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

Gram-negative sepsis is oftentimes complicated by activation of coagulation with disseminated intravascular coagulation and microthrombosis. This may contribute to the associated morbidity, multiple organ failure and death. Recent studies have established that the tissue factor-dependent pathway of blood coagulation has a significant participatory role in the initial endotoxin-induced activation of coagulation. Tissue factor (TF), expressed on the surface of activated monocytes and endothelial cells forms cell surface complexes with free circulating factors VII and VIIa. The latter complex proteolytically activates factors X and IX. Recent in vivo experiments have shown that a rapidly neutralizing TF monoclonal antibody prevents and arrests the endotoxin-induced activation of coagulation and similar studies have shown to reduce mortality in baboons. In this study we describe the preparation of a factor VII/VIIa neutralizing monoclonal Fab fragment and characterize its effect on in vivo activation of coagulation during experimental endotoxemia in chimpanzees. Four chimpanzees received a bolus intravenous injection of 4 ng/kg endotoxin in combination with Fab fragments of a factor VII/VIIa neutralizing murine monoclonal antibody (12D10) at a dose of either 50 micrograms/kg (n = 2) or 100 micrograms/kg (n = 2). Four control animals received a bolus injection of endotoxin alone. Administration of the 12D10 Fab fragments, immediately preceding the endotoxin bolus injection, effectively blocked the endotoxin-induced activation of coagulation. Plasma levels of products of in vivo activation, namely F1 + 2, TAT complexes and FpA remained at baseline values. The administration of 12D10 resulted in a rapid decline in factor VII/VIIa antigen levels which remained below 5 ng/ml for 180-240 min, followed by a rapid return to baseline levels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Complete inhibition of endotoxin-induced coagulation activation in chimpanzees with a monoclonal Fab fragment against factor VII/VIIa. 779 34

Reciprocal interactions between elements of the acute inflammatory response and the coagulation system play important roles in host defense homeostasis during Gram-negative bacterial sepsis. However, derangements in the regulation of the inflammatory-coagulant axis in this setting may result in progressive tissue damage and disseminated intravascular coagulation. In this article, the integrated responses in the baboon model of Escherichia coli sepsis are analyzed as a basis of understanding these response interactions in the critically ill. In particular, three topics will be reviewed. First, the role of tissue factor in mediating the coagulant response to inflammation and the role of tumor necrosis factor (TNF) in initiating and amplifying this coagulant response into a full-blown consumptive coagulopathy are defined. A second and parallel topic concerns the role played by tissue factor pathway inhibitor and other anticoagulant systems in not only regulating this coagulant response, but also in attenuating the initial inflammatory response. The third topic concerns the use of assays of enzyme inhibitor complexes composed of components of these regulatory anticoagulant systems to help define the hypercoagulable state and possibly to make an early, specific diagnosis of sepsis prior to overt failure of the hemostatic system.
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PMID:The inflammatory-coagulant axis in the host response to gram-negative sepsis: regulatory roles of proteins and inhibitors of tissue factor. 780 4

Endotoxin(lipopolysaccharide = LPS), cell wall component of gram-negative bacteria, activates monocytes and macrophages to release cytokines, reactive nitrogen intermediates (RNI), and to generate tissue factor(TF) which initiate coagulation. We have purified 7kDa and 18kDa cationic antibacterial proteins (CAP-7 and CAP-18) with LPS-binding and LPS-neutralizing activities from rabbit granulocytes using as an assay the agglutination of erythrocytes coated with Re-LPS. From protein sequencing, CAP-7 was identified as the C-terminal 37 amino acid fragment of CAP-18. Synthetic peptide #197 (identical sequence to CAP-7, Gly1-Try37) and #36-1 (a truncation of CAP consisting of 32 amino acid residues, Gly1-Ala32) showed LPS-binding activity. Each peptide inhibited LPS-induced tissue factor(TF) generation by murine peritoneal macrophages, even added 1-3 hours after stimulation of cells with LPS. C57BL/6 mice treated with #197 were significantly protected from lethal LPS challenge. Peptide #36 also blocked the LPS-induced lethality. These peptides had antibacterial activity to gram-negative bacteria, such as E.coli, S.typhimurium, K.pneumonia, Ps.aeruginosa and also to gram-positive S.aureus (Methicillin sensitive and resistant strains). Both peptides inhibited TF- and Xa-induced plasma clotting. Using synthetic chromotogenic substrates, both CAP7 peptides blocked the coagulation cascade at two sites, activation of factor X to Xa and conversion of Factor II (prothrombin) to factor IIa (thrombin). In vivo treatment of peptide #197 prevented acute lethality in mice injected with tissue factor (rabbit brain thromboplastin). Two other peptides, #32(Gly1-Phe9) and #50(Ile13-Typ37) failed to demonstrate LPS-binding, LPS-neutralizing, antibacterial and anticoagulant activities. The active peptides but not the inactive peptide maintain a putative heparin binding domain at their N-termini. This heparin binding domain is participate in the LPS-binding, LPS neutralizing, antibacterial and anticoagulant activities of CAP7. These active peptides may have a therapeutic potential for treatment for DIC due to sepsis and endotoxin shock.
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PMID:Endotoxin-binding synthetic peptides with endotoxin-neutralizing, antibacterial and anticoagulant activities. 783 55

Administration of purified hemoglobin (Hb) as a cell-free resuscitation fluid is associated with multiple organ toxicities. Many of these toxicities are characteristic of the pathophysiological effects of bacterial endotoxins (lipopolysaccharide, LPS). To better understand the potential role of LPS in the observed in vivo toxicities of Hb, we examined mixtures of Hb and LPS for evidence of LPS-Hb complex formation. LPS-Hb complexes were demonstrated by three techniques: ultrafiltration through 300 kDa cut-off membranes, which distinguished LPS in complexes (87-89% < 300 kDa) from LPS alone (90% > 300 kDa); density centrifugation through sucrose, which distinguished denser LPS alone from LPS-Hb complexes; and precipitation by 67% ethanol, which demonstrated 2-3 fold increased precipitability of Hb in complexes compared to Hb alone. Interaction of LPS with Hb was also associated with markedly increased biological activity of LPS, as manifested by enhancement of LPS activation of Limulus amebocyte lysate (LAL), increased release of human mononuclear cell tissue factor, and enhanced production of human endothelial cell tissue factor. These results demonstrated that hemoglobin can serve as an endotoxin binding protein, and that this interaction results in the alteration of several of the physical characteristics of LPS and enhancement of the biological activities of LPS. These findings suggest that a mechanism for the toxicity of infused Hb in vivo may involve potentiation of the biological effects of LPS. In addition, these observations suggest a mechanism by which LPS-related morbidity during sepsis could be enhanced by erythrocyte hemolysis.
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PMID:Hemoglobin: a newly recognized binding protein for bacterial endotoxins (LPS). 783 56

The baboon model of E. coli sepsis illustrates three concepts with respect to the host response and vascular endothelium. First, the endothelium is the primary target. E. coli sepsis is an acute inflammatory disease of the vascular endothelium. Second, the endothelium is not a passive target. Initially it regulates both the inflammatory and coagulopathic aspects of E. coli sepsis through membrane associated regulatory receptor/plasma protein assemblies including protein C/thrombomodulin, activated protein C/protein S, C4bBP/protein S, tissue factor pathway inhibitor/Xa, antithrombin III/glycosaminoglycans. Third, when overridden by inflammatory events, the endothelium can change its anticoagulant phenotype and mount a massive procoagulant fibrinolytic counter-attack on its luminal side through the expression of tissue factor and release of tissue plasminogen activator. Fourth, again when overridden by inflammatory events, the endothelium can change its antioxidant phenotype and produce a "distal" tissue hypoxia on its abluminal side through induction of free radical generation and peroxidation of mitochondrial lipid membranes of those tissues with high metabolic rates. It has become increasingly clear that the so-called anticoagulant systems which act on the proximal factors of the clotting cascade (protein C, TFPI, AT-III, PGI2) also attenuate the amplification of the inflammatory response. Aspects of the mechanism by which this occurs are coming to light. This includes the attenuation of Il-6 response by TFPI and the attenuation of the complement effects by C4bBP/PS. The specifics of these observations in the E. coli sepsis model will be reviewed.
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PMID:Studies on the inflammatory-coagulant axis in the baboon response to E. coli: regulatory roles of proteins C, S, C4bBP and of inhibitors of tissue factor. 783 58

Blood-borne lipopolysaccharide (LPS) is thought to be a major inducer of sepsis; however, it remains controversial whether an ongoing exposure to LPS is required to maintain the underlying systemic inflammatory response. To address this question, we have studied the expression of tumor necrosis factor alpha (TNF-alpha), interleukin 1-beta (IL-1 beta), and the procoagulant protein tissue factor induced by LPS ex vivo in whole human blood. The addition of a 1-ng/ml bolus of LPS to blood rapidly induced mRNA expression of all three genes. The mRNA levels peaked after 1 to 2 h, depending on the gene, and then declined to baseline after approximately 5 h. The decline in mRNA expression was not caused by a loss of responsiveness of the blood cells to LPS but rather correlated with the neutralization of LPS inflammatory activity by plasma components. Furthermore, administering a 1-ng/ml dose of LPS in six hourly aliquots of 167 pg/ml greatly prolonged the expression of mRNAs and induced a much greater release of TNF-alpha and IL-1 beta protein than did a single bolus. Dosing by repeated additions was more effective than a single bolus in inducing secretion of TNF-alpha and IL-1 beta at LPS levels of < or = 10 ng/ml, which corresponded to the LPS neutralization capacity of plasma. Finally, both mRNA expression and protein secretion induced by repeated administration of LPS were rapidly reversed by the addition of the LPS-neutralizing protein, bactericidal/permeability-increasing protein, even after several hours of stimulation. These results indicate that continuous or repeated exposure to LPS is required to maintain the expression of inflammatory genes and that the activated state is rapidly reversed with LPS neutralization.
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PMID:Prolonged expression of lipopolysaccharide (LPS)-induced inflammatory genes in whole blood requires continual exposure to LPS. 789 Mar 95

Sepsis is the most important cause of mortality in the Intensive Care Units. At present, sepsis is understood to be the inflammatory response of the host to infection, rather than a direct effect of microbial aggression. From the clinical standpoint, this inflammatory response is known as systemic inflammatory response syndrome (SIRS). Pathophysiologically, SIRS is characterized by the activation of several groups of cell (monocytes/macrophages, PMNs, and endothelial cells) and by the release of inflammatory mediators (cytokines and others). Tumor necrosis factor (TNF) is the first cytokine released by endotoxin action over monocyte/macrophage. TNF secretion, modulated by interferon gamma (IFN gamma) and interleukin 10 (IL-10), is followed by release of other cytokines such as interleukins (IL) (IL-1, IL-6 and IL-8). These mediators are able to act over hemostasis activating the extrinsic pathway through tissue factor expression. The action of the mediators over endothelial cells induces an increase in plasminogen activator inhibitor type 1 (PAI-1) levels with inhibition of fibrinolysis. Both coagulation activation and fibrinolysis blockade result in fibrin deposit in the microvascular system. The complexity of the mechanisms implicated in systemic inflammatory response make a general rule so difficult to establish, because patient response is highly individualized and it is not possible to know which moment of this dynamic process is being analyzed.
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PMID:Inflammatory mediators and their influence on haemostasis. 795 61

Nafamostat mesilate (NM), a synthetic protease inhibitor, is frequently used for the treatment of disseminated intravascular coagulation (DIC) in Japan. NM inhibits several proteases which may be importantly involved in the pathophysiology of DIC. Since tissue factor (TF) plays a critical role in DIC associated with septicemia, inhibition of the extrinsic pathway of coagulation by coagulation inhibitors may be useful for the treatment of DIC. NM inhibited extrinsic pathway activity (TF-F.VIIa mediated-F.Xa generation) in a concentration dependent manner; the IC50 was 1.0 x 10(-7) M. F.Xa was not inhibited by NM at the concentrations used in the experiment, suggesting that NM might inhibit TF-F.VIIa complex activity. When incubated with TF-F.VIIa complex, NM inhibited the complex activity with an IC50 of 1.5 x 10(-7) M, the same value that found for inhibition of extrinsic pathway activity. A Lineweaver-Bulk's plot of the inhibition demonstrated that NM inhibited TF-F.VIIa complex in a competitive fashion, with an inhibition constant (Ki) of 2.0 x 10(-7) M. These findings suggested that NM may be a potent inhibitor of TF-F.VIIa complex and the therapeutic effect of NM in DIC patients could be partly explained by inhibition of the extrinsic pathway of the coagulation system.
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PMID:Effect of nafamostat mesilate, a synthetic protease inhibitor, on tissue factor-factor VIIa complex activity. 802 16

Tissue factor, the obligate cofactor for coagulation factor VII, plays an essential role in hemostasis by initiating the extrinsic pathway of blood coagulation upon vascular damage, making it a promising target for new anticoagulant therapies in the treatment of thrombosis and sepsis. The three-dimensional structure of the extracellular domain of tissue factor, determined by X-ray crystallography at a resolution of 2.4 A, consists of two domains of approximately equal size, with a topology characteristic of fibronectin type III modules. Comparison of tissue factor with the extracellular domain of the growth hormone receptor, which belongs to the same receptor superfamily, shows that the relative orientation between these domains as well as the domain-domain interface is very different. These differences have dramatic consequences for the residues in tissue factor that are homologous to the binding determinants of the growth hormone receptor. Alanine-scanning mutagenesis has identified tissue factor residues important for factor VIIa binding. The structure shows that the binding site is located in the domain-domain interface region but on the opposite side of the molecule compared to the growth hormone receptor, with the binding determinants residing on beta-strands rather than on loops.
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PMID:Structure of the extracellular domain of human tissue factor: location of the factor VIIa binding site. 808 3

Cationic antibacterial proteins (CAP) were purified from rabbit granulocytes, and the effects of CAP on lipopolysaccharide (LPS)-induced tissue factor generation by murine peritoneal macrophages and human blood monocytes were studied. CAP were purified from rabbit peritoneal leukocytes by using as an assay the agglutination of erythrocytes coated with Re-LPS. Two proteins with CAP activity, CAP18 (18 kDa) and CAP7 (7 kDa), were isolated by acid extraction, ethanol precipitation, affinity chromatography, gel filtration, and reverse-phase high-pressure liquid chromatography. On the basis of protein sequencing, CAP7 was identified as the C-terminal fragment of CAP18, designated CAP18(106-142). Various forms of LPS (S-LPS, Re-LPS, and lipid A) activate murine macrophages and human blood monocytes to generate tissue factor (tissue thromboplastin). Incubation of LPS for 18 h with partially purified CAP (heparin-Sepharose fraction) inhibited the capacity of LPS to induce tissue factor; however, purified CAP18 inhibited about 75% of the activity of S-LPS after 1 h of incubation. CAP more effectively inhibited S-LPS than Re-LPS or lipid A. Synthetic CAP18(106-142) inhibited LPS-induced tissue factor generation by murine macrophages. CAP18(106-142) has greater LPS-binding and LPS-neutralizing activities than CAP18. We hypothesize that CAP18 and the derivative peptide, CAP18(106-142), bind to LPS and alter the capacity of LPS to initiate disseminated intravascular coagulation. In this regard, CAP may have therapeutic potential for sepsis and endotoxin shock.
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PMID:Characterization of a rabbit cationic protein (CAP18) with lipopolysaccharide-inhibitory activity. 813 48


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