UMLS:C0036690 - FACTA Search

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

Escherichia coli hemolysin (HlyA) and Staphylococcus aureus alpha-toxin are membrane-perturbating bacterial exotoxins that have been implicated as significant virulence factors in human diseases. We investigated the capacity of these toxins to cause cell activation and mediator release in human endothelial cells, compared with the efficacies of thrombin and the Ca2+ ionophore A23187. Concentration ranges tested were 1 to 1000 ng/ml (HlyA), 0.01 to 10 micro/ml (alpha-toxin), 0.01 to 10 U/ml (thrombin), and 0.01 to 10 microM (A23187). All stimuli caused dose-dependent generation of platelet-activating factor, nitric oxide, and prostaglandin I2. HlyA and thrombin effected time- and dose-dependent accumulation of large quantities of inositol phosphates, with maximum effects at 100 ng/ml and 1 U/ml, respectively. Corresponding time course and dose dependency were noted for HlyA-elicited diacylglycerol formation. In contrast, only the highest concentrations of alpha-toxin (10 microg/ml) and A23187 (10 microM) effected some moderate inositol phosphate accumulation, and this was suppressed in the presence of the platelet-activating factor antagonist WEB 2086. Metabolic and secretory responses elicited by alpha-toxin were dependent on the presence of extracellular Ca2+. We conclude that both HlyA and alpha-toxin are potent inductors of inflammatory and vasodilatory mediators in human endothelial cells. HlyA-elicited effects may proceed predominantly via activation of the phosphatidylinositol hydrolysis-related signal transduction pathway, whereas transmembrane Ca2+ flux appears to be the major event underlying the release of mediators in response to alpha-toxin. These toxin properties may contribute to vasoregulatory and inflammatory disturbances encountered in states of severe infection and sepsis.
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PMID:Human endothelial cell activation and mediator release in response to the bacterial exotoxins Escherichia coli hemolysin and staphylococcal alpha-toxin. 925 56

The effects of hydroxyethyl starch-conjugated deferoxamine (HES-DFO), a macromolecular iron chelator, were investigated on eicosanoid release and bowel wall perfusion following cecal ligation puncture (CLP) in rats. Animals were randomly given an intravenous dose of 3.0 ml of HES-DFO or either vehicle (HES) or 9.0 ml saline immediately following completion of the CLP procedure. At 30, 60, 120, and 240 min after sepsis induction, blood pressure and bowel perfusion were measured. The animals were sacrificed and blood was collected for subsequent analysis of thromboxane, prostacyclin, and prostaglandin F2 alpha. The tissue content of energy-rich phosphates was determined in small-bowel samples at each time point. The antioxidative HES-DFO therapy did not diminish the eicosanoid release after CLP when compared with either HES-treated or saline-infused rats. However, treatment with the polymeric iron chelator resulted in an impaired bowel wall perfusion that was not reflected in alterations in total adenine nucleotide content or in energy charge. Considering hemodynamic and biochemical endpoints, these results are contradictory to the hypothesis that iron-driven oxygen radicals are major determinants of the eicosanoid release that is elevated following CLP-induced sepsis.
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PMID:Effects of hydroxyethyl starch-deferoxamine on arachidonic acid metabolism and small bowel wall perfusion in early sepsis. 928 1

Plasma concentrations of the eicosanoids leukotriene (LT)B4, LTC4D4E4, thromboxane (TX)A2 and prostaglandin (PG)I2, and tumor necrosis factor (TNF) were measured during acute bacteremic shock and injury/hemorrhage in two porcine models. As TXA2 and PGI2 are rapidly metabolized, we measured their stable metabolites TXB2 and 6-keto-PGF1 alpha. Bacteremic shock was induced by a graded infusion of Aeromonas hydrophila over 4 h. Injury/hemorrhage was produced by a 30 min, 30% total blood volume hemorrhage followed by a 30 min shock period and then reinfusion of shed blood. Nociceptive afferent nerve stimulation was applied to the brachial plexi to mimic the cardiovascular responses to tissue injury. There was no increase in eicosanoid or TNF levels in the injury/hemorrhage model. In sepsis there was an early peak in TNF (at 60 min) followed by peaks in LTB4 and LTC4D4E4 at 180 min. Both TXB2 and 6-keto-PGF1 alpha showed large increases at the end of the study but there was no evidence that they had reached a peak. These results suggest that the very early inflammatory response in bacteremic shock and injury/hemorrhagic shock may be quite different. This may have implications for any therapies aimed at reducing the incidence of multiple organ failure after either of these physiological insults.
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PMID:Differences in eicosanoid and cytokine production between injury/hemorrhage and bacteremic shock in the pig. 932 29

Nitric oxide (NO) is a mediator that modulates vessel wall tone and hemostatic-thrombotic balance. Platelet function is regulated by NO generated from platelets, endothelial cells and leukocytes. Nitric oxide has been shown to inhibit platelet adhesion, aggregation, and stimulate disaggregation of preformed platelet aggregates. Many of the effects of NO are mediated by its stimulation of guanylate cyclase and the formation of cyclic GMP and its subsequent transduction mechanism. In vivo, NO is likely to interact with prostacyclin, metabolites of ecto-nucleotidase, and lipoxygenase to modulate platelet function in a synergistic manner. An imbalance of NO production (deficiency or overproduction) has been implicated in the pathogenesis of various vascular disorders including thrombosis, atherosclerosis, septicemia, and ischemia-reperfusion injury. It is likely that some of detrimental effects of NO are mediated through its reaction with superoxide anion to form the potent oxidant, peroxynitrite. Nitric oxide gas and NO donors are used for the pharmacological treatment of various vascular disorders. Because inhaled NO has been documented to improve systemic oxygenation and reduce the need for extracorporeal membrane oxygenation, it has been widely used in neonates with severe hypoxemia. An inhibition of platelet function, resulting in a prolonged bleeding time, has been shown in adults receiving inhaled NO. Because bleeding complications may occur in high-risk infants, it is important to evaluate the effect of inhaled NO on platelet function and its correlation with clinical consequences such as intracranial hemorrhage. For these reasons, hemostasis should be carefully monitored during the administration of inhaled NO to critically ill neonates.
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PMID:Nitric oxide and platelet function: implications for neonatology. 935 13

Acute respiratory distress syndrome (ARDS) adversely affects the outcome of patients with disseminated intravascular coagulation (DIC) associated with sepsis. To determine whether antithrombin III (AT III) is useful for the treatment of ARDS in sepsis, we evaluated the effect of AT III on lipopolysaccharide (LPS)-induced pulmonary vascular injury in rats. Although the intravenous administration of AT III (250 U/kg) prevented LPS-induced pulmonary accumulation of leukocytes, increases in pulmonary vascular permeability, and coagulation abnormalities, inactivated factor Xa, a selective inhibitor of thrombin generation, did not prevent such events other than the coagulation abnormalities. AT III promotes the endothelial release of prostacyclin by interacting with cell surface glycosaminoglycans in vivo. Trp49-modified AT III, which lacks affinity for heparin, did not prevent LPS-induced pulmonary vascular injury. Plasma levels of 6-keto-prostaglandin F1alpha were markedly increased in rats after the administration of LPS and significantly decreased in the LPS-treated rats administered Trp49-modified AT III, but not altered in those LPS-treated rats receiving AT III. Preventive effects of AT III were not observed in rats pretreated with indomethacin, which inhibits prostacyclin biosynthesis. Prostacyclin prevents LPS-induced pulmonary vascular injury by inhibiting leukocyte accumulation in the lungs. These observations strongly suggest that AT III prevents pulmonary vascular injury induced by LPS by promoting the endothelial release of prostacyclin, a potent inhibitor of leukocyte activation.
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PMID:Antithrombin III (AT III) prevents LPS-induced pulmonary vascular injury: novel biological activity of AT III. 946 34

Antithrombin (AT) is a single-chain glycoprotein in plasma and belongs to the family of the serpins. It is synthesized in liver parenchymal cells, and its plasma concentration is between 112-140 mg/L. AT is a unique inhibitor of the clotting system and neutralizes most of the enzymes generated during activation of the clotting cascade, especially thrombin, factors Xa and IXa. Equimolar, irreversible complexes are formed between AT and the enzymes. The interaction between AT and the activated clotting factors is at least 1,000-fold increased in the presence of heparins. Heparins bind to multiple sites of the AT molecule resulting in a steric reconfiguration. Heparins contain a specific pentasaccharide unit which is the minimum requirement for AT binding. The glycosaminoglycan (GAG) heparan sulfate found on endothelial cell surfaces also contains this pentasaccharide and can thus "activate" AT. It is believed that much of the physiological inactivation of enzymes by AT occurs on the endothelium, mediated by heparan sulfate. The binding of AT to the GAGs also releases prostacyclin which possesses strong antiinflammatory properties. Deficiencies of AT are inherited or acquired. Only acquired defects due to increased consumption are discussed, most notably AT in DIC, especially DIC in sepsis. During acute DIC, clotting factors and inhibitors are consumed faster than they can be reproduced. This consumption of AT is of great significance in DIC and sepsis, and plasma AT levels predict outcome. AT levels drop early in sepsis and laboratory signs of DIC can already be found in patients with SIRS and early sepsis. The important role of AT in DIC and sepsis is the basis for considering antithrombin concentrates as an additional therapeutic modality.
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PMID:Antithrombin: its physiological importance and role in DIC. 951 76

Antithrombin III (AT III) supplementation has proven to be effective in the treatment of disseminated intravascular coagulation. Administration of AT III is also useful for prevention of organ failure in animals challenged with endotoxin or bacteria and it increases the survival rate of such animals. Since inhibition of coagulation abnormalities failed to prevent organ failure in animals given bacteria, AT III may exert a therapeutic effect independent of its anticoagulant effect. This therapeutic mechanism of AT III has been explored using an animal model of septicemia. AT III prevented pulmonary vascular injury by inhibiting leukocyte activation in rats given endotoxin. This effect is mediated by the promotion of endothelial release of prostacyclin which inhibits leukocyte activation. Interaction of AT III with heparin-like glycosaminoglycans (GAGs) on the endothelial cell surface appears to be important for this effect. Heparin inhibits these therapeutic effects of AT III by preventing AT III from interacting with the cell surface heparin-like GAGs. This activity of AT III may explain why AT III prevents organ failure as well as coagulation abnormalities in patients with sepsis. This antiinflammatory activity of AT III may be useful for the treatment of organ failure such as in ischemia/reperfusion-induced organ dysfunction, in which activated leukocytes play a critical role.
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PMID:The anti-inflammatory properties of antithrombin III: new therapeutic implications. 951 77

We previously demonstrated that antithrombin III reduced the injury to endothelial cells caused by activated leukocytes in rats administered endotoxin. This occurred via the increase of the endothelial release of prostaglandin I2, which is a potent inhibitor of leukocyte activation. We evaluated the dose of antithrombin III required to prevent such endothelial cell injury in rats administered endotoxin, by comparing the effects of various antithrombin II doses on the pulmonary vascular injury. The intravenous administration of endotoxin, 5 mg/kg, produced a transient accumulation of leukocytes in the lung, followed by pulmonary vascular injury, as indicated by an increase in the pulmonary vascular permeability, and coagulation abnormalities. The dose of 250 U/kg significantly inhibited all such effects of endotoxin. While lower doses of antithrombin III (50 and 100 U/kg) significantly inhibited such coagulation abnormalities, they failed to prevent either the pulmonary accumulation of leukocytes or the subsequent pulmonary vascular injury. Rats administered endotoxin exhibited an accumulation of neutrophils and edematous changes in the pulmonary interstitial space. Although such changes were reduced after 250 U/kg of antithrombin III, they were unaffected by lower doses of 50 and 100 U/kg. Plasma levels of 6-keto-PGF1alpha were markedly increased in rats 90 min after the administration of endotoxin, and were significantly decreased in the endotoxin-treated rats administered the lower doses of antithrombin III (50 and 100 U/kg), but not altered in those endotoxin-treated rats receiving 250 U/kg of antithrombin III. These findings suggest that a higher antithrombin III dose is necessary to prevent endothelial cell injury than is required to inhibit coagulation abnormalities in an animal model of sepsis. These observations support the notion that antithrombin III may prevent endotoxin-induced endothelial cell injury by promoting endothelial release of prostaglandin I2 and thus inhibiting leukocyte activation.
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PMID:Effects of various doses of antithrombin III on endotoxin-induced endothelial cell injury and coagulation abnormalities in rats. 964 17

Replacement of antithrombin has proved to be effective for treating disseminated intravascular coagulation. The administration of antithrombin is also useful for preventing organ failure in animals challenged with endotoxin or bacteria, and it increases the survival rate of such animals. Since inhibition of coagulation abnormalities by heparin failed to prevent organ failure in animals challenged with bacteria, antithrombin might exert therapeutic effects independently of its anticoagulant effect. These therapeutic mechanisms of antithrombin have been explored by using animal models of septicemia. Antithrombin prevents pulmonary vascular injury by inhibiting leukocyte activation in rats challenged with endotoxin. A higher dose of antithrombin was required to prevent pulmonary vascular injury than was required to inhibit disseminated intravascular coagulation. This preventive effect of antithrombin is mediated by the promotion of endothelial release of prostacyclin, an inhibitor of leukocyte activation. An interaction between antithrombin and heparin-like glycosaminoglycans on the endothelial cell surface appears to be important for this effect. Heparin inhibits such therapeutic effects of antithrombin by preventing it from interacting with the cell surface heparin-like glycosaminoglycans. Since activated leukocytes are of critical importance in patients with sepsis-associated organ failure, this anti-inflammatory activity of antithrombin may explain why it can prevent organ failure as well as coagulation abnormalities in patients with sepsis.
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PMID:Antithrombin prevents endotoxin-induced pulmonary vascular injury by inhibiting leukocyte activation. 966 67

Antithrombin (AT) is an important inhibitor of the coagulation system, acting at many different levels of the coagulation cascade. This inhibitory action is enhanced several-fold by the glycosaminoglycan heparin. AT deficiency can be encountered in hereditary disorders, which are rare, or in acquired conditions, in which there is an excessive consumption of AT. Acquired AT deficiency is a common condition in sepsis, after major trauma or surgery, with or without associated disseminated intravascular coagulation (DIC). In these conditions, low levels of AT have been correlated with a poor outcome due to the development of multiple organ failure. Although supplementation with AT has been shown to attenuate the extent of organ failure in critically ill patients, it has not been possible to significantly improve the survival of these patients by administration of AT. An interesting new approach to AT treatment is based on the hypothesis that AT has specific effects that are independent of the coagulation cascade. Data from cell culture and animal experiments have demonstrated that AT can promote the endothelial production of prostacyclin and may therefore have anti-inflammatory actions. This effect is based on the interaction of AT with glycosaminoglycans in the cell membrane, and is independent of heparin. The role of AT in vessel wall antithrombogenicity is being increasingly appreciated. The concept of neointimal hyperplasia following vascular injury involves thrombin as an important mediator and thus, in addition to the anti-inflammatory effects of AT, new horizons in which AT may have an important role in the prevention of post-traumatic hyperplastic response are also evolving.
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PMID:Antithrombin: facts and new hypotheses. 1010 92

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