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)

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

Tissue factor (TF) is an integral membrane glycoprotein that serves as a cofactor for the blood coagulation factor VIIa. The induction of TF synthesis and activity on the surface of endothelial cell membrane is initiated by lipopolysaccharide (LPS), phorbol 12-myristate 13-O-acetate (PMA), and inflammatory factors such as interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF alpha). Treatment of cells with 1 micrograms/ml LPS induced an 8.7-fold increase in total TF activity compared with nontreated cells. Co-incubation with 1 micrograms/ml LPS and 30 microM W7, a potent calmodulin inhibitor, resulted an additional 2.0 fold increase in total TF activity. A similar tendency was observed after treatment with either TNF alpha plus W7, or IL-1 beta plus W7. The effect of W7 appeared to be synergistic since incubation with 30 microM W7 alone increased TF activity levels to only 1.5-fold that of control cells. Northern blot analysis showed that W7 and LPS-treated endothelial cells expressed about three times higher levels of TF mRNA compared to LPS-treated cells. Treatment with W7 and LPS resulted in a slow but large calcium influx into endothelial cells. This result suggest that the contribution of W7 may be dependent mainly on calcium influx by unknown mechanisms rather than direct inhibition of calmodulin, because calcium ionophore treatment also showed a synergistic effect on TF mRNA and activity expression.
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PMID:Up-regulation of tissue factor mRNA in human umbilical vein endothelial cells by calmodulin inhibitor W7. 819 11

Tissue factor (TF) is the predominant physiological initiator of coagulation, and its regulation is a critical aspect of endothelial cell hemostatic function. This report describes the regulation of TF mRNA expression by two physiological agonists: minimally oxidized low-density lipoprotein (MM-LDL), which may modulate endothelial hemostatic function in atherosclerosis, and lipopolysaccharide (LPS), which is a mediator of septic shock. Northern blot analysis of total RNA from human endothelial cells exposed to either MM-LDL or LPS for varying times showed that TF mRNA increased sharply at 1 hour, peaked at 2 to 3 hours, and declined to basal levels by 6 to 8 hours after treatment. The half-life of TF mRNA in MM-LDL- and LPS-exposed endothelial cells was approximately 45 minutes and 40 minutes, respectively. The rate of TF mRNA degradation was similar at 1 and 4 hours after exposure in either MM-LDL- or LPS-stimulated endothelial cells. Nuclear runoff transcription assays showed a significantly increased rate of TF gene transcription in both MM-LDL- and LPS-exposed endothelial cells. Cycloheximide inhibited the induction of TF protein activity, but it enhanced the accumulation of TF mRNA in MM-LDL- and LPS-induced endothelial cells. These results indicated that regulation of TF expression by MM-LDL and LPS in human endothelial cells occurs principally at the level of gene transcription.
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PMID:Regulation of endothelial cell tissue factor expression by minimally oxidized LDL and lipopolysaccharide. 821 12

To compare cytokine release and coagulation disturbances induced by administration of high versus low doses of endotoxin (lipopolysaccharide [LPS]), we used two endotoxin test systems similar in mortality but different in the degree of endotoxemia. One group of rats (n = 11) randomly received endotoxin (15.0 mg/kg of body weight intraperitoneally [i.p.]) and 1 ml of Ringer's solution (nonsensitized animals). The second group (n = 11) received 1 ml of D-galactosamine (500 mg/kg i.p.) and endotoxin (100 micrograms/kg i.p.) simultaneously (sensitized animals). Endotoxin levels in the plasma of nonsensitized rats were 1,000-fold higher than those in the plasma of sensitized rats (69.33 x 10(3) +/- 22.42 x 10(3) versus 75.8 +/- 27.08 ng of LPS per ml), leading to a mortality of 91% in nonsensitized rats versus 82% in the sensitized-rat model within 48 h postendotoxemia. Serum transaminase activity increased up to 100-fold in sensitized rats as a sign of hepatocyte damage. Despite the large difference in LPS levels in plasma, the time courses of the plasma tumor necrosis factor (TNF) increase were similar in the two groups, with a peak at 2 h (54 +/- 12 ng/ml in nonsensitized rats versus 43 +/- 12 ng/ml in sensitized rats), and also similar to that of a group of nonsensitized rats (n = 5) that received a low dose of LPS (100 micrograms/kg) only (52 +/- 21 ng/ml), while D-galactosamine alone did not induce TNF release. Despite similar TNF levels, a more pronounced coagulation disorder was observed at 4 h in nonsensitized rats (with the high LPS dose) as measured by platelet counts, plasma fibrinogen levels, and activated partial thromboplastin time prolongation (191 x 10(3) +/- 107 x 10(3) cells per microliter, 40 +/- 24 mg/dl, and 53 +/- 15 s, respectively) than in rats with the low LPS dose either sensitized (495 x 10(3) +/- 153 x 10(3), 95 +/- 49, and 38 +/- 16, respectively) or nonsensitized (439 x 10(3) +/- 62 x 10(3), 170 +/- 18, and 35 +/- 11, respectively).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Similar cytokine but different coagulation responses to lipopolysaccharide injection in D-galactosamine-sensitized versus nonsensitized rats. 826 55

Regulation of tissue factor (TF) gene expression was studied in vivo employing a murine model system. In untreated mice, TF mRNA was detected in brain, lung, kidney, and heart by Northern blot analysis. After administration of lipopolysaccharide, steady-state levels of TF mRNA were unchanged in brain, decreased in heart, and increased in both kidney and lung. In the brain, Bergmann glia within the Purkinje cell layer of the cerebellum and neuroglia within the cerebral cortex expressed TF mRNA by in situ hybridization. Epidermal cells of the skin and tongue also expressed TF mRNA. At present, we have not identified the cell type(s) in the kidney and lung responsible for increased TF gene expression. These results demonstrate tissue- and cell-specific TF gene expression in vivo. Lipopolysaccharide-mediated increases in TF expression in the kidney and lung may promote fibrin deposition in these organs during Gram-negative sepsis.
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PMID:Murine tissue factor gene expression in vivo. Tissue and cell specificity and regulation by lipopolysaccharide. 831 56

Stimulation of monocytic cells by inflammatory agents such as bacterial lipopolysaccharide or tumour necrosis factor-alpha leads to the rapid and transient expression of tissue factor, the major cellular initiator of the extrinsic coagulation cascade in both haemostasis and tissue inflammation. In this study we investigated whether the synthetic anti-inflammatory glucocorticoid, dexamethasone, would inhibit agonist induction of tissue factor expression in both monocytes and endothelial cells. Surprisingly, dexamethasone significantly enhanced the induction of tissue factor expression by peripheral blood mononuclear cells and an established monocytic cell line, THP-1, in response to lipopolysaccharide or tumour necrosis factor-alpha. However, unlike monocytic cells, dexamethasone did not enhance agonist induction of tissue factor in endothelial cells. Synergistic enhancement of tissue factor expression by dexamethasone was also reflected in tissue factor mRNA levels in THP-1 cells, but was not the result of improved TF mRNA stability. Synergism between bacterial lipopolysaccharide and glucocorticoid in the induction of monocyte effector function is extremely unusual and may help to explain the variable outcome of glucocorticoid treatment of septic shock.
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PMID:Dexamethasone enhances agonist induction of tissue factor in monocytes but not in endothelial cells. 832 65

Monocytes stimulated with bacterial lipopolysaccharide (LPS) generate a procoagulant activity (PCA) related to the induction of tissue factor (TF) expression at their surface. Since interleukin-10 (IL-10) was recently shown to inhibit LPS-induced cytokine production and is currently considered as a potential therapeutic agent in septic shock, we were interested to determine its effects on LPS-induced monocyte PCA. Peripheral blood mononuclear cells (PBMC) from healthy donors were incubated with 1 microgram/ml LPS in the presence of serial dilutions of recombinant human IL-10 and PCA was determined after 6 h in a one-stage clotting assay. IL-10 inhibited in a dose-dependent manner LPS-induced TF-dependent PCA: a significant effect was already observed with 30 pg/ml IL-10 while 64-97% inhibition was achieved with 120 pg/ml IL-10. In parallel flow cytometry experiments, IL-10 was shown to block LPS-induced TF expression at the surface of monocytes. In order to inhibit LPS-induced PCA, IL-10 had to be added to PBMC at least 6 h before LPS challenge. This inhibitory effect of IL-10 was already apparent at the TF mRNA level and was prevented by co-incubation with cycloheximide (20 micrograms/ml). These data suggest that IL-10 acts via the induction of protein(s) which might interfere with TF gene transcription or mRNA stability. We conclude that the protective effects of IL-10 in endotoxinemia might be related not only to cytokine synthesis blockade but also to inhibition of LPS-induced PCA.
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PMID:Interleukin-10 inhibits the induction of monocyte procoagulant activity by bacterial lipopolysaccharide. 840 69

These studies examine the molecular basis for increased transcription of tissue factor (TF) in THP-1 cells stimulated with lipopolysaccharide (LPS). DNase I footprinting identified six sites of protein-DNA interaction between -383 and the cap site that varied between control and induced extracts. Four footprints show qualitative differences in nuclease sensitivity. Footprints I (-85 to -52) and V (-197 to -175) are induction-specific and localize to regions of the promoter that mediate serum, phorbol ester, partial LPS response (-111 to +14), and the major LPS-inducible element (-231 to -172). Electrophoretic mobility shift assays with the -231 to -172 probe demonstrate JunD and Fos binding in both control and induced nuclear extracts; however, binding of c-Jun is only detected following LPS stimulation. Antibody inhibition studies implicate binding of Ets-1 or Ets-2 to the consensus site between -192 and -177, a region that contains an induction-specific footprint. The proximal region (-85 to -52), containing the second inducible footprint, binds Egr-1 following induction. These data suggest that LPS stimulation of THP-1 cells activates binding of c-Jun, Ets, and Egr-1 to the TF promoter and implicates these factors in the transcriptional activation of TF mRNA synthesis.
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PMID:Lipopolysaccharide induction of THP-1 cells activates binding of c-Jun, Ets, and Egr-1 to the tissue factor promoter. 864 47

The administration of gram-negative bacterial lipopolysaccharide (LPS) to rats results in hepatic parenchymal cell injury within 6 hr. The coagulation system is critical to the pathogenesis, but previously reported results suggested that its critical role is independent of insoluble clot formation and that thrombin may be a key mediator of liver injury. To test the hypothesis that thrombin is involved in LPS-induced liver injury, animals were treated with the selective thrombin inhibitor, hirudin. The hirudin treatment regimen effectively inhibited thrombin, as evidenced by prolonged activated partial thromboplastin time and by maintenance of plasma fibrinogen concentrations in LPS-treated rats. Treatment with hirudin prevented LPS-induced liver injury, assessed by plasma alanine aminotransferase activity and histological evidence of hepatocellular necrosis. Previous studies have shown that LPS exposure results in the accumulation of neutrophils and platelets within the liver and that both of these cell types are critical for the development of LPS-induced liver injury. Hirudin attenuated in part the decrease in blood platelet concentration that accompanied LPS administration, but did not alter hepatic platelet or neutrophil accumulation. These results support the hypothesis that thrombin is required for hepatic injury from LPS exposure, but that it does not act by promoting the accumulation of platelets or neutrophils within the liver.
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PMID:The thrombin inhibitor, hirudin, attenuates lipopolysaccharide-induced liver injury in the rat. 876 73

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

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