UMLS:C0243026 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tissue factor (TF) plays a crucial role in the pathogenesis of thrombotic, vascular and inflammatory disorders. Thus, the inhibition of this membrane protein provides a unique therapeutic approach for prophylaxis and/or treatment of various diseases. Tissue factor pathway inhibitor (TFPI), the only endogenous inhibitor of the TF/Factor VIIa (FVIIa) complex, has recently been characterised biochemically and pharmacologically. Studies in patients demonstrated that both TF and TFPI may be indicators for the course and the outcome of cardiovascular and other diseases. Based on experimental and clinical data, TFPI might become an important drug for several clinical indications. TFPI is expected to inhibit the development of post-injury intimal hyperplasia and thrombotic occlusion in atherosclerotic vessels as well as to be effective in acute coronary syndromes, such as unstable angina and myocardial infarction. Of special interest is the inhibition of TF-mediated processes in sepsis and disseminated intravascular coagulation (DIC), which are associated with the activation of various inflammatory pathways as well as of the coagulation system. A Phase II trial of the efficacy of TFPI in patients with severe sepsis showed a mortality reduction in TFPI- compared to placebo-treated patients and an improvement of organ dysfunctions. TFPI can be administered exogenously in high doses to suppress TF-mediated effects, alternatively high amounts of TFPI can be released from intravascular stores by other drugs, such as heparin and low molecular weight heparins (LMWH). Using this method high concentrations of the inhibitor are provided at sites of tissue damage and ongoing thrombosis. At present, clinical studies with TFPI are rather limited so that the clinical potential of the drug cannot be assessed properly. However, TFPI and its variants are expected to undergo further development and to find indications in various clinical states.
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PMID:Tissue factor pathway inhibitor: an update of potential implications in the treatment of cardiovascular disorders. 1177 96

Tissue factor, a 47 kDa membrane glycoprotein, lies at the basis of the extrinsic pathway of the coagulation cascade. Interaction of TF with factor VIIa results in the formation of fibrin from fibrinogen, thereby inducing the formation of a blood clot. In addition to this well-established role in blood coagulation, TF is associated with various other physiological processes such as sepsis, inflammation, angiogenesis, metastasis and atherosclerosis. The molecular basis of the latter events is slowly emerging. It has become clear that TF-FVIIa interaction elicits a variety of intracellular signalling events that may be implicated in these actions. These events include the sequential activation of Src-like kinases, MAP kinases, small GTPases and calcium signalling. How this progress in the understanding of TF associated signal transduction may generate answers as to the mechanism through which TF exerts it pleiotropic effects will be focus of this review.
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PMID:The pleiotropic effects of tissue factor: a possible role for factor VIIa-induced intracellular signalling? 1262 46

Tissue factor (TF) is a cell surface receptor for factor VII(a), and the binding of factor VII(a) to TF initiates the coagulation cascade. Inappropriate in vivo expression of TF in vascular cells has been shown to be responsible for thrombotic disorders associated with a variety of pathological conditions, including gram-negative sepsis, cancer and atherosclerosis. A number of epidemiological studies suggest that moderate consumption of red wine provides protective effects against coronary heart disease mortality. Recently, we have shown that resveratrol, a polyphenolic compound found in wine, inhibited the induction of TF expression in endothelial cells and mononuclear cells (Pendurthi UR, Williams JT, Rao LVM. Arterioscler Thromb Vasc Biol 1999: 19: 419-426). In the present study, we examined the mechanism by which resveratrol inhibits the expression of TF in monocytes by using a monocytic cell line, THP-1, as a model cell. Northern blot analysis, gel mobility shift assays and transfection studies with various TF promoter constructs, as well as other transcription regulatory constructs, were used to elucidate the inhibitory mechanism of resveratrol. The data show that resveratrol inhibited lipopolysaccharide (LPS)-induced expression of TF in human monocytes and monocytic cell line, THP-1 in a dose dependent manner. Resveratrol did not significantly alter the binding of various transcription factors involved in TF gene expression to DNA. However, resveratrol suppressed the transcription of cloned human TF promoter. Further experiments revealed that resveratrol reduced kappaB- but not AP-1-driven transcriptional activity. Additional experiments showed that resveratrol suppressed the phosphorylation of p65 and its transactivation. In summary, our results indicate that resveratrol does not inhibit the activation or translocation of NF-kappaB/Rel proteins but inhibits NF-kappaB/Rel-dependent transcription by impairing the transactivation potential of p65.
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PMID:Mechanism of resveratrol-mediated suppression of tissue factor gene expression. 1185 83

The enhanced extrinsic coagulation in response to inflammation could contribute to disseminated intravascular coagulation, often manifesting cardiovascular complications. The complex mechanism remains unclear. Nor is the effective anticoagulation well established. The search for arresting hypercoagulation is of antithrombotic relevance. The ability of polybrene (PB) to inhibit tissue factor (TF)-initiated extrinsic blood coagulation was demonstrated at the protein and cellular levels as well as in human plasma samples. In a single-stage clotting assay, PB dose-dependently offset bacterial endotoxin (lipopolysaccharide)-induced monocytic TF (mTF) hypercoagulation and inhibited rabbit brain thromboplastin (rbTF) procoagulation. Consistent with these findings, the significantly prolonged prothrombin time indicated the depressed extrinsic coagulation by PB. However, PB showed no effect on thrombin time. We dissected the extrinsic pathway to further determine the inhibitory site(s) of PB. A two-stage chromogenic assay monitoring S-2288 hydrolysis showed that PB readily blocked mTF-dependent or rbTF-dependent FVII activation, which was verified by the diminished activated factor VII (FVIIa) formation derived from the proteolytic cleavage of its zymogen factor VII on Western blotting analyses. PB had no effect on FVIIa and activated factor X amidolytic activity. Nor was the dissected TF/FVIIa-catalyzed factor X activation affected. In conclusion, the preferential downregulation of factor VII activation was responsible for the depressed extrinsic coagulation. PB could present a novel anticoagulant antagonizing the extrinsic hypercoagulation for the prevention of thrombotic complication following sepsis and inflammations.
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PMID:Novel anticoagulant activity of polybrene: inhibition of monocytic tissue factor hypercoagulation following bacterial endotoxin induction. 1191 54

The serpin antithrombin III (AT III), the most important natural inhibitor of thrombin activity, has been shown to exert marked anti-inflammatory properties and proven to be efficacious in experimental models of sepsis, septic shock, and disseminated intravascular coagulation. Moreover, clinical observations suggest a possible therapeutic role for AT III in septic disorders. The molecular mechanism, however, by which AT III attenuates inflammatory events is not yet entirely understood. We show here that AT III potently blocks the activation of nuclear factor kappaB (NF-kappaB), a transcription factor involved in immediate early gene activation during inflammation. AT III inhibited agonist-induced DNA binding of NF-kappaB in cultured human monocytes and endothelial cells in a dose-dependent manner, suggesting that AT III interferes with signal transduction leading to NF-kappaB activation. This idea was supported by demonstrating that AT III prevents the phosphorylation and proteolytic degradation of the inhibitor protein IkappaBalpha. In parallel to reducing NF-kappaB activity, AT III inhibited the expression of interleukin-6, tumor necrosis factor-alpha, and tissue factor, genes known to be under the control of NF-kappaB. The observation that chemically modified AT III that lacks heparin-binding capacity had no effect on NF-kappaB activation supports the current understanding that the inhibitory potency of AT III depends on the interaction of AT III with heparinlike cell surface glycosaminoglycans. This hypothesis was underscored by the finding that the AT III beta-isoform, known to have higher affinity for glycosaminoglycans, is more effective in preventing NF-kappaB transactivation than alpha-AT III. These data indicate that AT III can alter inflammatory processes via inhibition of NF-kappaB activation.
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PMID:Antithrombin III inhibits nuclear factor kappaB activation in human monocytes and vascular endothelial cells. 1201 Aug 2

Staphylococcus aureus is one of the most significant pathogens in human sepsis and endocarditis. S. aureus can initiate blood coagulation, leading to the formation of microthrombi and multiorgan dysfunction in sepsis, whereas in endocarditis the bacterium induces fibrin clots on the inner surface of the heart, so-called endocardial vegetations. In the present study, we show that live and heat-killed S. aureus bacteria are potent inducers of procoagulant activity in human peripheral blood mononuclear cells. Furthermore, purified peptidoglycan, the main cell wall component of S. aureus, induced procoagulant activity in mononuclear cells in a concentration-dependent fashion. The procoagulant activity in these cells was dependent on expression of tissue factor, since antibodies to tissue factor inhibited the effect of peptidoglycan. In mononuclear cells stimulated with peptidoglycan, reverse transcription-PCR showed tissue factor gene expression, and the gene product was detected by enzyme-linked immunosorbent assay. Finally, flow cytometry identified tissue factor at the surface of CD14-positive monocytes. Peptidoglycan is known to induce proinflammatory cytokine production in monocytes. The present investigation shows that peptidoglycan also activates the extrinsic pathway of coagulation by inducing the expression of tissue factor in these cells. This mechanism helps to explain the procoagulant activity, which plays such an important role in the pathogenicity of severe S. aureus infections.
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PMID:Peptidoglycan from Staphylococcus aureus induces tissue factor expression and procoagulant activity in human monocytes. 1201 Sep 95

FVIIa binding to tissue factor (TF) and subsequent signal transduction have now been implicated in a variety of pathophysiological processes, including cytokine production during sepsis, tumor angiogenesis and neoangiogenesis, and leukocyte diapedesis. The molecular details, however, by which FVIIa/TF affects gene expression and cellular physiology, remain obscure. Here we show that FVIIa induces a transient phosphorylation of p70/p85(S6K) and p90(RSK) in BHK cells stably transfected with either full-length TF or with a cytoplasmic domain-truncated TF but not in wild type BHK cells. Phosphorylation of these kinases was also observed in HaCaT cells, expressing endogenous TF. Phosphorylation of p70/p85(S6K) coincided with protein kinase B and GSK-3beta phosphorylation. Activation of p70/p85(S6K) was sensitive to inhibitors of phosphatidylinositol 3-kinase and to rapamycin, whereas phosphorylation of p90(RSK) was sensitive to PD98059. FVIIa stimulation of p70/p85(S6K) and p90(RSK) correlated with phosphorylation of the eukaryotic initiation factor eIF-4E, up-regulation of protein levels of eEF1alpha and eEF2, and enhanced [(35)S]methionine incorporation. These effects were not influenced by inhibitors of thrombin or FXa generation and were strictly dependent on the presence of the extracellular domain of TF, but they did not require the intracellular portion of TF. We propose that a TF cytoplasmic domain-independent stimulation of protein synthesis via activation of S6 kinase contributes to FVIIa effects in pathophysiology.
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PMID:VIIa/tissue factor interaction results in a tissue factor cytoplasmic domain-independent activation of protein synthesis, p70, and p90 S6 kinase phosphorylation. 1201 61

Tissue factor (TF) plays an important role in the pathogenesis of atherosclerotic, sepsis and disseminated intravascular coagulation (DIC). TF pathway is therefore an attractive therapeutic target in a number of disease states. Here two TF mutants were developed and named MCsTF and MFsTF, in which the amino acids of active sites were mutated. Both of them were expressed in E.coli and used to inhibit TF pathway through competitive FVII/VIIa binding with TF. The results indicated that rMCsTF almost lost all activities of FX activation and procoagulation, and rMFsTF lost 90% activity. The specific catalytic constant ( k ( cat )/ K (m)) of FX activation by the complex formed by FVIIa with rMCsTF or rMFsTF were 2.0% and 3.7%, respectively, compared to that of rsTF. The inhibition effects of the mutants were studied in vitro, and it appeared that the prothrombin time were prolonged in a dose-dependent manner. Therefore, these mutants of TF may become new kind of specific inhibitors of TF pathway, as a promising drug for the treatment of patients with over-expression of TF.
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PMID:[Molecular cloning, expression and characterization of the clones encoding soluble TF mutants]. 1201 50

The liberation of endotoxin by gram-negative bacteria upon antibiotic treatment might be of clinical relevance in terms of adverse effects of antibiotic therapy in patients with gram-negative infections. In this paper we have taken into consideration the endotoxic material released by Salmonella typhimurium SH9178 after treatment with either ofloxacin and norfloxacin (which act as DNA-gyrase inhibitors) or imipenem (which affects the bacterial cell wall) in its capacity to induce in-vitro production of procoagulant activity, tissue factor-like, by human mononuclear cells. Endotoxin released from Salmonella typhimurium after treatment with the above antibiotics behaves as the typical endotoxin of gram-negative bacteria in its capacity to induce procoagulant production. Indeed human mononuclear cells after prolonged incubation with supernatants of antibiotic-treated Salmonella were able to shorten the recalcification time of normal but not Factor VII deficient plasma (tissue factor-like activity). On this basis we hypothesize that this mechanism, leading to the activation of blood coagulation through the extrinsic pathway, might be closely involved in thrombohemorrhagic disorders sometimes complicating the antimicrobial therapy of gram-negative sepsis.
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PMID:Endotoxin release after antibiotic treatment and its potential pathogenetic role in coagulative disorders of patients with gram-negative sepsis. 1204 90

Monocytes and macrophages express cytokines and procoagulant molecules in various inflammatory diseases. In sepsis, lipopolysaccharide (LPS) from Gram-negative bacteria induces tumor necrosis factor-alpha (TNF-alpha) and tissue factor (TF) in monocytic cells via the activation of the transcription factors Egr-1, AP-1, and nuclear factor-kappa B. However, the signaling pathways that negatively regulate LPS-induced TNF-alpha and TF expression in monocytic cells are currently unknown. We report that inhibition of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway enhances LPS-induced activation of the mitogen-activated protein kinase pathways (ERK1/2, p38, and JNK) and the downstream targets AP-1 and Egr-1. In addition, inhibition of PI3K-Akt enhanced LPS-induced nuclear translocation of nuclear factor-kappa B and prevented Akt-dependent inactivation of glycogen synthase kinase-beta, which increased the transactivational activity of p65. We propose that the activation of the PI3K-Akt pathway in human monocytes limits the LPS induction of TNF-alpha and TF expression. Our study provides new insight into the inhibitory mechanism by which the PI3K-Akt pathway ensures transient expression of these potent inflammatory mediators.
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PMID:The phosphatidylinositol 3-kinase-Akt pathway limits lipopolysaccharide activation of signaling pathways and expression of inflammatory mediators in human monocytic cells. 1205 30

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