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

After the discovery by Furchgott and colleagues in 1980 that the endothelium plays an obligatory role in acetylcholine-induced vasodilation many investigators have elucidated the role of the endothelium in the regulation of vascular tone. While the sympathetic nervous system serves the organism as a whole, the endothelium appears to act as a local regulator adapting blood flow to local metabolic needs. A variety of endothelium-derived relaxing and contracting factors such as nitric oxide, prostacyclin, endothelium-derived hyperpolarizing factor, endothelin and thromboxane A2 play a role in the endothelium-dependent control of vascular tone. Furthermore, nitric oxide inhibits thrombocyte aggregation and adhesion. Many diseases have been reported to be associated with an impaired endothelium-dependent vasodilation which may contribute to an increased susceptibility to vasospasm, decreased inhibition of thrombus formation and an impaired ability to reduce vascular resistance in ischaemic conditions. In hypertension, hypercholesterolaemia and diabetes mellitus this impairment may be interpreted as an early marker of a process that ultimately will lead to atherosclerosis. The impaired endothelium-dependent vasodilation probably contributes to the increased peripheral vascular resistance in hypertension and heart failure. The role of the endothelium does not seem to be restricted to cardiovascular diseases. Several mediators of inflammation stimulate the endothelium to release nitric oxide, suggesting an important role of the endothelium in the haemodynamic sequelae of sepsis.
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PMID:Endothelium and the regulation of vascular tone with emphasis on the role of nitric oxide. Physiology, pathophysiology and clinical implications. 820 3

Eicosanoids were discovered as "prostaglandins" in the mid-1930s. The discovery that eicosanoids were ubiquitous in mammalian cells and that nonsteroidal anti-inflammatory drugs worked by inhibiting enzymes that synthesized these chemicals heralded their extensive investigation in all fields of biology. Precursor fatty acids (arachidonic acids) are stored in cell phospholipids, acted on by two enzymes (cyclooxygenase and lipooxygenase) that yield prostaglandins, thromboxane, prostacyclin, and leukotrienes. Knowledge of their biochemical processes continue to unfold, but it is now believed that eicosanoids are part of a larger group of agents termed phospholipid mediators. Eicosanoids are intimately involved with cardiovascular function as well as central and peripheral vascular disease processes and ischemia. In the gastrointestinal tract, these potent lipids not only participate in many normal functions (eg, acid secretion and motility) but also in disease states (eg, inflammatory bowel disease and peptic ulcer disease). In shocklike states of sepsis and/or endotoxemia, eicosanoids have assumed a major role in many events that occur. Recently, discoveries have demonstrated that platelet-activating and tumor necrosis factors exert their effects in part through eicosanoids. The future will demonstrate these compounds to be critical not only in intracellular (molecular) events but also in the effects they produce that are far from the source of origin.
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PMID:Eicosanoids. Critical agents in the physiological process and cellular injury. 823 81

The aim of this study was to investigate a possible activation of human endothelial cells in monolayer culture by a purified neutrophil-derived proteinase, i.e. elastase. Cells were isolated from human umbilical cord veins, and incubated either in primary culture or after two passages, in the presence of various concentrations of this proteinase. Although a lack of prostacyclin formation was noted, elastase induced a large release of von Willebrand factor (vWf) in a concentration-dependent manner. Thus, upon incubation with 1 microgram.ml-1 elastase for 30 min, 70 mU.ml-1 vWf were detected in the incubation medium, as compared to 5 mU.ml-1 for control. Using cells in primary culture, a fivefold higher concentration of vWf was recovered following incubation with 10 micrograms.ml-1 elastase than with 0.5 IU.ml-1 thrombin. This effect was linked to the enzymatic activity of elastase and not to its cationic charge, as deduced from the inhibition by eglin C, and the lack of effect of the phenylmethylsulphonyl fluoride (PMSF) treated proteinase. We conclude that vWf release was not due to cell activation, since cytoplasmic calcium mobilization was absent, and inhibition of protein kinase C did not modify the response. In fact, this release was the consequence of cell damage, since concentrations of vWf recovered correlated with cell lysis. These results support the hypothesis that the high level of plasma vWf in patients with sepsis or adult respiratory distress syndrome could result from damage to the endothelial cells by elastase released from activated neutrophils.
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PMID:Leucocyte elastase-mediated release of von Willebrand factor from cultured endothelial cells. 833 96

Two case reports are presented where inhaled aerosolized prostacyclin (IAP) was used to good effect as a selective pulmonary vasodilator. It was used in the treatment of a patient with severe hypoxaemia secondary to amniotic fluid embolism and for hypoxaemia secondary to the acute respiratory distress syndrome (ARDS) in a patient with acute on chronic liver failure and intra-abdominal sepsis. An apparent dose-response curve is demonstrated in the second case. A dose of IAP of 30-40 ng/kg/min produced an effect on oxygenation in the patient with liver failure equal to that seen at the maximal dose of (50 ng/kg/min). Reduction in dose below 30 ng/kg/min resulted in a deterioration in oxygenation towards baseline/pre-treatment levels. Inhaled aerosolized prostacyclin is a potent pulmonary vasodilator with little or no systemic hypotensive effect. It is simple to administer and would appear to be a viable alternative to inhaled nitric oxide.
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PMID:Inhaled aerosolized prostacyclin as a selective pulmonary vasodilator for the treatment of severe hypoxaemia. 886 63

We evaluated the effect of interleukin-6 (IL-6) on the production of prostacyclin (PGI2) by cultured human pulmonary artery smooth muscle cells (HPASMC). Incubation of these cells for up to 48 h with IL-6 led to a dose- and time-dependent decrease in the concentration of PGI2 in the culture medium. The incubation of HPASMC with 10 micrograms/ml of lipopolysaccharide (LPS), 200 U/ml of IL-1 beta, or 500 U/ml of TNF alpha for 24 hr significantly increased the concentration of PGI2 in the medium. However, the addition of IL-6 to a medium containing LPS, IL-1 beta, or TNF alpha significantly inhibited the stimulatory effect of those substances on PGI2 production. Such inhibition was closely related to the concentration of IL-6. IL-6 may counteract the roles of LPS and of other cytokines on the regulation of pulmonary vascular tension in endotoxin- and cytokine-mediated disorders such as sepsis and the acute respiratory distress syndrome (ARDS).
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PMID:Inhibitory effects of interleukin-6 on release of PGI2 by cultured human pulmonary artery smooth muscle cells. 888 Aug 95

A wide range of immunomodulating agents are now available which may be of benefit in reducing inflammatory cell activation in meningococcal sepsis. In order to facilitate selection of candidate anti-inflammatory agents for clinical trials, we have used an in vitro whole blood model to evaluate the effects on meningococcal induced neutrophil and monocyte activation, of dexamethasone, prostacyclin, pentoxifylline and a human IgM anti-lipid A monoclonal antibody (HA-1A). Known concentrations of heat and penicillin killed meningococci were added to whole blood and the time course of cellular activation was determined. Using elastase alpha 1-antitrypsin (elastase-alpha 1-AT) and TNF alpha production as markers of neutrophil and monocyte activation respectively, plasma levels of elastase-alpha 1-AT and TNF alpha were found to increase in a dose-dependent manner. Elastase-alpha 1-AT was detected early, with most release occurring between 15-30 min whereas TNF alpha was detected later, between 120-180 min. Dexamethasone, prostacyclin and pentoxifylline caused a dose-dependent inhibition of TNF alpha release but had no effect on elastase release. HA-1A had no effect on either TNF alpha or elastase release. This model may be useful in determining the sequence of inflammatory cell activation and in selecting candidate anti-inflammatory agents for evaluation in clinical trials.
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PMID:Assessment of the effect of candidate anti-inflammatory treatments on the interaction between meningococci and inflammatory cells in vitro in a whole blood model. 901 41

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

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


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