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Query: UMLS:C0012739 (disseminated intravascular coagulation)
 8,673 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intravenous administration of bacterial endotoxin (lipopolysaccharide: LPS) induces shock and disseminated intravascular coagulation in rats. Our report here shows that LPS-administered rats (10 mg/100 g) develop tissue injuries and functional disorders in multiple vital organs. In the present study, we investigated changes in tissue antioxidant enzyme activities, neutrophil sequestration, and lipid peroxides in multiple organs (lung, stomach, small intestine for antioxidant enzyme activities and neutrophil sequestration; lung, stomach, small intestine, liver, abdominal aorta for lipid peroxides) of LPS-treated rats. LPS-treated animals morphologically revealed pulmonary interstitial edema, alveolar hemorrhage, and mucosal hemorrhage in the small intestine 45 min after LPS administration. Blood samples withdrawn from LPS-treated animals exhibited increases in serum amylase, blood urea nitrogen, creatinine, and transaminase levels up to 180 min post-LPS infusion. LPS-treated animals showed a significant increase in tissue myeloperoxidase (MPO) activities of the lung, but not of the small intestine and stomach 45 min after LPS infusion. Thiobarbituric acid reactive substances (TBARS) in the lung, small intestine, stomach, liver, and abdominal aorta significantly increased at 45 min post-LPS-infusion. Tissue superoxide dismutase (SOD) activities of the LPS-treated animals demonstrated a significant decrease in the lung, which suffered from severe insults and neutrophil sequestration; no significant change in the small intestine, which suffered from morphological insults without neutrophil sequestration, and a significant increase in the stomach, which showed no histological impairment, at 180 min post-LPS administration. Glutathione peroxidase (GSH-PX) activities of the lung and small intestine showed no significant change in LPS-treated rats, while those of the stomach revealed a marked increase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Changes in tissue antioxidant enzyme activities and lipid peroxides in endotoxin-induced multiple organ failure. 814 10

Human endothelial cells respond to bacterial endotoxin (lipopolysaccharide [LPS]) with changes that transform the endothelium into a surface with prominent procoagulant properties. Production of tissue factor (TF) in response to LPS is a major alteration that favors coagulation. Biologic activities of LPS have previously been shown to be enhanced by the presence of hemoglobin. Therefore, the ability of human hemoglobin (Hb) to modulate TF production by cultured human umbilical vein endothelial cells (HUVEC) was investigated. Cell-free Hb (10 mg/mL), either purified native (HbAo) or chemically cross-linked (alpha alpha Hb), was incubated with LPS (0.1 microgram/mL), and the mixtures then were added to HUVEC in culture. TF activity was quantified with a clotting assay and TF protein was measured with an enzyme-linked immunosorbent assay. Hb preparations greatly enhanced the production of TF activity (11- to 25-fold greater than TF produced by HUVEC alone) compared with minimal TF activity generated by LPS alone (only twofold greater than HUVEC alone). The enhancement of LPS-induced TF activity was Hb concentration-dependent over a range of 1 to 100 mg/mL. Cross-linked alpha alpha Hb also greatly enhanced the production of TF protein compared with TF protein generated by LPS alone (12-fold greater v 3.5-fold greater than HUVEC alone, respectively). The enhancement of LPS-induced TF protein was Hb concentration-dependent over a range of 0.1 to 2 mg/mL. Enhancement of TF activity by Hb required new protein synthesis. These results show that human Hb can augment the ability of LPS to induce endothelial cell TF and suggest that hemolysis associated with disseminated intravascular coagulation during sepsis may further stimulate coagulation. In addition, these results suggest a potential mechanism for generalized thrombosis in animals that has been associated with the infusion of cell-free Hb for resuscitation.
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PMID:Hemoglobin enhances the production of tissue factor by endothelial cells in response to bacterial endotoxin. 818 Mar 81

The effects of E. coli lipopolysaccharide (LPS) on washed platelets of the healthy volunteers were studied by measuring ADP induced aggregation and intracellular ionized calcium concentration ([Ca2+]i) by fluorescent calcium indicator, quin 2. Addition of LPS in platelets suspension in saline, caused an increased platelet aggregation. Adding LPS, however, in platelet suspension in Na(+)-citrated platelet poor plasma inhibited ADP aggregation. These trends were not affected by cyclooxygenase inhibitor, but partially antagonized by dibutyryl cyclic AMP, and verapamil. The intracellular calcium ion concentration ([Ca2+]i) was significantly increased (334 +/- 141 nM to 150 +/- 45 nM in control) on addition of LPS in platelet suspension containing ionized calcium. On the other hand, there was no significant difference observed with those suspended in calcium free solution (50 +/- 16 to 45 +/- 15 in control). These results indicate that changes of platelet aggregation by LPS were mediated by cyclic AMP and Ca2+, but not by arachidate derivatives. The author concludes that LPS changed the mechanism of Ca2+ influx of platelet membrane and elevated [Ca2+]i of platelets. These findings, however, probably are not the cause of aggregation of platelets during DIC.
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PMID:[Effects of E. coli LPS on human platelet aggregation]. 818 78

Overwhelming bacterial infection is accompanied by fever, hypotension, disseminated intravascular coagulation, and multiple organ failure leading to death in 30-80% of cases. These classical symptoms of septic shock are caused by potent cytokines that are produced in response to endotoxin released from Gram-negative bacteria. Treatments with antibodies and receptor antagonists to block endotoxin or cytokine mediators have given mixed results in clinical trials. High density lipoprotein (HDL) is a natural component of plasma that is known to neutralize endotoxin in vitro. We report here that raising the plasma HDL concentration protects mice against endotoxin in vivo. Transgenic mice with 2-fold-elevated plasma HDL levels had more endotoxin bound to HDL, lower plasma cytokine levels, and improved survival rates compared with low-HDL mice. Intravenous infusion of HDL also protected mice, but only when given as reconstituted HDL prepared from phospholipid and either HDL apoprotein or an 18-amino acid peptide synthesized to mimic the structure of apolipoprotein A-I of HDL. Intact plasma HDL was mildly toxic, and HDL apoprotein was ineffective. The effectiveness of the reconstituted peptide renders very unlikely any significant contribution to protection by trace proteins in apo-HDL. These data suggest a simple leaflet insertion model for binding and neutralization of lipopolysaccharide by phospholipid on the surface of HDL. Plasma HDL may normally act to protect against endotoxin; this protection may be augmented by administration of reconstituted HDL or reconstituted peptides.
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PMID:In vivo protection against endotoxin by plasma high density lipoprotein. 826 67

Hemorrhagic intracerebral lesions, analogous to multiple punctate hemorrhagic necrosis seen in the brain of human disseminated intravascular coagulation (DIC), can be induced in rats by continuous intravenous infusion of E. coli endotoxin lipopolysaccharide (ET) at 88.5 micrograms/hour. The occurrence of cerebral lesions increases with time of ET infusion initially, but levels off after 120 hours of the continuous administration. To investigate protective effects of methylprednisolone (MP) against intracerebral vascular injury, 122 male rats were divided into the basic endotoxemic rats without MP medication (Group 1), and MP medication of 0.2mg/kg body weight, 1.0mg/kg, 2.0mg/kg and 20.0mg/kg immediately before induction of endotoxemia (Groups 2-5), one dose of 20.0mg/kg MP at 48 hours and 2 doses at 48 and 72 hours after induction of endotoxemia (Groups 6-7), and 3 doses each of 2.0mg/kg, 20.0mg/kg and 100.0mg/kg MP for 3 days immediately before and at 24 and 48 hours after induction of endotoxemia (Groups 8-10). All surviving rats were autopsied after 120 hours of ET infusion and histologic sections were made. Multiple hemorrhagic intracerebral lesions developed in 83% (10/12) of Group 1 rats, whereas the frequency of brain lesions in Groups 4, 5, 8, 9 and 10 was significantly lower than that in Group 1 (p < 0.05). Electron microscopically, the frontal lobe cortex of Group 1 after 120 hours of ET infusion showed subendothelial dilatation containing macrophages, and perivascular accumulation of erythrocytes (diapedesis). In contrast, the frontal lobe cortex of Group 5 revealed no appreciable electron microscopic changes of intracerebral blood vessels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Brain injury induced by continuous infusion of endotoxin in rats--protective effects of methylprednisolone on intracerebral blood vessels]. 847 54

Adult respiratory distress syndrome (ARDS) is a serious complication of disseminated intravascular coagulation (DIC) or multiple organ failure. To determine whether recombinant soluble human thrombomodulin (rsTM) may be useful in treating ARDS due to sepsis, we investigated the effect of rsTM on lipopolysaccharide (LPS)-induced pulmonary vascular injury in rats. The intravenous administration of rsTM prevented the increase in pulmonary vascular permeability induced by LPS. Neither heparin plus antithrombin III (AT III) nor dansyl Glu Gly Arg chloromethyl ketone-treated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, prevented LPS-induced vascular injury. The agents rsTM, heparin plus AT III, and DEGR-Xa all significantly inhibited the LPS-induced intravascular coagulation. Recombinant soluble TM pretreated with a monoclonal antibody (moAb) that inhibits protein C activation by rsTM did not prevent the LPS-induced vascular injury; in contrast, rsTM pretreated with a moAb that does not affect thrombin binding or protein C activation by rsTM prevented vascular injury. Administration of activated protein C (APC) also prevented vascular injury. LPS-induced pulmonary vascular injury was significantly reduced in rats with leukopenia induced by nitrogen mustard and by ONO-5046, a potent inhibitor of granulocyte elastase. Results suggest that rsTM prevents LPS-induced pulmonary vascular injury via protein C activation and that the APC-induced prevention of vascular injury is independent of its anticoagulant activity, but dependent on its ability to inhibit leukocyte activation.
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PMID:Recombinant human soluble thrombomodulin reduces endotoxin-induced pulmonary vascular injury via protein C activation in rats. 860 7

Thrombus formation and the sequential expression of tissue factor (TF), interleukin-1 beta (IL-1 beta) and interleukin-1 receptor antagonist (IL-1 ra) in several organs were examined immunohistochemically and morphometrically in a novel model of disseminated intravascular coagulation (DIC) developed by modifying the generalized Shwartzman reaction (GSR) in rabbits. The new model [carrageenan (CA)-lipopolysaccharide (LPS)] was induced by the administration of a priming dose of intraperitoneal CA, 10 mg/kg, followed 24 h later by a provocative dose of LPS 25 micrograms/kg, while GSR was induced by the intravenous injection of two doses of LPS 25 micrograms/kg. CA was detected predominantly within macrophages in the spleen and liver. Fibrin thrombi were formed as early as 1 h after the second LPS treatment in all examined organs reaching a peak at 3-9 h and their prevalence was higher in the CA-LPS group (p < 0.05). The sequential expressions of TF and IL-1 beta correlated well with each other in both groups reaching a peak at 3-9 h with the CA-LPS group showing a more pronounced expression than the GSR group. Macrophages in the liver, spleen and lungs, and Bowman's epithelial cells expressed both proteins, while IL-1 beta was also expressed by endothelial and epithelial cells. IL-1 ra was expressed by the same cells expressing IL-1 beta, however, its expression continued to increase gradually over 24 h. The mortality rate was lower (p < 0.05) and neutrophilic sequestration less prominent in the CA-LPS group than in the GSR group. These findings indicate that CA efficiently replaced the priming LPS treatment and the consequently enhanced production of IL-1 beta may have resulted in the upregulation of TF expression leading to the high level of thrombi in this new model which may provide a tool for further studies on the role of cytokines in DIC.
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PMID:Expression of tissue factor and interleukin-1 beta in a novel rabbit model of disseminated intravascular coagulation induced by carrageenan and lipopolysaccharide. 873 72

We have evaluated the effect of plasminogen activators (t-PA and urokinase) on an experimental model of disseminated intravascular coagulation (DIC) in rabbits by injection of 20 micrograms/kg/h of E. coli lipopolysaccharide during 6 h t-PA (0.2 mg/kg and 0.7 mg/kg), urokinase (3000 U/kg/h) and saline (control) were given simultaneously with endotoxin. Results indicated that urokinase and low dose of t-PA significantly reduced the increase of plasminogen activator inhibitor (PAI) activity observed 2 h after endotoxin (p < 0.001). High t-PA dose also diminished the PAI levels at 6 h (p < 0.001). A significant reduction of fibrin deposits in kidneys was observed din both t-PA treated groups as compared with findings in the group of rabbits infused with saline solution (p < 0.005), whereas urokinase had no significant effect on the extent of fibrin deposition. Finally, the mortality rate in the control group (70%) was reduced to 50% in rabbits receiving high doses of t-PA. In conclusion, treatment with t-PA resulted in reduced PAI generation, fibrin deposits and mortality in endotoxin-treated rabbits.
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PMID:Endotoxin-induced intravascular coagulation in rabbits: effect of tissue plasminogen activator vs urokinase of PAI generation, fibrin deposits and mortality. 877 40

1. The effects of the selective and potent novel platelet-activating factor (PAF) antagonist, UR-12633 (1-(3,3-diphenylpropionyl)-4-(3-pyridylcyanomethyl)piperidin e) on several markers of endotoxic shock syndrome were evaluated in rats and mice. 2. UR-12633, administered 60 min after E. coli lipopolysaccharide (LPS), reversed the LPS-induced sustained hypotension in rats at doses of 0.01 to 1 mg kg-1, i.v. The reference compound WEB-2086 (1 mg kg-1) also reversed the LPS-induced hypotension. UR-12633 (1 mg kg-1), administered 10 min before LPS, almost fully inhibited sustained hypotension. The immediate hypotension (within 1 min) caused by LPS was not prevented by either UR-12633 or WEB-2086. 3. Pretreatment with 10 mg kg-1, i.v. of either UR-12633 or WEB-2086 inhibited the increase in disseminated intravascular coagulation markers, such as activated partial thromboplastin time (55 and 74% inhibition, respectively), and prothrombin time (22 and 72% inhibition) and prevented the decrease in plasma fibrinogen content (100 and 29% inhibition). 4. Increases in acid phosphatase (ACP) plasma activity, a marker of lysosomal activation, and in lactate dehydrogenase (LDH), a marker of tissue damage, were inhibited by pretreatment with 10 mg kg-1, i.v. of either UR-12633 or WEB-2086 (100% and 69% inhibition, ACP; 62 and 48% inhibition, LDH). Hyperglycaemia (71 and 46%) and hyperlactacidaemia (92 and 56%) were also inhibited. 5. UR-12633, but not WEB-2086, inhibited the LPS-induced increase in vascular permeability in rats, as shown by prevention of haemoconcentration and, to a lesser degree, the increase in Evans blue dye extravasation. 6. In a series of nine reference compounds and UR-12633, we found a high correlation (P < 0.001) between PAF antagonist activity, measured as the inhibition of PAF-induced rabbit platelet aggregation or PAF-induced mortality in mice and the inhibition of LPS-induced mortality. 7. In spite of the multifactorial nature of endotoxic shock, in which many mediators may be involved, the new potent PAF antagonist, UR-12633, proved effective in protecting against changes in most shock markers. These data strongly suggest a key role for PAF in the pathogenesis of endotoxic shock in rodents.
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PMID:Effects of UR-12633, a new antagonist of platelet-activating factor, in rodent models of endotoxic shock. 881 47

Thrombosis and disseminated intravascular coagulation (DIC) are common complications of infections. Abnormal activation of coagulation is due in part of expression of tissue factor on intravascular cells in response to cytokines, including interleukin-1 beta (IL1 beta ) and tumor necrosis factor (TNF). Both TNF and IL1 beta are thought to play significant roles in producing the pathologic manifestations of sepsis. Therefore, we examined the effects of thrombin on TNF and IL1 beta secretion of monocytes, and the ability of monocyte products to promote tissue factor expression by endothelial cells. Human monocytes were treated with thrombin or a thrombin receptor agonist peptide (SFLLRN), and/or bacterial lipopolysaccharide (LPS). The agonists were removed, and monocytes cultured 18 hours. The monocyte-conditioned supernatants were assayed for TNF and IL1 beta antigen, and for their ability to induce tissue factor expression on human umbilical vein endothelial cells and the Ea.hy endothelial cell line. Thrombin alone did not promote monocyte TNF or IL-1 beta secretion. However, thrombin enhanced LPS-induced TNF and IL1 secretion. Supernatants from monocytes exposed to LPS plus thrombin promoted greater tissue factor expression on endothelial cells than supernatants from those treated with LPS only. SFLLRN did not increase TNF secretion in response to LPS, but did enhance LPS-induced IL1 beta secretion and tissue factor-inducing activity. Neither SFLLRN nor active thrombin augmented the level of mRNA for TNF above that induced by LPS alone. However, both increased the LPS-induced level of IL1 beta message. Thus, thrombin enhanced LPS-induced TNF and IL1 beta secretion by monocytes. Unexpectedly, the effects on these two cytokines were mediated by different mechanisms. Enhancement of LPS-induced IL1 beta secretion was largely mediated via the tethered ligand type thrombin receptor and correlated with an increase in the steady state level of mRNA. By contrast, enhanced TNF required proteolytically active thrombin, but was not mediated by the tethered ligand receptor. These data demonstrate that physiologically relevant amounts of thrombin can synergize with endotoxin to stimulate monokine release. Thrombin could thereby play a role in the complex network of mediators involved in the pathophysiology of sepsis. We speculate that limiting thrombin activity during DIC could be a beneficial adjunct in the management of sepsis.
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PMID:Thrombin enhances monocyte secretion of tumor necrosis factor and interleukin-1 beta by two distinct mechanisms. 884 45


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