Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have evaluated the quantitative relationship between lipopolysaccharide (LPS, endotoxin), fibrinopeptide A (FPA), antithrombin (AT), protein C (PC) and extrinsic pathway inhibitor (EPI) in plasma from 39 consecutively admitted patients with systemic meningococcal disease (SMD). The most severely ill patients with fulminant meningococcal septicemia (n = 13, 6 dead) had significantly (p less than 0.01) higher plasma levels of LPS and FPA and lower levels of PC and AT on admission as compared with the less severe clinical presentations (n = 26, 1 dead). The levels of EPI on admission were significantly (p less than 0.05) higher in nonsurvivors vs survivors with fulminant septicemia. As the disease progressed, the levels of LPS, FPA, AT and PC declined, while the levels of EPI increased. Three of six nonsurviving septicemic patients had levels of EPI greater than 200% within 16 hours of admission vs two of 30 survivors (p = 0.02). The results suggest that increasing levels of LPS in SMD elicit increasing consumption coagulopathy, contributing to the organ pathophysiology. The kinetics of EPI, inhibiting the thromboplastin-FVIIa-FXa complex, differs markedly from the kinetics of AT and PC i.e. increases as opposed to decreases.
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PMID:The quantitative association of plasma endotoxin, antithrombin, protein C, extrinsic pathway inhibitor and fibrinopeptide A in systemic meningococcal disease. 251 Mar 54

The monocyte is the only circulating cell type capable of initiating blood coagulation by the expression of tissue factor (TF). The mechanism and kinetics of TF mRNA and TF activity induction in human peripheral blood monocytes (HPBM) in response to bacterial lipopolysaccharide (LPS) and phorbol myristate acetate (PMA) were investigated. Northern blot analysis showed that both LPS and PMA induce a transient accumulation of TF mRNA in HPBM, that reaches maximum levels after 3-6 h and rapidly declines thereafter. Nuclear run-on experiments demonstrated that the accumulation of TF mRNA requires de novo transcription of the TF gene. Since cycloheximide alone also caused an increase of TF mRNA levels and gene transcription it is concluded that the transcriptional activation of the TF gene does not require protein synthesis. Using specific protein kinase inhibitors, it was further demonstrated that activation of the protein kinase C pathway is involved in the induction of TF mRNA in HPBM. The accumulation of TF mRNA in LPS-stimulated HPBM is followed by an increase of TF activity on the cell surface. The kinetics of TF mRNA induction were found to be very similar in HPBM stimulated with LPS or PMA. However, in the latter case TF activity appeared considerably later on the cell membrane than in the LPS-stimulated cells. Non-stimulated HPBM contain very low levels of mRNA of the tissue factor pathway inhibitor (TFPI). No induction of TFPI (mRNA, activity or antigen) in HPBM after LPS or PMA treatment was demonstrated. This seems to be in contrast with the earlier observation that the human monocyte cell line U937 produces significant amounts of TFPI in response to treatment with LPS and PMA.
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PMID:Expression of tissue factor and tissue factor pathway inhibitor in monocytes in response to bacterial lipopolysaccharide and phorbolester. 805 53

Acute inflammatory illnesses, including the sepsis syndrome, often include a component of coagulation. A human whole blood culture system was developed so that the relationship between coagulation activation and cytokine responses in the presence or absence of lipopolysaccharide (LPS) could be evaluated. In the absence of LPS stimulation, coagulation activation resulted in a novel pattern of cytokine production. During a 4-hour culture of coagulating blood, significant production of interleukin-8 (IL-8; >2,000 pg/mL) was observed, whereas other proinflammatory cytokines including IL-1 beta, IL-6, or tumor necrosis factor a were undetectable or less than 35 pg/mL. The cytokine profile was distinct from that of fully anticoagulated, LPS-stimulated blood, which showed levels of all the indicated proinflammatory cytokines > or = 2,000 pg/mL over the same time period. Over 24 to 48 hours, the coagulation-induced cytokine response was characterized by marked and sustained IL-8 production, limited IL-6 generation (with kinetics delayed relative to IL-8), and minimal or undetectable tumor necrosis factor alpha levels. The magnitude of the whole blood IL-8 response correlated with the level of coagulation activation as determined by measurement of thrombin-antithrombin III complex formation. The combined stimuli of coagulation activation and LPS challenge induced a synergistic enhancement of IL-8 production but not of IL-6. Coagulation-induced cytokine production and the synergistic production of IL-8 by coagulation and LPS could be attenuated by hirudin or tissue factor pathway inhibitor (TFPI). Studies to elucidate mechanisms implicated (1) the TFPI third Kunitz and carboxy-terminus as important structural components for TFPI regulation of coagulation activation and (2) thrombin as a candidate mediator of the mononuclear cell cytokine response to coagulation activation. In summary, a unique aspect of the crosstalk between the coagulation and cytokine cascades in whole blood is shown with the identification of IL-8 as a key proinflammatory participant.
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PMID:The proinflammatory cytokine response to coagulation and endotoxin in whole blood. 865 18

The direct effects of recombinant human erythropoietin(rHuEPO) on coagulation and fibrinolysis factors were evaluated in a cultured endothelial cell (EC) system. Confluent quiescent ECs were incubated with or without 5.0 U/ml rHuEPO for 1, 6, and 18 hours, and supernatant concentrations of plasminogen activator inhibitor-1 (PAI-1): antigen (Ag), tissue plasminogen activator and thrombomodulin, and supernatant activities of tissue factor pathway inhibitor and von Willebrand factor were measured. The results showed that only PAI-1 levels were increased by the presence of rHuEPO. In order to assess the effect of rHuEPO on PAI-1 production by EC more precisely, confluent ECs were incubated with various doses of rHuEPO (0, 1.0, 2.5, 5.0, 10.0 U/ml) for 1, 6, 12, and 18 hours, and PAI-1:Ag concentrations in the supernatants of media were measured. PAI-1:Ag in the supernatants were increased by the presence of rHuEPO at all incubation times (P < 0.01) and the increase in PAI-1:Ag was dependent on rHuEPO concentration. The increases in PAI-1:Ag by 5.0 U/ml rHuEPO were comparable to those by 0.1 U/ml tumor necrosis factor-alpha, 1.0 microgram/ml lipopolysaccharide, and 0.5 U/ml thrombin. The increase in PAI-1:Ag by rHuEPO was suppressed by pre-incubation with 10 micrograms/ml cycloheximide (P < 0.01) or 0.2 microgram/ml actinomycin D (P < 0.01). These results indicate that rHuEPO directly stimulates PAI-1 production in cultured EC via de novo protein and RNA syntheses.
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PMID:rHuEPO enhances the production of plasminogen activator inhibitor-1 in cultured endothelial cells. 880 78

Fibrin formation within the glomeruli has been observed in various forms of human and experimental glomerulonephritis and it may play an important role in progressive glomerular injury. Furthermore it has been hypothesized that glomerular fibrin deposition may occur through activation of either the intrinsic or extrinsic coagulation pathway. It has been demonstrated that a procoagulant activity (PCA) which is compatible with tissue factor is present in the glomeruli and becomes increased in human proliferative glomerulonephritis and in animal models of nephritis. Tissue factor pathway inhibitor (TFPI) regulates the extrinsic pathway of blood coagulation through its ability to inhibit tissue factor activity. TFPI is present in plasma and in platelets, and it is now thought to be produced mainly by endothelial cells. We examined whether human mesangial cells (HMC) could produce TFPI and attempted to clarify regulatory factors which affect TFPI production. Cultured HMC were used and TFPI in the cell supernatants was measured by ELISA using a specific antibody. Cultured HMC showed the production of TFPI. Immunoblot analysis revealed 40 kD protein of TFPI. The concentration of TFPI was significantly increased following the incubation with thrombin and heparin, including low molecular weight heparin, in a dose- and time-dependent manner. However, fetal calf serum, phorbol myristate acetate, lipopolysaccharide, IL-1 beta and tissue factor did not stimulate TFPI synthesis. Our data show that cultured HMC have the ability to produce TFPI which inhibits fibrin formation. It is possible that thrombin-induced enhancement of TFPI synthesis may be caused by the autoregulatory system of blood coagulation and that with heparin it may represent another anticoagulatory effect of heparin.
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PMID:Tissue factor pathway inhibitor production by human mesangial cells in culture. 886 34

The effect of inhibitors of cytokine release and plasma coagulation on lipopolysaccharide (LPS)-induced tissue factor and interleukin-6 (IL-6) was investigated. Dexamethasone, an inhibitor of cytokine production, inhibited LPS-induced tissue factor and IL-6 release by mononuclear cells (MNC), but enhanced IL-1beta-evoked tissue factor activity. Clinical antithrombin (AT) concentrates inhibited, in a dose-dependent manner, tissue factor and IL-6 production by MNC and human umbilical vein endothelial cells (HUVEC). The three AT preparations tested, when compared using the same antithrombin unit, had different potencies. Activated protein C (APC) augmented LPS stimulation of HUVEC and further increased the production of tissue factor and IL-6. The same effect was not observed with MNC; LPS-induced tissue factor and IL-6 release were unaffected by APC. Truncated tissue factor pathway inhibitor (TFPI1-161) inhibited LPS-induced MNC tissue factor and IL-6 production, but was unable to prevent LPS stimulatory activity on HUVEC. These data suggest a complex interaction between the coagulation pathway and the cytokine network.
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PMID:Inhibition of tissue factor and cytokine release. 890 80

Tissue factor pathway inhibitor (TFPI) plays a key role in modulating tissue factor-dependent blood coagulation. This study was done to determine not only the inhibitory effects of recombinant human TFPI (rTFPI) on thrombus formation in rat models with disseminated intravascular coagulation (DIC), but also to identify the distribution of exogenous TFPI in vivo. Disseminated intravascular coagulation was induced by administering a priming dose of carrageenan 10 mg/kg body weight and was followed 24 hours later by a provocative dose of lipopolysaccharide (LPS) 500 mg/kg body weight. The rTFPI was administered intravenously at a dose of either 1 or 4 mg/kg body weight immediately after LPS treatment. Exogenous rTFPI at a dose of 4 mg/kg significantly inhibited the consumption of fibrinogen, platelets and factor VIIa (P < .05) and also reduced the number of fibrin thrombi formed in the liver, lungs, kidneys, and spleen (P < .05), whereas rTFPI at a dose of 1 mg/kg had no significant inhibitory effect on these DIC parameters. Recombinant human rTFPI activity was rapidly cleared from the plasma; however, a significant amount of the inhibitor was still present in tissues even 3 to 6 hours after intravenous administration. Exogenous TFPI was mainly identified in Kupffer cells, macrophages, and on the microvascular endothelial lining of different organs. In the kidney, rTFPI was identified on both the abluminal surface of the renal tubules and the luminal surface of the proximal convoluted tubules. No rTFPI, however, was detected in the hepatocytes. Tissue factor was mainly expressed by monocytes/macrophages. These findings suggest that TFPI plays an important role in modulating TF-dependent thrombogenesis. The elucidation of the rTFPI distribution and interactions in vivo might thus provide valuable insight into its inhibitory mechanisms as well as its therapeutic implications in DIC.
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PMID:Effects of recombinant human tissue factor pathway inhibitor on thrombus formation and its in vivo distribution in a rat DIC model. 892 65

Inflammatory mediators like bacterial lipopolysaccharide induce monocytes to express tissue factor (TF), the cell-surface protein that triggers the blood clotting cascade in hemostasis and thrombotic disease. The physiologic ligand for TF is the serine protease, factor VIIa (FVIIa), and the resulting bimolecular enzyme, TF/FVIIa, can be reversibly inhibited by tissue factor pathway inhibitor (TFPI). Culturing monocytic cells in the presence of both FVIIa and TFPI caused down-regulation of TF expression via reducing its half-life. To exert this effect, FVIIa had to be competent to bind both TF and TFPI, and TFPI had to contain the C-terminal domain required for binding to other cell-surface receptors, including the low density lipoprotein receptor-related protein (LRP). TF down-regulation by FVIIa plus TFPI was abrogated by the 39-kDa receptor-associated protein, which blocks binding of all known ligands to LRP. Furthermore, treatment with FVIIa plus TFPI caused monocyte TF to colocalize with alpha-adaptin, a component of clathrin-coated pits. Thus, in addition to reversibly inhibiting TF/FVIIa catalytic activity, TFPI also mediates the permanent down-regulation of cell-surface TF in monocytic cells via LRP-dependent internalization and degradation. This represents an unusual mechanism for receptor internalization, requiring ligand-dependent bridging of one cell-surface receptor (TF) to a second cell-surface receptor (LRP), the latter being capable of clathrin-mediated internalization.
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PMID:Down-regulation of monocyte tissue factor mediated by tissue factor pathway inhibitor and the low density lipoprotein receptor-related protein. 998 40

Tissue factor pathway inhibitor (TFPI) is the primary physiological inhibitor that regulates tissue factor-induced blood coagulation. TFPI is thought to be synthesized, in vivo, primarily by microvascular endothelial cells. Little is known about how TFPI is regulated under pathophysiological conditions. In this study, we determined mechanisms by which TFPI expression is regulated by human pulmonary artery smooth muscle cells (PASMC), because these cells contribute to remodeling of the pulmonary vasculature in disease. PASMC in culture constitutively synthesize and secrete TFPI. Exposure of PASMC to phorbol myristate acetate, lipopolysaccharide, tumor necrosis factor alpha, thrombin, interleukin-1, and transforming growth factor-beta had no significant effect on expression of TFPI by PASMC. By contrast, treatment of PASMC with serum and basic fibroblast growth factor (bFGF)/heparin markedly upregulated the expression of TFPI activity and antigen. On Western blot analysis, a protein consistent with full-length TFPI (42 kD) was identified in the conditioned media of PASMC, and the levels of the protein were much higher in the conditioned media of serum and bFGF/heparin-treated cells. Northern blot analysis showed that PASMC constitutively express TFPI mRNA, and treatment of cells with serum and bFGF/heparin had a minimal effect on the steady-state levels of TFPI mRNA. Nuclear run-on analysis did not show a significant increase in the transcriptional rate of TFPI gene in PASMC treated with serum or bFGF/heparin. Cycloheximide, but not actinomycin-D, treatment inhibited the serum and bFGF/heparin-induced increase in TFPI activity in PASMC. In conclusion, our data demonstrate that PASMC constitutively synthesize and secrete TFPI and serum or bFGF upregulate its expression, suggesting that growth factors that can stimulate the vessel wall in vivo might locally regulate TFPI expression. Our study also suggests that control of TFPI expression by serum or bFGF occurs via translational rather than transcriptional regulation.
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PMID:Regulation of tissue factor pathway inhibitor expression in smooth muscle cells. 1039 25

Monocytes are potent regulators of blood coagulation through the expression of tissue factor (TF) on stimulation and of tissue factor pathway inhibitor (TFPI), a selective inhibitor of TF pathway. As hyperlipidemia can modify some monocyte functions, we compared the TF and TFPI expression by circulating monocytes and the plasma TFPI levels between 65 healthy normolipemic controls and 38 nontreated hyperlipemic patients. TF and TFPI relationships with plasma lipoproteins are also examined. TF and TFPI expression were evaluated in peripheral mononuclear cells after isolation from blood by density gradient centrifugation and after short culture with or without lipopolysaccharide (LPS). TF and TFPI activity and antigen were measured in mononuclear cell lysates using amidolytic assay and enzyme-linked immunosorbent assay, respectively. TFPI activity and antigen were measured in plasma using the same methods. Plasma factor VII (FVII) activity and antigen were also determined. LPS-stimulated monocyte TF activity and antigen were lower in hyperlipidemic patients than in controls (0.0001<p<0.03). This decrease of monocyte TF expression in hyperlipidemic patients was not related to an increase of monocyte TFPI. Monocyte TF activity was negatively correlated to atherogenic fractions and positively correlated to protective fractions, specially after ex vivo LPS stimulation. Increased TFPI and FVII plasma levels were found in hyperlipidemic patients compared to controls. These results indicate an impairment of TF production by circulating monocytes from hyperlipidemic subjects, which is linked to the increase of atherogenic lipoprotein fractions. Further studies are required to elucidate the mechanism of this inhibition.
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PMID:Monocyte tissue factor response is decreased in patients with hyperlipidemia. 1059 31


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