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

We examined the effects of tumor necrosis factor-alpha (TNF alpha) stimulation of endothelial cells on the increase in endothelial permeability induced by H2O2. Bovine pulmonary microvascular endothelial cells (BPMVEC) were grown to confluence on a microporous filter and the 125I-albumin clearance rate across the monolayer was determined. Pretreatment with TNF alpha (100 U/ml) for 6 h had no direct effect on transendothelial 125I-albumin permeability. However, TNF alpha pretreatment enhanced the susceptibility of BPMVEC to H2O2; that is, H2O2 (10 microM) alone had no direct effect, whereas H2O2 increased 125I-albumin permeability more than threefold when added to monolayers pretreated for 6 h with TNF alpha. Determination of lactate dehydrogenase release indicated that increased permeability was not due to cytolysis. We measured the intracellular contents of GSH and catalase to determine their possible role in mediating the increased susceptibility to H2O2. TNF alpha treatment (100 U/ml for 6 h) decreased total GSH content and concomitantly increased the oxidized GSH content, but did not alter the cellular catalase activity. The role of GSH was examined by pretreating endothelial cells with 2 mM GSH for 3 h, which produced an 80% increase in intracellular GSH content. GSH repletion inhibited the increased sensitivity of the TNF alpha-treated endothelial cells to H2O2. We tested the effects of xanthine oxidase (XO) inhibition since XO activation may be a source of oxidants responsible for the decrease in cellular GSH content. Pretreatment with 0.5 mM oxypurinol attenuated the synergistic effect of TNF alpha and H2O2 on endothelial permeability. The results indicate that decreased oxidant buffering capacity secondary to TNF alpha-induced reduction in intracellular GSH content mediates the increased susceptibility of endothelial cells to H2O2. This mechanism may contribute to oxidant-dependent vascular endothelial injury in septicemia associated with TNF alpha release.
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PMID:Tumor necrosis factor-alpha-mediated decrease in glutathione increases the sensitivity of pulmonary vascular endothelial cells to H2O2. 154 73

TNF is a major mediator in the pathogenesis of endotoxic shock, and its inhibition has a protective effect in various animal models of sepsis or endotoxin (lipopolysaccharide, LPS) toxicity. LPS treatment also induces an oxidative damage mediated by increased production of reactive oxygen intermediates. N-Acetylcysteine (NAC) is an antioxidant and a precursor of the synthesis of glutathione (GSH) and was reported to protect against LPS toxicity and LPS-induced pulmonary edema. In this study we investigated the effect of NAC on TNF production and LPS lethality in mice. The results indicated that oral administration of NAC protects against LPS toxicity and inhibits the increase in serum TNF levels in LPS-treated mice. The inhibition was not confined to the released form of TNF, since NAC also inhibited LPS-induced spleen-associated TNF. On the other hand, the inhibitor of GSH synthesis, DL-buthionine-(SR)-sulfoximine (BSO), had the opposite effect of potentiating LPS-induced TNF production, and this was associated with a decrease in liver GSH levels. Repletion of liver GSH with NAC reversed this effect. NAC was also active in inhibiting TNF production and hepatotoxicity in mice treated with LPS in association with a sensitizing dose of Actinomycin D. These data indicate that GSH can be an endogenous modulator of TNF production in vivo. On the other hand, NAC pretreatment did not inhibit other effects of LPS, particularly induction of serum IL-6, spleen IL-1 alpha, and corticosterone, in the same experimental model, suggesting that the observed effect could be specific for TNF.
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PMID:N-acetylcysteine and glutathione as inhibitors of tumor necrosis factor production. 154 68

Group B streptococcus (GBS), a common neonatal gram-positive pathogen, causes similar pathophysiology in human newborns and neonatal animal models of sepsis. Animal models of GBS sepsis demonstrate a two-phase response: 1) an acute phase (less than 1 h) of increased pulmonary artery pressure (Ppa) and reduced arterial oxygen pressure (PaO2) that is associated with increased serum thromboxane B2 (TxB2) and 2) a late phase (2-4 h) of persistently increased Ppa and reduced PaO2, reduced systemic arterial pressure, and progressive fall in cardiac output that is associated with increased serum TxB2, 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), and tumor necrosis factor-alpha (TNF alpha). We hypothesized that pretreatment of piglets with both pentoxifylline (PTF), an inhibitor of TNF alpha production and activity, and indomethacin (INDO) would 1) inhibit GBS-induced TxB2, 6-keto-PGF1 alpha, and TNF alpha and 2) prevent both the acute- and late-phase physiologic responses of GBS sepsis. Combined PTF and INDO pretreatment of anesthetized, mechanically ventilated piglets infused with GBS (1.25 x 10(9) colony forming units/kg/h) for 4 h prevented GBS-induced increases in Ppa at 1 h (GBS + PTF + INDO: 1.8 +/- 0.07 kPa versus GBS alone: 4.7 +/- 0.1 kPa) and markedly attenuated increases in Ppa at 4 h (GBS + PTF + INDO: 2.1 +/- 0.1 kPa versus GBS alone: 4.4 +/- 0.1 kPa).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Group B streptococcal sepsis in piglets: effect of combined pentoxifylline and indomethacin pretreatment. 156 Oct 7

The cytokine tumor necrosis factor-alpha (TNF alpha) is one of the major mediators of septic shock. Because vasodilation is a hallmark of sepsis and decreased vascular responsiveness has been implicated in the pathogenesis of septic shock, we studied the effect of TNF alpha on the mean blood pressure in conscious rats and vascular responsiveness to vasoconstrictors ex vivo using the standard organ bath method. Intravenous infusion of TNF alpha (0.006 or 0.06 mg/kg/hr for 10 hours) decreased mean blood pressure in a dose-dependent fashion. Contractile responses to norepinephrine were depressed dose-dependently in the aortic rings both with and without its endothelium. Aortic contractions by potassium depolarization were also depressed. These results suggest that TNF alpha induces non-specific vascular hyporesponsiveness, which is independent of the presence of the endothelium. The TNF alpha-induced vascular hyporesponsiveness might contribute to the hypotensive action of TNF alpha.
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PMID:Tumor necrosis factor-alpha induces vascular hyporesponsiveness in Sprague-Dawley rats. 157 76

Endotoxin in the form of a lipooligosaccharide (LOS) plays a key role in the development of shock in meningococcal sepsis. To examine hemodynamic and biochemical alterations during meningococcal endotoxic shock, we established a rabbit model. Thirty-nine rabbits, weighing 2.5-4.4 kg, were studied. After anesthesia with intramuscular ketamine (20 mg/kg) and xylazine (4 mg/kg), femoral venous and arterial catheters were inserted. Control animals received only saline, while rabbits in each of four additional groups were given LOS in 10-fold increments from 0.1 microgram/kg to 100 microgram/kg. Mean arterial pressure (MAP), heart rate (HR), respirations (RR), temperature (T), urine output, and arterial blood gases (pH, PCO2, PO2, and bicarbonate) were determined at baseline and hourly. Endotoxin levels and TNF levels were measured at 30, 60, 120, 180, 240, 300, and 360 min post-LOS. Survival was recorded. One-way analysis of variance (ANOVA) and the Scheffe procedure, paired samples t-test, two-tailed t-test, and Fisher's exact test were used. Pearson's coefficients were calculated. Animals receiving meningococcal LOS developed tachycardia and compensated metabolic acidosis with an initially normal pH and MAP. With progression of the shock state, the pH decreased and hypotension ensued. Maximal levels of endotoxin were measured 30 min after LOS injection and declined during the ensuing 6 hr. TNF rose from undetectable to markedly elevated levels and peaked at 60-120 min post-LOS. Increasing the amount of injected endotoxin produced more profound degrees of shock until a dose of 10.0 micrograms/kg was reached. There was no correlation between serum TNF at 60 min and survival at 6 hr or 24 hr.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of meningococcal endotoxin in a rabbit model of shock. 158 1

Tumor necrosis factor-alpha (TNF alpha) has been implicated as an endogenous mediator of the cardiovascular manifestations of sepsis and septic shock. We studied the acute effects of a single dose (50 or 200 micrograms/kg) of intravenous recombinant human TNF alpha (rhTNF alpha) on myocardial function in halothane-anesthetized dogs. Regional cardiac dimensions were measured by using sonomicrometry. Intracavitary left ventricular, ascending aortic, and pulmonary artery pressures were measured by use of micromanometers. Cardiac index was determined by means of thermodilution. Myocardial performance was analyzed by assessing changes in the slope of the left ventricular end-diastolic length-stroke work relationship obtained by performing transient vena caval occlusions. Animals were resuscitated by means of normal saline solutions to maintain baseline regional end-diastolic length. Over a 3-hour period of observation, rhTNF alpha decreased systemic vascular resistance index, but the cytokine did not compromise intrinsic myocardial performance. The circulatory response to rhTNF alpha was a hyperdynamic state characterized by tachycardia, augmented cardiac index, and increased intrinsic myocardial contractility (leftward shift of the left ventricular end-diastolic length-stroke work relationship). In addition, rhTNF alpha caused systemic acidosis and increased plasma levels of prostacyclin metabolite (6-keto-prostaglandin F1 alpha). After the dose of rhTNF alpha large volumes of fluid were required to maintain baseline end-diastolic length. We conclude that in the acute setting, rhTNF alpha elicits abnormalities in peripheral vascular tone that are not accompanied by depression of myocardial function.
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PMID:Load-insensitive assessment of myocardial performance after tumor necrosis factor-alpha in dogs. 159 65

To reduce the very high mortality rate due to septic shock, a new clinical entity has been defined: sepsis syndrome. The aggressive treatment of any sepsis syndrome should prevent the evolution towards a state of shock and thus reduce the risk of a fatal outcome. It consists in broad spectrum antibiotic therapy associated with hemodynamic support (volume resuscitation, vasopressors and inotropic agents) at the first signs of cardiocirculatory failure. Several pharmacological or immunological interventions--antagonists directed at mediators and multiple cytokines involved in the pathogenesis and perpetuation of sepsis syndrome and septic shock--have been successful experimentally. However, new therapies, such as those using monoclonal antibodies against endotoxins of TNF, cannot yet be considered established.
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PMID:[Sepsis syndrome: progress and therapeutic perspectives]. 160 83

To study the role of interferon-gamma (IFN-gamma) in gram-negative shock, mortality was compared in mice receiving either a monoclonal antibody to IFN-gamma (H22) or an irrelevant monoclonal antibody (L2-3D9) before or after an LD90 dose of Escherichia coli O111:B4. H22 given either 1 h before or 0.5 h after bacterial challenge protected mice from death (mortality at 48 h, 28% vs. 83%, P less than .001). Serum tumor necrosis factor-alpha (TNF alpha) levels and bacterial counts in blood and organs (liver, spleen, heart, and brain) were similar in H22-treated animals and controls. The peak serum TNF alpha levels were 95.7 +/- 16.4 ng/mL and 80.7 +/- 14.9 ng/mL in the H22 and control groups, respectively. These results indicate that IFN-gamma plays a significant role in the pathogenesis of gram-negative sepsis.
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PMID:Role of interferon-gamma in experimental gram-negative sepsis. 163 4

Sepsis or septic shock is frequently associated with activation of the complement system, coagulation and fibrinolytic changes and the release of several cytokines. In this study we analyzed the relation of complement activation to the inflammatory mediators, hemodynamic and biochemical parameters and severity of illness and outcome in 20 consecutive patients with clinically defined sepsis. Levels of C3a and C3d were elevated in 90% of the patients (median levels 0.19 mg/l and 8.6 mg/l respectively) in comparison to 14% and 42%, respectively of 7 patients with non-septic shock. Levels of C4 were decreased in only 1 of the 20 septic patients. Levels of TNF and IL-6 were elevated in 94% and 100% of the patients, Levels of TNF and IL-6 were elevated in 94% and 100% of the patients, respectively (median levels 122 ng/l and 1300 U/ml) and were clearly interrelated (r = 0.67, p less than 0.01). C3a levels correlated with the APACHE II score (r = 0.57, p less than 0.05) and high C3a levels were associated with fatal outcome (p less than 0.05). C3a was also correlated inversely with mean arterial pressure (r = 0.50, p less than 0.01). Levels of complement C3a and C3d significantly correlated with levels of plasminogen activator inhibitor-1 (PAI) and correlated inversely with AT-III levels. We found no correlation between these complement products and leukocyte counts or lactate levels, nor was there a correlation between C3a or C3d and the cytokines TNF and IL-6. Levels of C3a and C3d did not decrease significantly during the first 24 h of treatment, in contrast to a clear decrease in IL-6 levels in all patients and a decrease in TNF in the surviving patients. TNF levels remained stable or increased in the non-survivors. We conclude that both the complement system and the cytokine system are involved in the pathogenesis of septic shock and may be involved in the development of some of the fatal complications like hypotension and disseminated intravascular coagulation.
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PMID:Complement activation and the production of inflammatory mediators during the treatment of severe sepsis in humans. 164 97

We investigated the production of chemical mediators by hepatic macrophages from rats with sepsis and the modulation of hepatocyte function by these hepatic macrophages. The chemical mediators we measured were superoxide (O2-), TNF, IL-1, and PGE2. Production of these mediators by hepatic macrophages from rats with sepsis was significantly increased. Furthermore, protein synthesis by cultured hepatocytes was inhibited in a co-culture system of hepatocytes and hepatic macrophages from rats with sepsis, and it was even inhibited by the supernatant of cultured hepatic macrophages from septic rats. These results demonstrate that hepatic macrophages are activated in sepsis and may play a role in inducing hepatic dysfunction in sepsis.
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PMID:Enhancement and hepatocyte-modulating effect of chemical mediators and monokines produced by hepatic macrophages in rats with induced sepsis. 165


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