UNIPROT:P43026 - FACTA Search

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Query: UNIPROT:P43026 (lipopolysaccharide)
62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tissue factor (TF) is the major activator of the coagulation protease cascade and contributes to lethality in sepsis. Despite several studies analyzing TF expression in animal models of endotoxemia, there remains debate about the cell types that are induced to express TF in different tissues. In this study, we performed a detailed analysis of the induction of TF mRNA and protein expression in two rabbit models of endotoxemia to better understand the cell types that may contribute to local fibrin deposition and disseminated intravascular coagulation. Northern blot analysis demonstrated that lipopolysaccharide (LPS) increased TF expression in the brain, lung, and kidney. In situ hybridization showed that TF mRNA expression was increased in cells identified morphologically as epithelial cells in the lung and as astrocytes in the brain. In the kidney, in situ hybridization experiments and immunohistochemical analysis showed that TF mRNA and protein expression was increased in renal glomeruli and induced in tubular epithelium. Dual staining for TF and vWF failed to demonstrate TF expression in endothelial cells in LPS-treated animals. These results demonstrate that TF expression is induced in many different cell types in LPS-treated rabbits, which may contribute to local fibrin deposition and tissue injury during endotoxemia.
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PMID:Lipopolysaccharide induction of tissue factor expression in rabbits. 1022 18

We compared lethal toxicity and potential for splenomegaly and disseminated intravascular coagulation (DIC) of the lipid A derivative DT-5461 with those of compound 506 (C506) and bacterial lipopolysaccharide (LPS). These agents were given intravenously, by either bolus intravenous injection (2 ml/min) or drip infusion (3 ml/4 h), into the tail vein of rats under various regimens. In naive rats, the lethal dose after bolus intravenous injection was clearly higher than that after drip infusion for C506 and LPS, but not for DT-5461. In partially hepatectomized or D-galactosamine-treated rats, a marked enhancement of the lethality was observed for all agents relative to that in naive rats. Splenomegaly was commonly seen in all surviving rats after treatment, and histopathological examination revealed lymphoid hyperplasia in the B-cell area of the white pulp zone and lympho-reticular cell proliferation of the red pulp zone. When administered intravenously by drip infusion to rats pretreated with 0.4 M lactic acid, both C506 and LPS provoked DIC. This was manifested by a decrease in platelet counts, prolongation of activated partial thromboplastin time (APTT), and an increase in fibrin-fibrinogen degradation products (FDP), with hepatocellular necrosis and glomercular fibrin thrombus formation. In contrast, DT-5461 showed no such toxic events with the same protocol. In14-day intravenous toxicity studies of DT-5461, rats were more susceptible to hepatocellular necrosis and splenomegaly than squirrel monkeys. These results demonstrate that DT-5461 is a promising compound, with antitumor activity dissociated from its toxic potential.
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PMID:Toxic characteristics of the synthetic lipid A derivative DT-5461 in rats and monkeys. 1041 79

Perfluorotributylamine/Pluronic F68 Stem-Emulsion (FC43se), which is a blood substitute, was assessed for its effectiveness on disseminated intravascular coagulation (DIC) in the rat model. Rats were infused intravenously with 2.5 mg/kg of Escherichia coli lipopolysaccharide (Escherichia coli 055:B5 lipopolysaccharide B) for four hours. At the same time, FC43se or normal physiological saline was infused at 2.5 ml/kg/hr. The white blood cell and platelet counts, prothrombin time (PT), activated partial thromboplastin time (APTT), and the plasma levels of interleukin-1 beta (IL-1 beta), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor alpha (TNF alpha) were determined at 4 hr. The infusion of FC43se markedly prevented a decrease in platelet counts (p = 0.0004) and a prolongation of both PT and APTT (p < 0.05 and p < 0.03 each). The serum level of IL-1 beta and IL-4 showed no significant change. The serum level of IL-6, IL-10 and TNF alpha increased significantly (p = 0.0007, p = 0.0004 and p < 0.05 each) with infusion of FC43se in rats treated with bacterial endotoxin. FC43se has beneficial effects on endotoxin-induced DIC as an anticoagulant and anti-inflammatory cytokine induced agent.
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PMID:Effect of FC43se on endotoxin-induced disseminated intravascular coagulation in rats. 1043 77

Tissue factor (TF) production is under strict control in mature monocytic cells. However, constitutive expression of TF can be found in myelomonocytic cells and in haematopoietic cells arrested at an early stage of differentiation. In this paper we show that TF expression is down-regulated during the monocyte/granulocyte differentiation process, using the human monoblastic U-937 and the acute promyelocytic leukaemia NB4 cell lines as models. Expression of TF mRNA, protein and procoagulant activity (PCA) was constitutively high in untreated cells. Exposure of U-937 cells to 1alpha,25-dihydroxycholecalciferol (VitD3) and all-trans retinoic acid (ATRA) resulted in down-regulation of TF expression and PCA. In NB4 cells induction by ATRA, but not VitD3, resulted in the down-regulation of TF expression and PCA. Consistent with this, induction of terminal differentiation, as confirmed by the expression of differentiation associated antigens and cell cycle arrest, was inversely correlated to TF expression in U-937 and NB4 cells. Moreover, terminally differentiated U-937 cells retained the capacity to respond to inflammatory mediators, i.e. lipopolysaccharide and interferon-gamma, by a rapid increase in TF expression. In conclusion, we show that not only ATRA but also VitD3 is a potent suppressor of monocytic TF expression and thus might have potential clinical use for the treatment of coagulopathies.
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PMID:Induction of differentiation in U-937 and NB4 cells is associated with inhibition of tissue factor production. 1048 Feb 90

Antiphospholipid antibodies (aPL) may stimulate tissue factor (TF) expression in cultured endothelial cells and monocytes, but there are discrepancies as to the expression of TF in the patients with antiphospholipid syndrome (APS). By using reverse transcription and polymerase chain reaction amplification, we have analysed TF mRNA accumulation in freshly isolated mononuclear blood cells (MBC) of 14 patients with primary APS (PAPS) and six normal controls. TF mRNA accumulation was low or absent in uncultured MBC from all normal controls, but was elevated in uncultured MBC from nine of the patients as well as in normal MBC incubated with 100 ng/ml lipopolysaccharide (LPS). Mean levels of TF mRNA, as measured by densitometry, were higher in MBC from patients (N = 14) than in those from controls (N = 6, P = 0.009), and in MBC from patients with a history of thrombosis (N = 9) than in those from patients without thrombosis (N = 5, P = 0.02). Uncultured MBC of patients with thrombosis accumulated TF mRNA at similar levels to LPS-treated normal MBC. Increased levels of TF mRNA were found in eight of ten patients with conventional aPL (ie, anti-cardiolipin antibodies [aCL] and/or lupus anticoagulant [LA]) and little if any accumulation of TF mRNA was observed in three of four patients without aPL at the time of study. These data strongly suggest that circulating monocytes of many patients with PAPS are subjected to an up-regulated TF expression that may well explain their prothrombotic state. Although the presence or absence of TF mRNA in MBC was associated with, respectively, the presence or absence of conventional aPL in 11 of the 14 patients studied, our study cannot exclude the involvement of factors other than aCL or LA in inducing TF expression.
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PMID:Increased levels of tissue factor mRNA in mononuclear blood cells of patients with primary antiphospholipid syndrome. 1061 37

Tissue factor (TF) triggers the coagulation cascade reaction in vivo. Overexpression of TF mRNA is one leading cause of disseminated intravascular coagulation and thrombosis-related organ failure. In response to lipopolysaccharide (LPS) stimulation, various cell types can produce TF mRNA in vitro. However, there is currently no agreement on what types of cells in the liver overexpress TF mRNA after LPS treatment. For the first report, we found the increased TF mRNA with reverse transcription-polymerase chain reaction (RT-PCR), and confirmed a fourfold increase (p<0.001 vs. control, t-test) of the TF mRNA level with RT-competitive PCR in the liver of LPS-treated (2.0 mg/kg i.v. injection) rats. There was no significant difference in the glyceraldehyde-3-phosphate dehydrogenase mRNA level between LPS-treated rats and control rats. To clarify the localization and cellular source of LPS-induced TF mRNA, we performed in situ hybridization analysis with [35S]-labeled oligonucleotides probes, which we originally designed. We detected intense signals of TF mRNA in mononuclear cells but not in endothelial cells around the hepatic vein of LPS-treated rats. In this study, we showed that the TF mRNA level induced by LPS treatment, which may indicate mononuclear cells associated, significantly increased in the liver of rats. These results will provide circumstantial support for the therapeutic strategy that mononuclear cell should be one of the target cells to be treated in the early phase of disseminated intravascular coagulation in the liver, and that the need to suppress its overexpression of TF mRNA is essential for preventing hypercoagulable condition.
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PMID:Detection of mononuclear cells as the source of the increased tissue factor mRNA in the liver from lipopolysaccharide-treated rats. 1068 Jun 46

During sepsis, lipopolysaccharide (LPS) triggers the development of disseminated intravascular coagulation (DIC) via the tissue factor-dependent pathway of coagulation resulting in massive thrombin generation and fibrin polymerization. Recently, animal studies demonstrated that hirudin reduced fibrin deposition in liver and kidney and decreased mortality in LPS-induced DIC. Accordingly, the effects of recombinant hirudin (lepirudin) was compared with those caused by placebo on LPS-induced coagulation in humans. Twenty-four healthy male subjects participated in this randomized, double-blind, placebo-controlled, parallel group study. Volunteers received 2 ng/kg LPS intravenously, followed by a bolus-primed continuous infusion of placebo or lepirudin (Refludan, bolus: 0.1 mg/kg, infusion: 0.1 mg/kg/h for 5 hours) to achieve a 2-fold prolongation of the activated partial thromboplastin time (aPTT). LPS infusion enhanced thrombin activity as evidenced by a 20-fold increase of thrombin-antithrombin complexes (TAT), a 6-fold increase of polymerized soluble fibrin, termed thrombus precursor protein (TpP), and a 4-fold increase in D-dimer. In the lepirudin group, TAT increased only 5-fold, TpP increased by only 50%, and D-dimer only slightly exceeded baseline values (P <.01 versus placebo). Concomitantly, lepirudin also blunted thrombin generation evidenced by an attenuated rise in prothrombin fragment levels (F(1 + 2), P <. 01 versus placebo) and blunted the expression of tissue factor on circulating monocytes. This experimental model proved the anticoagulatory potency of lepirudin in LPS-induced coagulation activation. Results from this trial provide a rationale for a randomized clinical trial on the efficacy of lepirudin in DIC. (Blood. 2000;95:1729-1734)
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PMID:Lepirudin blunts endotoxin-induced coagulation activation. 1068 31

Our previous study has demonstrated a unique biological function of compound 48/80 (48/80) in the downregulation of monocytic tissue factor (TF)-initiated hypercoagulation in response to bacterial endotoxin (lipopolysaccharide, LPS) [A. J. Chu et al. (1999) Biochim. Biophys. Acta 1472, 386-395]. The inhibition was not due to the blockade of LPS cell signaling as evidenced by the unaffected LPS-induced TF synthesis. In the present study, we investigate the direct inhibitory action of 48/80 on the extrinsic coagulation cascade. TF-initiated coagulation was assayed by a single-stage clotting assay. Chromogenic assays dissected the extrinsic pathway to measure the activities of FVII, FX, and prothrombin by monitoring the hydrolyses of nitroaniline-conjugated substrates, identifying the inhibitory site(s). We report that 48/80 in vitro instantaneously inhibited rabbit brain thromboplastin (rbTF)-initiated coagulation in a dose-dependent manner. 48/80 preferentially inhibited FVII activation without any detectable effect on FVIIa, FXa, and thrombin activities. Neither FX activation nor prothrombin activation was affected. The significant inhibition on FVII activation was found to be noncompetitive with a fourfold reduction in the apparent Vmax of FVIIa formation from 7.1 to 1.7 nM/min, while the apparent Km (approximately 365 nM) remained unaffected. Western blotting analysis further confirmed that FVIIa formation derived from FVII was significantly diminished by 48/80, which was accompanied by blocked FVII binding to rbTF. In conclusion, 48/80 readily blocked FVII binding to rbTF, leading to diminished FVII activation and FVIIa formation. As a result, TF-initiated extrinsic coagulation was downregulated.
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PMID:III. Instantaneous inhibition by compound 48/80 of tissue factor-initiated extrinsic coagulation is mediated by the downregulation of factor VII activation. 1084 14

Accelerated coronary atherosclerosis in cardiac allografts is a major factor limiting survival after heart transplantation, and activation of the coagulation system contributes to accelerated transplant atherosclerosis. Accordingly, increased tissue factor (TF) expression by monocyte/macrophages may play a pivotal role underlying deposition of fibrin in the affected vessels. To evaluate the potential effects of an important immunosuppressive agent, tacrolimus hydrate (FK-506), on monocyte/macrophages and their response to lipopolysaccharide (LPS), we exposed human monocyte/macrophage cell line (THP-1 cells), to LPS and characterized its procoagulant activity (PCA). FK-506 exerted a concentration-dependent inhibitory effect on LPS (10 micrograms/ml) induction of procoagulant activity, identified as TF activity as judged from immunostaining of TF antigen and by functional characterization with the use of coagulation factor VII-deficient plasma and an antibody against human TF. In addition, the reverse transcription polymerase chain reaction demonstrated reduced expression of TF mRNA in LPS-stimulated THP-1 cells exposed to FK-506. Thus, FK-506 acts favorably not only as a direct immunomodulating agent but also as an alleviator of local activation of the coagulation cascade contributing to transplant arteriopathy through modulation of monocyte expression of TF.
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PMID:Effects of tacrolimus hydrate (FK-506) on the expression of tissue factor in THP-1 human monocyte cell line. 1088 73

Triggering of the tissue factor (TF)-dependent coagulation pathway is considered to underlie the generation of a procoagulant state during endotoxemia. To determine the in vivo pattern of monocytic TF messenger RNA (mRNA) expression during endotoxemia, 10 healthy volunteers were injected with lipopolysaccharide (LPS, 4 ng/kg) and blood was collected before and 0.5, 1, 2, 3, 4, 6, 8, and 24 hours after LPS administration. Total blood RNA was isolated and amplified by NASBA (nucleic acid sequence-based amplification), followed by quantitation of TF mRNA by an electrochemiluminescence (ECL) assay. To compare the pattern of coagulation activation with the kinetics of monocytic TF mRNA expression, we measured plasma levels of markers of thrombin generation, thrombin-antithrombin (TAT) complexes, and prothrombin fragment 1 + 2 (F1 + 2). Baseline value (mean +/- SEM) of the number of TF mRNA molecules per monocytic cell was 0.08 +/- 0.02. A progressive and significant (P <.0001) increase in TF expression was observed after LPS injection (+0.5 hour: 0.3 +/- 0.1, +1 hour: 1.3 +/- 0.9, +2 hours: 4.1 +/- 0.9), peaking at +3 hours (10 +/- 1.9 TF mRNA molecules per monocyte). As TF mRNA levels increased, thrombin generation was augmented. Peak levels of TAT and F1 + 2 were reached later (at t +4 hours) than those of TF mRNA. TF mRNA, TAT, and F1 + 2 levels returned to baseline after 24 hours. In conclusion, we used a NASBA/ECL-based technique to quantify TF mRNA in whole blood during human endotoxemia and observed a 125-fold increase in TF mRNA levels. Our data demonstrate a pivotal role for enhanced TF gene activity in the activation of coagulation after LPS challenge. (Blood. 2000;96:554-559)
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PMID:The in vivo kinetics of tissue factor messenger RNA expression during human endotoxemia: relationship with activation of coagulation. 1088 18

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