconeogenesis associated with increased plasma glucagon.
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PMID:Tumor necrosis factor alpha stimulates gluconeogenesis from alanine in vivo. 763 Jan 67

It is not known how the decrease in left ventricular contractility following endotoxin exposure is mediated, or whether this decrease is preventable by antibodies to tumor necrosis factor-alpha (TNF alpha). Four groups of six anesthetized and instrumented pigs were pretreated with ovine polyclonal antibody to human TNF alpha (anti-TNF alpha), nonspecific IgG, or saline, and then treated with either endotoxin or saline. We measured hemodynamics and left ventricular pressures (Millar catheter) and volumes (conductance catheter). Left ventricular contractility was assessed using the slope (Emax) of the end-systolic pressure-volume relationship. Four hours after the start of endotoxin infusion in the nonspecific IgG pretreated group, Emax had decreased by 44 +/- 6% (p < 0.05), mean arterial pressure had decreased from 115 +/- 7 mm Hg to 70 +/- 10 mm Hg (p < 0.05), and cardiac output was rapidly decreasing after an initial increase (p < 0.05). Anti-TNF alpha significantly reduced the decrease in Emax (11 +/- 9%, p < 0.05), and the systemic hypotension (108 +/- 15 mm Hg to 99 +/- 6 mm Hg, p < 0.05), at 4 h, and prevented the late decrease in cardiac output. This suggests that TNF alpha is an important early mediator in sepsis leading to decreased left ventricular contractility.
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PMID:Anti-tumor necrosis factor-alpha prevents decreased ventricular contractility in endotoxemic pigs. 763 96

The multiorgan failure syndrome caused by group A streptococci (GAS) designated streptococcal toxic shock syndrome (STSS) is believed to be mediated by cytokines induced by superantigens. In order to study the relationship between superantigen production, cytokine levels in patient sera, and clinical GAS manifestation we examined acute-phase sera and strains from 25 patients with GAS bacteremia. The patients had various disease manifestations, including STSS (44%), erysipelas (28%), septicemia (24%), wound infections (16%), and pneumonia (12%). Serotype T1M1 dominated, representing 56% of the isolates, but also strains of other serotypes were identified. The strains were found to produce the streptococcal pyrogenic exotoxins (Spe) A, B, and F, as determined by immuno-blot analyses. There was no difference in amounts of toxin produced between strains isolated from patients with different manifestations of disease. Levels of TNF alpha, IL1 alpha, IL6, IL8, and IFN gamma in acute-phase sera were determined by use of ELISA and RIA assays. The analyses showed higher levels of IL6 in sera from patients with STSS than in sera from patients with bacteremia without shock. TNF alpha was elevated in sera from patients with STSS, as compared to sera from patients with uncomplicated pharyngotonsillitis. No increase in the levels of IL1 alpha, IL8, and IFN gamma could be found in the patient sera and there was no difference in the level of those cytokines between the various patient categories.
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PMID:Correlation between serum TNF alpha and IL6 levels and severity of group A streptococcal infections. 766 74

The early phase of endotoxin-induced acute hemodynamic disturbances and hypoxemia is mediated by various factors, including eicosanoids and tumor necrosis factor-alpha (TNF alpha). Thromboxane A2 is the major mediator of the early pulmonary hypertension associated with endotoxemia, but the mechanisms underlying the prolonged hemodynamic disturbances observed in ongoing endotoxemia are not well understood. The authors used a chronically instrumental young piglet model to determine the roles of several eicosanoids and of TNF alpha in the prolonged endotoxin-induced pulmonary hypertension and other cardiovascular derangements. Animals were given 40 micrograms/kg endotoxin intravenously per hour for 30 minutes, followed by 20 micrograms/kg per hour. In all animals, persistent pulmonary hypertension, lowered cardiac output, any hypoxemia developed during endotoxin infusion. After 3 hours of endotoxin infusion, randomly ordered infusions of 1 mg/kg dazmegrel (a thromboxane A2 synthesis inhibitor), 5mg/kg nordihydroguaiaretic acid (a 5-lipoxygenase inhibitor), and 20 mg/kg pentoxifylline (A TNF alpha inhibitor) were given intravenously at 30-to-60-minute intervals. Dazmegrel and pentoxifylline lowered pulmonary arterial pressure and resistance and raised arterial oxygen tension. Cardiac output increased significantly after pentoxifylline. These hemodynamic effects persisted for 30-60 minutes, despite continued endotoxin infusion. The elevated plasma concentrations of thromboxane B2 and TNF alpha returned toward preendotoxin baseline values after dazmegrel and pentoxifylline treatment, respectively. No beneficial effects were noted after administration of nordihydroguaiaretic acid. Based on these results, both thromboxane A2 and TNF alpha, but not 5-lipoxygenase products, play active roles in prolonged endotoxin-induced pulmonary hypertension and hypoxemia in young piglets. Combined thromboxane A2 and TNF alpha blockade may be clinically useful in treatment of advanced sepsis in neonates.
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PMID:Delayed thromboxane or tumor necrosis factor-alpha, but not leukotriene inhibition, attenuates prolonged pulmonary hypertension in endotoxemia. 766 5

Gram-negative sepsis and administration of tumor necrosis factor alpha (TNF alpha) are associated with hypotension and peripheral neuropathies suggestive of impaired sympathetic neurotransmission. We examined the effect of TNF alpha on the responses of the bovine pulmonary artery (BPA) to transmural sympathetic nerve stimulation (SNS). BPA contracted to SNS (0.5-32 Hz, 5-10 V, 2-msec duration, 2-msec delay) in a frequency-dependent manner. The contractions of the BPA to SNS were mediated by norepinephrine and activation of postsynaptic alpha 1-adrenoceptors, since they were attenuated by prazosin. Maximum contraction of the BPA to SNS was significantly enhanced (148 +/- 37% increase, n = 6) after inhibition of nitric oxide synthase with L-NG-monomethylarginine (LNMMA, 500 microM), an effect abrogated by L-arginine (1 mM). TNF alpha (0.0042, 0.042, and 0.42 micrograms/ml) selectively inhibited contractions of the BPA to SNS without affecting the contraction of the BPA to exogenous norepinephrine. In BPA incubated with LNMMA (5-500 microM), TNF alpha facilitated rather than inhibited SNS. TNF alpha increased the formation of amperiometrically measured free nitric oxide in bovine adrenal chromaffin cells in primary culture. The data show that in the absence of LNMMA, TNF alpha releases free nitric oxide from a sympathetic neuron and selectively inhibits the contractions of the BPA to SNS. In BPA in which nitric oxide synthase I is inhibited by LNMMA, TNF alpha amplifies the contractions to SNS, even in the absence of endothelium. Thus, TNF alpha can modify vascular smooth muscle tone by affecting SNS. TNF alpha inhibits SNS at the level of the neuron by a mechanism involving the L-arginine-nitric oxide pathway. TNF alpha-induced suppression of SNS and neurotransmission may contribute to the hypotension and peripheral neuropathy of sepsis.
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PMID:Tumor necrosis factor alpha inhibits contractions to sympathetic nerve stimulation by a nitric oxide-dependent mechanism. 768 1

The study deals with an animal model for the problems of surgical intensive care patients. Following repeated applications of E. coli endotoxin WO 111:B4 under standard conditions, specific hemodynamic and biochemical (TNF, TXA2, PGI2, IL-6, PAF) and morphological (endothelium of the lung) alterations were detected. ARDS patterns induced by the sepsis were analyzed by high-frequency measurement of pressure and flow (385 measurements per breathing cycle). The role of the intestine in sepsis was investigated by ion-selective monitoring of surface potassium activity comparing mucosa and serosa. Every injection of endotoxin was followed by a selective increase of the potassium activity revealing relative ischemia induced by the endotoxin. The profile of the potassium levels on the surface correlates both with the cardiac output and with the prostacyclin levels. The continuous narrowing of the difference between mucosa and serosa, potassium during the period of investigation can be regarded as evidence for pathologic change in permeability fostering the septic course.
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PMID:[Septic shock and multiple organ failure in surgical intensive care. An animal experiment model on the analysis of pulmonary and intestinal dysfunction]. 769 Jan 6


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