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

The in vitro effect of a purified endotoxin preparation from culture fluids of Shigella sonnei, phase I (purified free endotoxin, PFE) and of three endotoxin preparations chemically extracted from the intact parent cells on human blood mononuclear leucocytes and platelets was investigated. PFE, like cell-extracted preparations, caused generation of strong procoagulant activity (tissue factor) by human mononuclear cells. PFE-stimulated cells, however, developed significantly greater activity than cells stimulated by the other endotoxins. they had about 4-fold more activity. Neither free nor cell-extracted preparations induced aggregation in human citrated or heparinized platelet-rich plasma (PRP) or unmasking of platelet factor 3 (PF3). These findings suggest that free endotoxin from Shigella sonnei, phase I resembles endotoxin extracted from cells by conventional procedures in their interaction with human platelets and mononuclear leucocytes. In view of the possible contribution of free endotoxin to endotoxemia in human and experimental gram-negative sepsis, our data that free endotoxin stimulates human mononuclear leucocytes to produce a potent trigger of blood coagulation (tissue factor) may be relevant to the understanding of the mechanism(s) responsible for the initiation of intravascular coagulation in severe human infections.
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PMID:In vitro effect of endotoxin from Shigella sonnei. phase I on human blood platelets and mononuclear leucocytes: comparison of "free endotoxin" with cell-extracted preparations. 705 Jun 35

Mononuclear phagocytes, stimulated by bacterial lipopolysaccharide (LPS), have been implicated in the activation of coagulation in sepsis and endotoxemia. In monocytes LPS induces the synthesis of tissue factor (TF) which, assembled with factor VII, initiates the blood coagulation cascades. In this study we investigated the mechanism of LPS recognition by monocytes, and the consequent expression of TF mRNA and TF activity. We also studied the inhibition of these effects of LPS by rBPI23, a 23-kD recombinant fragment of bactericidal/permeability increasing protein, which has been shown to antagonize LPS in vitro and in vivo. Human peripheral blood mononuclear cells, or monocytes isolated by adherence, were stimulated with Escherichia coli O113 LPS at physiologically relevant concentrations (> or = 10 pg/mL). The effect of LPS was dependent on the presence of the serum protein LBP (lipopolysaccharide-binding protein), as shown by the potentiating effect of human recombinant LBP or serum. Furthermore, recognition of low amounts of LPS by monocytes was also dependent on CD14 receptors, because monoclonal antibodies against CD14 greatly reduced the LPS sensitivity of monocytes in the presence of serum or rLBP. Induction of TF activity and mRNA expression by LPS were inhibited by rBPI23. The expression of tumor necrosis factor showed qualitatively similar changes. Considering the involvement of LPS-induced TF in the potentially lethal intravascular coagulation in sepsis, inhibition of TF induction by rBPI23 may be of therapeutic benefit.
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PMID:Monocyte tissue factor induction by lipopolysaccharide (LPS): dependence on LPS-binding protein and CD14, and inhibition by a recombinant fragment of bactericidal/permeability-increasing protein. 751 3

Human monoclonal IgM antibody HA-1A, which recognizes the lipid A component of bacterial lipopolysaccharide (LPS), has been shown to reduce mortality in Gram negative septicemia. The vascular endothelial lining of blood vessels, which controls leucocyte traffic and activation, as well as haemostatic balance, may be one of the primary targets of LPS action during sepsis. In earlier studies we have described HA-1A-induced immune adherence of LPS to complement receptors on erythrocytes, and showed that pre-incubation with HA-1A, in the presence of complement and red blood cells, markedly reduced LPS-induced cytokine production from peripheral blood mononuclear cells. In the present study, we measured the effect of immune adherence of LPS in the presence of HA-1A on the responses of cultured endothelial cells, and found that subsequent expression of adhesion molecules such as E-selectin, ICAM-1 and VCAM-1, and secretion of the cytokines interleukin-6 and granulocyte-macrophage colony stimulating factor were markedly reduced. Moreover, the ability of LPS to increase levels of tissue factor procoagulant activity on endothelial cells was markedly diminished by LPS immune adherence to HA-1A. This decrease in endothelial activation in response to LPS following immune adherence to HA-1A may play a significant role in the protective effect of HA-1A in vivo during the course of Gram negative sepsis.
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PMID:Antilipid A monoclonal antibody HA-1A decreases the capacity of bacterial lipopolysaccharide to activate human vascular endothelial cells by an immune adherence mechanism. 751 52

Endotoxic shock is associated with a coagulopathy, organ failure, and death. Tissue factor (TF) expression by monocytes exposed to bacterial endotoxin (lipopolysaccharide [LPS]) may mediate the coagulopathy and contribute to the high mortality of this disease. We examined the role of the LPS-binding protein (LBP)/CD14 receptor pathway in the LPS induction of TF expression in human monocytic THP-1 cells and peripheral blood monocytes. In THP-1 cells, the threshold concentration of LPS required to induce TF activity in serum-free medium was reduced 20-fold by purified LBP, which also enhanced TF mRNA synthesis. Similarly, monocytes cultured in the presence of serum were induced to express TF antigen at LPS concentrations 100 times lower than monocytes cultured in serum-free medium. An anti-LBP monoclonal antibody indicated that this effect was dependent on the presence of LBP in serum. LPS/LBP induction of TF activity and TF antigen expression in these monocytic cells were also inhibited by an anti-CD14 monoclonal antibody, indicating a requirement for the CD14 receptor. Thus, we suggest that low levels of LPS (5 to 100 pg/mL) present during sepsis induce TF expression in monocytes via the LBP/CD14-dependent pathway.
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PMID:Role of the lipopolysaccharide (LPS)-binding protein/CD14 pathway in LPS induction of tissue factor expression in monocytic cells. 751 85

Bacterial lipopolysaccharide (LPS) initiates the cascade of inflammatory events that, in infected patients, often result in a lethal systemic inflammatory response known as the sepsis syndrome. We studied LPS-stimulated expression of tissue factor (TF) in human peripheral blood mononuclear cells (PBMCs) and cultured endothelial cells or tumor necrosis factor-alpha (TNF-alpha) in PBMCs. CD14, a PBMC membrane protein, is involved in LPS signaling and is also present as a soluble molecule in serum. CD14 is absent from endothelial cells and, in varying degrees, from monocytes of patients with paroxysmal nocturnal hemoglobinuria (PNH). LPS stimulation of TF in normal monocytes was enhanced > 30-fold by serum at low concentrations of LPS (< or = 10 ng/ml). The serum dependence of endothelial cells was even more pronounced; a full response to LPS was not observed in endothelium under serum-free conditions, even with LPS concentrations as high as 100 ng/ml. To better define the role of CD14, CD14-deficient PBMCs from two patients with PNH were compared with normal PBMCs. Although less than 3% of PNH monocytes expressed CD14, LPS-induced synthesis of TF and TNF-alpha by PBMCs from PNH patients was inhibited by anti-CD14 antibodies. Because patient serum samples were found to contain soluble CD14, we sought to determine whether PNH monocytes might respond to LPS through an activation pathway dependent on soluble CD14. Recombinant soluble CD14 substituted for serum to enable LPS stimulation of endothelium, PNH PBMCs, and surprisingly, CD14-replete normal PBMCs. In addition, a truncated sCD14 containing the N-terminal 152 amino acids similarly enabled LPS stimulation of normal PBMCs. These data underscore the importance of soluble CD14 and suggest that CD14 present in serum enables LPS responses in PNH monocytes and endothelial cells and may even influence the effects of LPS in normal human phagocytes.
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PMID:Soluble CD14 promotes LPS activation of CD14-deficient PNH monocytes and endothelial cells. 753 90

Tissue factor (TF), a 46-kD glycoprotein receptor for coagulation factors VII and VIIa, is expressed on the surface of endothelial cells in response to a variety of agonists and is thought to play an important role in initiating the thrombosis associated with inflammation during infection, sepsis, and organ transplant rejection. The induction of TF activity by lipopolysaccharide (LPS) is regulated, at least partially, at a transcriptional level and an LPS response element containing two activator protein-1 sites and a nuclear factor-kappa B (NF kappa B)-like site has been localized to the 5' flanking region of the TF gene by transfection studies of TF promoter/reporter gene constructs. We have examined the effect of pyrrolidine dithiocarbamate (PDTC), a specific inhibitor of the NF kappa B pathway on the expression of the endogenous TF gene in human umbilical vein endothelial cells (HUVEC). Preincubation of HUVEC for 60 minutes with PDTC inhibited LPS induction of TF activity on the cell surface in a dose-dependent manner, with 50% inhibition occurring at 10 mumol/L PDTC and 100% inhibition at higher concentrations (> or = 100 mumol/L). Furthermore, PDTC inhibited TF expression in response to tumor necrosis factor-alpha, interleukin-1 beta, and phorbol 12-myristate 13-acetate. The effect of PDTC was at the mRNA level, as seen by the complete abrogation of the large increase in TF mRNA observed in LPS-treated HUVEC. These results suggest that endothelial cell activation by diverse agonists initiates intracellular signaling events that converge upon a common pathway involving NF kappa B and, furthermore, that NF kappa B activation is an obligatory step induction of TF.
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PMID:Pyrrolidine dithiocarbamate abrogates tissue factor (TF) expression by endothelial cells: evidence implicating nuclear factor-kappa B in TF induction by diverse agonists. 760 83

1. Disseminated intravascular coagulation frequently accompanies Gram-negative sepsis and may contribute to widespread deposition of microthrombi. Besides the endotoxin-induced activation of coagulation, an important role for the fibrinolytic system has been postulated. The precise mechanisms underlying these fibrinolytic changes during endotoxaemia are not known but have been suggested to be mediated directly by cytokines or secondary to thrombin generation. 2. In the present study we have delineated in detail the fibrinolytic response to a bolus injection of endotoxin in non-human primates and analysed the contribution of cytokines and thrombin generation to the endotoxin-induced release of tissue-type plasminogen activator and plasminogen activator inhibitor 1. Chimpanzees received a bolus injection of endotoxin alone or in combination with blocking monoclonal antibodies directed against tumour necrosis factor or interleukin 6 or in combination with pentoxifylline. Furthermore, to assess the effect of coagulation activation on the activation of fibrinolysis, another group of chimpanzees received endotoxin in combination with either anti-tissue factor antibodies or recombinant hirudin. 3. Infusion of endotoxin induced a rapid increase in plasminogen activator activity and tissue-type plasminogen activator antigen levels and subsequent plasmin generation, reaching peak levels 2h after endotoxin administration. Plasminogen activator inhibitor 1 levels remained constant for the first 2 h, after which time a steep increase was observed. Plasminogen activator activity and plasmin generation decreased simultaneously with the rise in plasminogen activator inhibitor 1 levels. Fibrinolytic activity remained suppressed during the remainder of the study owing to sustained increased levels of plasminogen activator inhibitor 1. The administration of pentoxifylline strongly attenuated the release of tissue-type plasminogen activator and plasminogen activator inhibitor 1, whereas the antitumour necrosis factor antibodies blocked the fibrinolytic response entirely. In contrast, interleukin 6-neutralizing antibodies did not affect the fibrinolytic response. Although endotoxin-induced generation of thrombin was completely prevented by the administration of tissue factor-neutralizing antibodies or by hirudin, no effect on the fibrinolytic response was observed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Plasminogen activator and plasminogen activator inhibitor I release during experimental endotoxaemia in chimpanzees: effect of interventions in the cytokine and coagulation cascades. 761 18

Tissue factor (TF), a transmembrane surface protein, is known to initiate thrombogenesis through plasmatic and cellular activation processes. Besides complexing with factor VII, eventually leading to fibrin generation via the extrinsic pathway, TF can also activate factor IX, resulting in the intrinsic activation of coagulation. Other functions of TF are currently unknown, although various cells are believed to have TF receptors. Many of the post-surgical and post-interventional thrombotic events are due to the release of TF. Increased levels of TF are associated with several pathologic conditions such as cancer, sepsis and inflammation. Cellular necrosis also results in an increase of TF as the cells in the traumatized area lyse and release endogenous cell surface-bound TF. An ELISA method (American Diagnostica, Greenwich, CT) has been developed to assay TF antigen levels in various biological fluids. This ELISA employs a murine monoclonal antibody raised against native human TF for antigen capture. In this study, cerebrospinal fluid, peritoneal fluid, pleural effusion and urine from patients were assayed for their TF content using this ELISA method. Normal individual serum and plasma were also assayed as controls against which the levels of TF in the patients' body fluids could be compared. The amount of TF antigen in normal human plasma and serum was 165 +/- 139 pg/ml and 165 +/- 110 pg/ml, respectively. Concentrations of TF antigen in other fluids were: cerebrospinal fluid 868 +/- 721 pg/ml, peritoneal fluid 124 +/- 247 pg/ml, pleural effusion 385 +/- 569 pg/ml, synovial fluid 97 +/- 23 pg/ml, seminal plasma 11,485 +/- 875 pg/ml and urine 86 +/- 57 pg/ml.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tissue factor antigen levels in various biological fluids. 764 18

Disseminated intravascular thrombosis is a frequent complication of endotoxic shock, and modulation of endothelial cell hemostatic properties has been proposed to play a role in its pathogenesis based on studies of endothelial cells in culture. This study examined the in vivo expression of tissue factor (TF) and thrombomodulin (TM) in a baboon model of lethal Escherichia coli sepsis using immunohistochemistry with monospecific antibodies. Expression of E-selectin (E-sel) was also determined as a marker of endothelial cell activation. Correlation of immunoreactivity with procoagulant activity in lipopolysaccharide-stimulated cultured human endothelial cells showed that immunohistochemistry was sufficiently sensitive to detect as little as 5% of the maximum in vitro endothelial cell TF response. Vascular endothelium of control animals expressed TM but had no detectable TF or E-sel. Following E. coli infusion, widespread E-sel expression and microvascular fibrin deposition was evident within 6 hours. However, expression of TF by endothelial cells became detectable only in the splenic microvasculature, where endothelial specificity of TF expression was confirmed by dual immunofluorescence of TF with von Willebrand's factor and with TM. In the spleen, there was a dissociation of expression of TF and E-sel, with marginal zone vessels being TF-positive and E-sel-negative, whereas sinusoidal endothelium was E-sel-positive but TF-negative. TM expression was unchanged from controls. Additionally, expression of TF by lung alveolar epithelial cells, splenic macrophages, and epithelial cells of the renal glomeruli was observed to be enhanced in septic animals. This study documents endothelial cell expression of TF in vivo in a relevant pathological setting. At the same time, compared with endothelial cells in culture, there is in vivo both significantly greater control of TF expression than expected, given the strong positive stimuli present in lethal E. coli septic shock and an unpredicted heterogeneity of activation responses.
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PMID:Expression of tissue factor, thrombomodulin, and E-selectin in baboons with lethal Escherichia coli sepsis. 768 96

Tissue factor (TF) expression by endothelial cells is implicated in thrombotic episodes in patients with a variety of clinical disorders. In a baboon model of lethal sepsis, TF is expressed by endothelial cells in the splenic microvasculature. In vitro, endothelial cells are induced to express TF in response to tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and bacterial endotoxin (lipopolysaccharide [LPS]). Here, we identified cis-acting regulatory elements that control TF gene transcription in primary human endothelial cells. Functional studies showed that the TF promoter contained a 56-bp enhancer (-227 to -172 bp), which included two activator protein-1 (AP-1) sites and a kappa B-like site, that mediated induction by TNF-alpha, IL-1 beta, and LPS. Electrophoretic mobility shift assays demonstrated that endothelial cells contained constitutive AP-1 binding activity, whereas the kappa B-like site, 5'-CGGAGTTTCC-3', bound an inducible nuclear complex composed of c-Rel-p65 heterodimers. Taken together, our data suggest that induction of TF gene transcription in endothelial cells is mediated by functional interactions between Fos-Jun and c-Rel-p65 heterodimers.
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PMID:Transcriptional regulation of tissue factor expression in human endothelial cells. 774 75


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