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

Thrombotic complications are observed in patients undergoing bone marrow transplantation despite thrombocytopenia and impaired coagulation due to liver function disturbances. Endothelial cell damage which is involved in the pathogenesis of major transplant related complications like graft-versus-host disease, veno-occlusive disease, sepsis or microangiopathy may be a contributing factor. Little is known about platelet function in bone marrow transplant recipients. In order to study functional alterations in circulating platelets we investigated unstimulated and ADP-stimulated platelets of 10 bone marrow transplant recipients ex vivo by flow cytometry in a pilot study using a panel of monoclonal antibodies to characterize changes in membrane glycoproteins. Samples were collected before and during conditioning and at three timepoints after engraftment. 10 healthy volunteers served as controls. Platelets of bone marrow transplant recipients showed partly a significant, higher expression of surface bound fibrinogen, activated fibrinogen receptor, and glycoprotein Ib as compared to controls. P-selectin, a marker of platelet degranulation was significantly elevated after ADP-induced stimulation at all timepoints compared to controls. Only marginal differences were found for GP IIb/IIIa surface expression. The data point to an increased platelet activation state in bone marrow transplant recipients which might contribute to the thrombotic phenomena observed in these patients.
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PMID:Changes in platelet membrane glycoproteins before bone marrow transplantation and after engraftment--a pilot study. 975 3

These serial clinical and experimental studies were designed to clarify the pathogenesis of postburn MODS. Both animal and clinical studies were performed. In animal experiments, 46 male cross-bred dogs were cannulated with Swan-Ganz catheters and 39 of them were inflicted with 50% TBSA third degree burns (7 were used as controls). The burned dogs were randomly divided into 4 groups: immediate infusion, delayed infusion, delayed fast infusion and delayed fast infusion combined with ginsenosides. All dogs were kept under constant barbiturate sedation during the whole study period. Hemodynamics, visceral MDA, mitochondrial respiratory control rate (RCR) and ADP/O ratio, ATP, succinic dehydrogenase (SDH), organ water content as well as light and electron microscopy of visceral tissues were determined. In the clinical study, 61 patients with extensive deep burns were chosen, of which 16 sustained MODS. Plasma TXB2/6-keto-PGF1alpha ratio, TNF, SOD, MDA, circulatory platelet aggregate ratio (CPAR), PGE2, interleukin-1, total organ water content and pathological observations of visceral tissues from patients who died of MODS were carried out. Results demonstrated that ischemic-reperfusion damage due to severe shock, sepsis and inhalation injury are three main causes of postburn death. All inflammatory mediators increased markedly in both animals and patients who sustained organ damage or MODS. SDH, RCR, ADP/O and ATP decreased significantly. These findings suggested that ischemic damage and systemic inflammatory response syndrome (SIRS) initiated by mediators or cytokines might be important in the pathogenesis of postburn MODS.
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PMID:Serial experimental and clinical studies on the pathogenesis of multiple organ dysfunction syndrome (MODS) in severe burns. 991 70

Endotoxemia secondary to gram-negative sepsis has been shown to inhibit endothelium-dependent vasomotion in numerous vascular beds, including guinea pig aortae and coronary arteries. We tested the hypothesis that in vivo endotoxin impairs endothelium-dependent nitric oxide-mediated relaxation responses of pulmonary arteries isolated from guinea pigs given intraperitoneal injections of Escherichia coli endotoxin lipopolysaccharide (LPS) or saline (control) 16 h before sacrifice. Pulmonary rings from the main artery and primary branches were isolated and studied in vitro using conventional isometric techniques. Interestingly, endotoxemia resulted in enhanced pulmonary artery relaxation in response to the endothelium-dependent receptor agonists acetylcholine (10(-10) -10(-5) M) and adenosine diphosphate (ADP; 10(-9) -10(-5) M), as compared with control responses (p < .05). Nitric oxide synthase inhibitors N-monomethyl-L-arginine (300 microM) and N-nitro-L-arginine methyl ester (100 microm) reduced acetylcholine- and adenosine diphosphate-mediated relaxation in both groups (p < .05); however, vasodilation responses in arteries from LPS animals remained enhanced relative to those of control arteries. In contrast to nitric oxide synthase inhibitors, the cyclooxygenase inhibitor indomethacin markedly inhibited acetylcholine- and adenosine diphosphate-mediated relaxation responses of pulmonary arteries isolated from LPS-treated animals (p < .05) but not control arteries; indomethacin effectively reversed LPS-induced enhanced vasodilation of pulmonary arteries. Relaxation responses to the receptor-independent calcium ionophore (A23187) and to the direct smooth muscle vasodilator sodium nitroprusside (+ N-nitro-L-arginine methyl ester) were not significantly altered by LPS treatment (p > .05). These data suggest that in pulmonary arteries, unlike aortae and coronary arteries isolated from the same model, in vivo LPS enhances agonist-mediated endothelium-dependent vasodilation responses to acetylcholine and adenosine diphosphate. Underlying mechanisms appear to involve increased dependency upon vasodilator prostanoids and decreased dependency on nitric oxide synthesis/release for LPS-induced alterations in pulmonary relaxation responses.
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PMID:Enhanced prostanoid-mediated vasorelaxation in pulmonary arteries isolated during experimental endotoxemia. 1045 35

Contraction-induced respiratory muscle fatigue and sepsis-related reductions in respiratory muscle force-generating capacity are mediated, at least in part, by reactive oxygen species (ROS). The subcellular sources and mechanisms of generation of ROS in these conditions are incompletely understood. We postulated that the physiological changes associated with muscle contraction (i.e., increases in calcium and ADP concentration) stimulate mitochondrial generation of ROS by a phospholipase A(2) (PLA(2))-modulated process and that sepsis enhances muscle generation of ROS by upregulating PLA(2) activity. To test these hypotheses, we examined H(2)O(2) generation by diaphragm mitochondria isolated from saline-treated control and endotoxin-treated septic animals in the presence and absence of calcium and ADP; we also assessed the effect of PLA(2) inhibitors on H(2)O(2) formation. We found that 1) calcium and ADP stimulated H(2)O(2) formation by diaphragm mitochondria from both control and septic animals; 2) mitochondria from septic animals demonstrated substantially higher H(2)O(2) formation than mitochondria from control animals under basal, calcium-stimulated, and ADP-stimulated conditions; and 3) inhibitors of 14-kDa PLA(2) blocked the enhanced H(2)O(2) generation in all conditions. We also found that administration of arachidonic acid (the principal metabolic product of PLA(2) activation) increased mitochondrial H(2)O(2) formation by interacting with complex I of the electron transport chain. These data suggest that diaphragm mitochondrial ROS formation during contraction and sepsis may be critically dependent on PLA(2) activation.
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PMID:PLA(2) dependence of diaphragm mitochondrial formation of reactive oxygen species. 1090 37

The most common cause of death in patients with sepsis is the multiple organ dysfunction syndrome (MODS). One important factor underlying the pathogenesis of MODS may be sepsis-induced alterations in cellular energy metabolism due to acquired intrinsic derangements in cellular respiration, a phenomenon that might be called "cytopathic hypoxia". A number of different biochemical mechanisms have been postulated to account for cytopathic hypoxia in sepsis, including reversible inhibition of cytochrome oxidase by nitric oxide, irreversible inhibition of one or more mitochondrial respiratory complexes by peroxynitrite, and activation of the nuclear enzyme, poly-(ADP-ribosyl)-polymerase.
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PMID:Cytopathic hypoxia. A concept to explain organ dysfunction in sepsis. 1096 12

It is increasingly apparent that organ dysfunction in sepsis is caused, at least in part, by an acquired intrinsic derangement in cellular oxidative adenosine triphosphate (ATP) production. We have termed this phenomenon "cytopathic hypoxia". Although several different but mutually compatible mechanisms might account for the development of cytopathic hypoxia in sepsis, recent data from our laboratory point to activation of the nuclear enzyme, poly-ADP-ribosyl polymerase (PARP), as being the most important.
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PMID:Cytopathic hypoxia in sepsis: a true problem? 1137 26

Glutamine has beneficial effects on enterocytes and the immune system in sepsis, but its effects on hepatic metabolism remain unknown. The aim of the present study was to determine the effects of glutamine on hepatocyte energy metabolism under conditions of neonatal endotoxaemia. Suckling Wistar rats were injected intraperitoneally with 200 microg/kg lipopolysaccharide. Oxygen consumption was measured polarographically in hepatocytes respiring on either palmitate (0.5 mM) or palmitate plus glutamine (10 mM). Total hepatocyte oxygen consumption was similar in hepatocytes from control and endotoxic rats, but this was due to a decrease in intramitochondrial and an increase in extramitochondrial oxygen consumption in the cells from endotoxic animals. The addition of glutamine to hepatocytes from endotoxic rats restored intramitochondrial oxygen consumption to control levels. Although glutamine did not reverse the inhibition of the thermogenic proton leak observed in endotoxaemia, it significantly increased oxygen consumption due to mitochondrial ATP synthesis (P=0.03). Glutamine significantly increased the hepatocyte ATP/ADP ratio (P=0.02 compared with hepatocytes from endotoxic rats). Electron microscopy revealed morphological damage to the mitochondria of hepatocytes from endotoxic rats, and a return to a normal appearance with the addition of glutamine. We conclude that glutamine reverses the inhibition of mitochondrial metabolism that is observed in endotoxaemia. The effect is primarily at the level of ATP synthesis.
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PMID:Hepatocyte mitochondrial metabolism is inhibited in neonatal rat endotoxaemia: effects of glutamine. 1186 75

Sepsis is associated with a widespread production of proinflammatory cytokines and various oxidant species. Activation of the enzyme poly(ADP-ribose) polymerase (PARP) has been shown to contribute to cell necrosis and organ failure in various diseases associated with inflammation and reperfusion injury. The aim of the current study was to elucidate the role of PARP activation in the multiple organ dysfunction complicating sepsis in a murine model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). Mice genetically deficient in PARP (PARP-/-) and their wild-type littermates (PARP+/+) were subjected to CLP. After 12 and 24 h, the proinflammatory cytokines TNF-alpha and IL-6, as well as the anti-inflammatory cytokine IL-10, and nitrite/nitrate were measured in plasma samples. Organs were harvested for the measurement of myeloperoxidase (MPO) and malondialdehyde (MDA) levels, and immunohistochemical staining for nitrotyrosine and poly(ADP ribose) was performed in gut sections. PARP-/- mice, and their wild-type littermate showed a similar time-dependent increase in plasma nitrite/nitrate and in gut and lung MDA content, as well as the presence of nitrotyrosine in the gut. In contrast to wild-type mice showing a PARP activation in the gut, PARP-/- mice had no staining for poly(ADP ribose). PARP-/- mice had significantly lower plasma levels of TNF-alpha, IL-6, and IL-10, and they exhibited a reduced degree of organ inflammation, indicated by decreased MPO activity in the gut and lung. These effects were associated with a significant improvement in the survival of CLP in PARP-/- mice. Thus, PARP activation has an important role in systemic inflammation and organ damage in the present model of polymicrobial septic shock.
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PMID:Resistance to acute septic peritonitis in poly(ADP-ribose) polymerase-1-deficient mice. 1195 28

Peritonitis generally results from gastrointestinal perforation, with systemic sepsis developing over hours or days from an initially localized nidus of infection. The consecutive inflammatory response induces the widespread generation of oxidants and free radicals, which are potent inducers of breaks and nicks in double-stranded DNA. This genetic damage triggers the activation of the nuclear enzyme poly(ADP-ribose) polymerase 1, which, in turn, cleaves the respiratory coenzyme nicotinamide adenine dinucleotide into nicotinamide and ADP ribose. The consecutive decrease in cellular nicotinamide adenine dinucleotide inhibits glycolysis and mitochondrial respiration, leading to cellular energy collapse and necrotic cell death. In parallel, poly(ADP-ribose) polymerase 1 positively regulates inflammatory signal transduction pathways through a functional association with the transcription factor nuclear factor kappaB, resulting in a progressive amplification of local inflammation. Recent data indicate that these molecular mechanisms are instrumental in the development of cardiovascular collapse and multiple organ dysfunction in sepsis, supporting the view that pharmacologic inhibitors of poly(ADP-ribose) polymerase 1 may represent useful tools for the treatment of this condition.
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PMID:Role of poly(adenosine diphosphate-ribose) polymerase 1 in septic peritonitis. 1265 79

Abnormalities in blood rheology and platelet dysfunction might play a role in the pathogenesis of multiple organ failure in septic patients by reducing microvascular blood flow. To determine whether alterations in blood rheology and in platelet function are related to the severity of organ dysfunction, we prospectively studied plasma fibrinogen, red cell aggregation, plasma viscosity, hematocrit, whole blood viscosity and platelet aggregation in relation to the Sepsis-related Organ Failure Assessment (SOFA) score in 34 consecutive patients with severe sepsis/septic shock. We found that patients had higher plasma fibrinogen, red cell aggregation and plasma viscosity (p < 0.01), but lower hematocrit, whole blood viscosity and ADP-induced platelet aggregation than controls (p < 0.01). Platelet aggregation (p < 0.01), but not other rheological variables, were inversely related to the SOFA score. Only platelet count was linked to poor clinical outcome (p < 0.05). We conclude that blood rheology and platelet function are severely altered in patients with severe sepsis/septic shock. Our findings suggest progressive platelet dysfunction with advancing severity of the disease. Platelet dysfunction might play a more important role in the pathogenesis of the multi organ dysfunction syndrome than abnormalities in blood rheology.
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PMID:Platelet aggregation and blood rheology in severe sepsis/septic shock: relation to the Sepsis-related Organ Failure Assessment (SOFA) score. 1500 35


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