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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 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

In an uncontrolled clinical trial the effects of repeated administration of the F(ab')2 fragment of a murine monoclonal anti-tumor necrosis factor alpha (TNF alpha)-antibody (MAK 195F) on cytokine levels and the cardiovascular system were studied in 20 patients with severe sepsis. Patients were treated with a total of 11 single dosages of the anti-TNF alpha-antibody intravenously over 5 days using either 1 mg/kg (n = 10) or 3 mg/kg (n = 10). The anti-TNF alpha-antibody was well tolerated in all patients without signs of toxicity and without development of anti-murine antibodies. As assessed by cytokine levels (TNF alpha, Interleukin-6) and hemodynamics there was no evidence that the higher dosage of the anti-TNF alpha-antibody (3 mg/kg per dose) was more effective than the lower dosage (1 mg/kg per dose). Comparison of our data with recent data from phase I or II trials using a complete murine monoclonal anti-TNF alpha-antibody suggest that the F(ab')2 fragments of the murine monoclonal anti-TNF alpha-antibody may be of similar efficacy. Definitive conclusions, however, with respect to improvement of mortality and improvement of the cardiovascular system, await the results of larger ongoing placebo-controlled trials.
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PMID:Repeated administration of a F(ab')2 fragment of an anti-tumor necrosis factor alpha monoclonal antibody in patients with severe sepsis: effects on the cardiovascular system and cytokine levels. 773 57

In 20 patients with severe sepsis, skeletal muscle pO2 was continuously measured in order to assess whether a decrease of skeletal muscle pO2 was accompanied by an improvement of sepsis after repeated administration of F(ab')2 fragments of a murine anti-TNF alpha-antibody. Abnormally high skeletal muscle pO2 decreased from 43.5 +/- 10.9 mmHg (day 0) to 36.4 +/- 10.1 mmHg within 24 h after the first administration of anti-TNF alpha-antibody (day 1, p = .006, n = 20) and remained at 34.6 +/- 7.7 mmHg thereafter (mean day 2-7, p = .004). The decrease of skeletal muscle pO2 within 24 h exceeded 5 mmHg (-7 to -19 mmHg) in 11 patients in contrast to nine patients (-4 to +4 mmHg). Only in the patients showing a decrease of skeletal muscle pO2 did sepsis improve as determined by Elebute score, APACHE II score, and interleukin-6 serum levels. The change of skeletal muscle pO2 within 24 h was associated with a change of interleukin-6 serum levels within 24 h (r = .5, n = 20), with a change of Elebute score (r = .7, n = 20) and of APACHE II score (r = .62). These data suggest that a decrease of skeletal muscle pO2 might be an early indicator of improvement of sepsis after administration of anti-TNF alpha-antibodies.
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PMID:Changes in skeletal muscle pO2 after administration of anti-TNF alpha-antibody in patients with severe sepsis: comparison to interleukin-6 serum levels, APACHE II, and Elebute scores. 773 58

Septic shock is characterized by surges of tumor necrosis factor-alpha (TNF-alpha) along with myocardial dysfunction and systemic hypotension. TNF-alpha promotes the release of immunoreactive endothelin (ET). Because TNF-alpha is elevated in septic shock, we hypothesized that elevated levels of endothelin can contribute to cardiac dysfunction and hypotension. We infused live Pseudomonas aeruginosa into anesthetized, hemodynamically monitored young swine and measured ET and TNF-alpha. Septic swine developed systemic arterial hypotension and had significantly elevated TNF-alpha (4.15 +/- .41 U/ml at 1 h versus .40 +/- .13 U/ml at time zero) compared to control animals. ET levels were significantly elevated at 4 h (52.38 +/- 12.88 pg/ml vs. 10.45 +/- 1.82 pg/ml at time zero) and correlated negatively with the decline in cardiac output. We then passively immunized swine using anti TNF-alpha prior to the induction of sepsis to examine if TNF played a central role in the release ET. The anti TNF-alpha effectively removed circulating TNF-alpha bioactivity in septic animals. Anti-TNF-alpha-treated animals did not develop significant systemic arterial hypotension and had significant attenuation in endothelin (19.01 +/- 4.18 pg/ml at 4 h compared to 52.38 +/- 12.88 pg/ml in septic animals at 4 h) which correlated with preservation of cardiac output. TNF-alpha may cause cardiac dysfunction in sepsis syndrome through increased release of ET.
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PMID:Release of endothelin in relation to tumor necrosis factor-alpha in porcine Pseudomonas aeruginosa-induced septic shock. 774 36

Group B streptococci (GBS) are an important cause of sepsis and shock in the new-born. We have previously reported that GBS induce the production of tumour necrosis factor-alpha (TNF-alpha) by human monocytes and culture-derived macrophages. We have also shown that fibronectin (FN) promotes interaction between GBS and human phagocytes. In the present study, we investigated the effect of FN and GBS on the production of TNF-alpha by adult and neonatal culture-derived macrophages. We report that soluble FN alone was a strong stimulus for the production of TNF-alpha by culture-derived macrophages (FN 50 micrograms/ml = 623.33 +/- 47 pg/ml TNF, versus media alone 3 +/- 1.5 pg/ml; P < 0.0001). While GBS also induce the production of TNF-alpha by macrophages, the addition of FN to GBS had more than an additive effect on TNF-alpha levels. FN-mediated TNF-alpha production by macrophages was inhibited by both soluble arginine-glycine-aspartic acid (RGD) peptide (71%; P < 0.0001) and anti-beta 3-integrin monoclonal antibody 7G2 (54%; P < 0.0001). Neonatal culture-derived macrophages produced significantly more TNF-alpha in response to GBS (356.4 pg/ml +/- 27.7) than adult cells did (222.0 pg/ml +/- 21.0; P = 0.037), and dramatically more in response to FN alone (neonatal 1931.0 pg/ml +/- 23.0 versus adult 463.5 43.5 pg/ml; P < 0.0001). FN may contribute to the high levels of TNF-alpha production implicated in the pathophysiology of GBS sepsis and shock.
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PMID:Effects of fibronectin and group B streptococci on tumour necrosis factor-alpha production by human culture-derived macrophages. 775 Oct 28

Tumor necrosis factor-alpha (TNF-alpha), a monokine that contributes to vascular dysfunction accompanying the host response to gram-negative sepsis, has been shown to increase vascular permeability in vivo and to diminish the barrier function of cultured endothelial cell (EC) monolayers. The studies reported here indicate that a mechanism through which TNF alters EC barrier function involves a reduction in intracellular adenosine 3',5'-cyclic monophosphate (cAMP) content, due in part to increased cyclic nucleotide phosphodiesterase (CNPDE) activities. TNF increased the diffusional transit of [3H]sorbitol, [3H]inulin, and 125I-labeled albumin across confluent bovine aortic EC monolayers. This effect of TNF was both time and dose dependent and occurred in parallel with a fall in EC cAMP. cAMP analogues, such as dibutyryl cAMP (DBcAMP), prevented TNF-induced perturbation of EC barrier function. TNF also mediated another important alteration in the EC phenotype, in that both mRNA and activity of the anticoagulant cofactor thrombomodulin were reduced after exposure of EC to TNF and were normalized by the addition of DBcAMP. EC monolayers exposed to TNF-alpha showed increased cAMP levels when exposed to 3-isobutyl-1-methylxanthine, a nonspecific CNPDE inhibitor. Ion exchange chromatography of cytosol derived from TNF-treated EC consistently showed an approximately 245% increase in phosphodiesterase (PDE) IV (high-affinity, cAMP-specific PDE) activity as identified by rolipram inhibition. PDE II activity was increased by 150% after TNF-alpha treatment of early passage EC, which was identified by cGMP-activated hydrolysis of cAMP. Western and Northern analyses, as well as activity studies, revealed that TNF treatment did not change the amount of PDE IV protein or mRNA but rather increased the specific activity of the isozyme, suggesting that a posttranslational modification had occurred. These data indicate that activation of EC CNPDE activity and decreased intracellular cAMP may represent a mechanism by which TNF increases EC permeability and promotes a procoagulant EC phenotype.
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PMID:TNF modulates endothelial properties by decreasing cAMP. 776 2


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