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

Studies indicate that hepatocellular dysfunction occurs at 2 h after cecal ligation and puncture (CLP, i.e., sepsis model) despite the increased cardiac output (CO) and hepatic perfusion. It, however, remains unknown whether hepatocellular function is depressed earlier than the onset of hyperdynamic circulation in sepsis. To determine this, rats were subjected to sepsis by CLP. At .5, 1, 1.5, or 2 h after CLP, CO was measured by dye dilution. Hepatocellular function (i.e., maximum velocity of indocyanine green clearance and the efficiency of the active transport) was determined using an in vivo indocyanine green clearance technique. Microvascular blood flow was measured by laser Doppler flowmetry. To determine whether there is any association between hemodynamics and prostaglandins (PGs), plasma levels of PGE2 and PGI2 were measured by radioimmunoassay. The results indicate that hepatocellular function decreased significantly as early as 1.5 h after CLP. Cardiac output and microvascular blood flow in the liver and small intestine, however, increased and vascular resistance decreased at 2 h after CLP. Thus, hepatocellular dysfunction occurs earlier than the occurrence of hyperdynamic circulation during sepsis. Although circulating PGE2 levels were not altered, plasma PGI2 increased significantly at 2 h after CLP. The elevated circulating PGI2 levels, therefore, may be partially responsible for the decreased vascular resistance and increased tissue perfusion at 2 h after CLP. Our findings also suggest that cellular dysfunction, observed in the very early stage of sepsis, is not due to any hyperdynamic circulation/hypermetabolism-related events, but may be associated with the release of proinflammatory cytokines.
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PMID:Hepatocellular dysfunction occurs earlier than the onset of hyperdynamic circulation during sepsis. 785 May 75

To examine the roles of thromboxane A2 and prostaglandin I2, which are arachidonic acid metabolites found in patients with sepsis, we measured the serum levels of their respective stable metabolites, thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) in 22 patients with sepsis. Results were analyzed in relation to patients' survival. The levels of both TXB2 and 6-keto-PGF1 alpha were significantly higher in patients who died than in those who survived, thus reflecting the severity of the patients' illness. There was a significant correlation between the levels of TXB2 and 6-keto-PGF1 alpha. These findings suggest that TXA2 and PGI2 are chemical mediators involved in the severity of clinical sepsis.
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PMID:Relationship between thromboxane B2 and 6-keto-prostaglandin F1 alpha in sepsis. 800 79

Nitric oxide (NO) and prostaglandins (PG) both possess the ability to induce vasodilatation and prevent the aggregation of platelets. The synthesis of these substances is increased following in vivo lipopolysaccharide (LPS) infusion, but their function during sepsis is incompletely understood. We studied the role of NO and PG in a murine model of chronic hepatic inflammation (Corynebacterium parvum injection), which is known to progress to sudden hepatic necrosis after LPS injection. NO synthesis, which is induced in hepatocytes by C. parvum treatment and in nonparenchymal cells by LPS treatment, was inhibited using NG-monomethyl-L-arginine (L-NMMA). High-dose aspirin (ASA) was used to block PG synthesis. Treatment with L-NMMA or ASA alone, in the absence of LPS, resulted in no increase in hepatic injury. C. parvum-treated mice that received both L-NMMA and ASA without LPS developed marked hepatic damage as reflected by increased hepatocellular enzyme release (aspartate aminotransferase and L-ornithine carbamoyl-transferase). Marked hepatic damage was seen after LPS administration, and ASA pretreatment alone had no effect on the LPS-induced hepatic injury, whereas L-NMMA markedly increased the hepatic damage. The combination of L-NMMA and ASA after LPS resulted in the greatest hepatocellular enzyme release, characterized histologically by intravascular thrombosis with diffuse infarction and necrosis. Simultaneous treatment with either PGI2 or L-arginine partially prevented this injury. These data demonstrate that NO and PG function synergistically to maintain hepatocellular integrity; thus increased synthesis of these mediators protects the liver from the pathophysiological effects of LPS in this model.
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PMID:Nitric oxide and prostaglandins interact to prevent hepatic damage during murine endotoxemia. 802 33

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

The effects of a 21-aminosteroid, tirilazad mesylate (U74006F; The Upjohn Co., Kalamazoo, MI), developed for treatment of central nervous system trauma in human beings, on eicosanoid and tumor necrosis factor (TNF) generation were evaluated in both healthy and endotoxin-challenged neonatal calves. Endotoxemia was induced in 24 neonatal calves by intravenous infusion of Escherichia coli lipopolysaccharide (3.25 micrograms/kg) over 3 hr. Group I calves received the endotoxin infusion alone; group II calves received an infusion of 0.9% saline and were treated with tirilazad mesylate (1.5 mg/kg) 1 hr after the infusion was started, group III and IV calves were treated with tirilazad mesylate 1 hr after or before endotoxin infusion was started. Tirilazad mesylate effectively suppressed production of plasma prostacyclin (6-keto-PGF1 alpha) and TNF in endotoxin-challenged neonatal calves. In addition, production of thromboxane B2 was mitigated by treatment with tirilazad mesylate both 1 hr before and 1 hr after initiation of endotoxin infusion. It appears that tirilazad mesylate effectively suppresses eicosanoid and TNF generation induced by endotoxin, and thus may be beneficial in the treatment of endotoxemia and septicemia in neonatal calves.
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PMID:Effect of tirilazad mesylate (U74006F) on eicosanoid and tumor necrosis factor generation in healthy and endotoxemic neonatal calves. 837 24

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


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