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

Tissue factor pathway inhibitor (TFPI) is an important physiologic inhibitor of the extrinsic pathway of the coagulation system. We investigated whether recombinant TFPI (rTFPI) could reduce pulmonary vascular injury by inhibiting leukocyte activation in rats given lipopolysaccharide (LPS). Pre- or posttreatment of animals with rTFPI significantly inhibited LPS-induced pulmonary vascular injury, as well as coagulation abnormalities. rTFPI significantly inhibited increases in lung tissue levels of tumor necrosis factor (TNF)-alpha, cytokine-induced neutrophil chemoattractant, and myeloperoxidase. Expression of TNF-alpha messenger RNA in the lung after LPS administration was significantly reduced by rTFPI administration. However, neither DX-9065a, a selective inhibitor of Factor Xa, nor recombinant Factor VIIa treated with dansyl-glutamylglycylarginyl-chloromethyl ketone, a selective inhibitor of Factor VIIa, had any effects on LPS-induced pulmonary vascular injury despite their potent anticoagulant effects. rTFPI significantly inhibited TNF-alpha production by LPS-stimulated monocytes in vitro. rTFPI also significantly inhibited several formyl-Met-Leu-Phe-induced neutrophil functions, as well as increases in the expression of CD11b and CD18 on the neutrophil cell surface in vitro. Additionally, rTFPI inhibited increases in levels of intracellular calcium, a second messenger of neutrophil activation, in formyl-Met-Leu-Phe-stimulated neutrophils in vitro. These results strongly suggested that rTFPI reduces pulmonary vascular injury by inhibiting leukocyte activation, as well as coagulation abnormalities in rats given LPS.
 ...
PMID:Recombinant tissue factor pathway inhibitor reduces lipopolysaccharide-induced pulmonary vascular injury by inhibiting leukocyte activation. 1106 8

Tissue factor pathway inhibitor (TFPI) is the protease inhibitor that regulates the extrinsic coagulation pathway initiated by the factor VIIa/TF complex. In this study, we first investigated tissue distribution of TFPI mRNA in the mouse and found that TFPI mRNA expression level was by far the highest in the lung, followed by the heart, adrenal, and adipose tissue. Since little has been known concerning the regulation of TFPI gene expression in vivo, we further analyzed the changes in the TFPI mRNA level in murine tissues after intraperitoneal injection of lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 (IL-1). LPS and TNF-alpha dramatically decreased TFPI mRNA expression in four tissues examined (e.g., lung, heart, kidney, and adipose tissue), whereas the suppressive effect of IL-1 on TFPI mRNA was limited. The down-regulation of TFPI mRNA expression by LPS and TNF-alpha was also observed in cultured mouse endothelial cells and in cardiomyocyte cell lines. The decreased TFPI mRNA expression by LPS and TNF-alpha in tissues and in the specific cell types may contribute to an increase in the local procoagulant potential, resulting in the thrombotic tendency under septic and/or inflammatory conditions.
 ...
PMID:Down-regulation of murine tissue factor pathway inhibitor mRNA by endotoxin and tumor necrosis factor-alpha in vitro and in vivo. 1110 8

Following vessel wall injury, tissue factor (TF) is being exposed and forms complexes with the already activated FVII (FVIIa) present in the circulating blood, providing a limited amount of thrombin molecules that activate a number of coagulation proteins as well as the platelets. As a result of activation with thrombin the platelet surface exposes negatively charged phospholipids to which activated coagulation proteins bind tightly, and full thrombin generation occurs, resulting in the conversion of fibrinogen into fibrin. After the first FXa is formed, the tissue factor pathway inhibitor (TFPI) forms a complex with FXa. In the next step a quaternary complex is being formed, TF/FVIIa/FXa/TFPI, which inhibits the first step of the haemostatic pathway. Recombinant FVIIa (rFVIIa) has been developed for use as a haemostatic agent (NovoNordisk A/S, Denmark). Inactivated rFVIIa (rFVIIai) has also been prepared, and it has similar binding capacity to TF as rFVIIa but it blocks the catalytic activity of the TF complex. In various animal models rFVIIai has been demonstrated to prevent or diminish immediate thrombus formation at the site of vessel wall injury (athroplasty or other forms of mechanical injury) as well as the development of long-term intima thickening. Also, topical application of rFVIIai was found to block the formation of a thrombus. rFVIIai was shown to have an anti-inflammatory effect in lipopolysaccharide (LPS)-induced sepsis, and postischaemic reperfusion injury was found to be reduced by the administration of rFVIIai. In a limited number of patients undergoing percutaneous transluminal coronary angioplasty (PTCA), rFVIIai was observed to allow PTCA to be performed at lower doses of heparin than what has been reported previously. Recombinant TFPI has been shown to attenuate the lethal inflammatory and coagulopathic response. Furthermore, topical application of rFVIIai has been found to increase the patency rate in a model of graft surgery.
 ...
PMID:Future possibilities in the regulation of the extrinsic pathway: rFVIIa and TFPI. 1120 85

Excessive production of nitric oxide (NO) by the inducible form of NO synthase (iNOS) plays a key role in the development of endotoxin shock. Tumor necrosis factor-alpha (TNF-alpha) induces iNOS, thereby contributing to the development of shock. We recently reported that recombinant tissue factor pathway inhibitor (r-TFPI), an important inhibitor of the extrinsic pathway of the coagulation system, inhibits TNF-alpha production by monocytes. In this study, we investigated whether r-TFPI could ameliorate hypotension by inhibiting excessive production of NO in rats given lipopolysaccharide (LPS). Pretreatment of animals with r-TFPI prevented LPS-induced hypotension. Recombinant TFPI significantly inhibited the increases in both the plasma levels of NO2-/NO3- and lung iNOS activity 3 h after LPS administration. Expression of iNOS mRNA in the lung was also inhibited by intravenous administration of r-TFPI. However, neither DX-9065a, a selective inhibitor of factor Xa, nor an inactive derivative of factor VIIa (DEGR-F.Vlla) that selectively inhibits factor VIIa activity, had any effect on LPS-induced hypotension despite their potent anticoagulant effects. Moreover, neither the plasma levels of NO2-/NO3- nor lung iNOS activity were affected by administration of DX-9065a and DEGR-F.VIIa. These results suggested that r-TFPI ameliorates LPS-induced hypotension by reducing excessive production of NO in rats given LPS and this effect was not attributable to its anticoagulant effects, but to the inhibition of TNF-alpha production.
 ...
PMID:Recombinant tissue factor pathway inhibitor prevents lipopolysaccharide-induced systemic hypotension in rats by inhibiting excessive production of nitric oxide. 1177 29

Proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) are critically involved in activation of the coagulation system in sepsis, leading to disseminated intravascular coagulation (DIC). Natural anticoagulants such as antithrombin (AT) and activated protein C (APC) regulate the coagulation system by inhibiting thrombin generation. In addition to these anticoagulant effects, both AT and APC have been shown to attenuate inflammatory responses induced by various noxious stimuli in rats such as lipopolysaccharide (LPS) challenge. AT promotes the endothelial release of prostacyclin, a potent anti-inflammatory prostaglandin that inhibits the monocytic production of TNF-alpha, by interacting with cell-surface heparin-like substances. APC directly inhibits the production of TNF-alpha by inhibiting the activation of both nudear factor kappaB (NFkappaB) and activator protein-1 in monocytes stimulated with LPS. Thrombomodulin, an endothelial membranous integral protein that binds thrombin, exerts anti-inflammatory effects by generating APC. Furthermore, tissue factor pathway inhibitor, a natural anticoagulant for the extrinsic pathway of the coagulation system, also attenuates LPS-induced inflammatory responses in rats by inhibiting TNF-alpha production by monocytes. These findings strongly suggest that natural anticoagulants could regulate inflammatory responses as well as the coagulation system in rats by inhibiting the monocytic production of TNF-alpha. Such anti-inflammatory properties of natural anticoagulants are potentially important for their replacement in patients with sepsis who frequently develop DIC and organ failure as inflammatory responses.
 ...
PMID:Regulation of inflammatory responses by natural anticoagulants. 1191 84

The liver can be injured and its functions altered by activation of the coagulation and inflammatory processes in sepsis. The objective of the present study was to investigate the pattern of protease- activated receptors (PARs) over time in a model of acute liver injury induced by lipopolysaccharide (LPS); and whether PARs play a role in this process and exert their effects through inflammation and coagulation. Levels of tumor necrosis factor-a (TNF-a) were significantly expressed 1 h after LPS administration followed by: i) an increase in levels of tissue factor, factor VIIa, thrombin and plasminogen activator inhibitor-1; ii) unchanged or steady levels of tissue factor pathway inhibitor; and iii) subsequent deposition of fibrin in the liver tissue, that led to the elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), which are associated with liver injury. The expression of all PAR isoforms (1-4) was elevated, and each isoform had a distinct cellular localization (hepatocytes, Kupffer cells, the portal triad area, and central veins) and a time-dependent pattern of expression. The immuno-reactivity of PAR2 and 4 in Kupffer cells was intense. Interestingly, PAR2 blocking peptide improved the healing of liver injuries, an effect that was associated with suppression of TNF-a elevation, and normalization of coagulation and fibrinolysis. This ultimately led to decreased fibrin formation in the injured liver. The present study reveals a distinct chronological expression and cellular localization of PARs in LPS-mediated liver injury and shows that blockade of PAR2 may play a crucial role in treating liver injury, via normalization of inflammation, coagulation and fibrinolytic pathways.
 ...
PMID:Chronological expression of PAR isoforms in acute liver injury and its amelioration by PAR2 blockade in a rat model of sepsis. 1713 80

Adrenomedullin (ADM) is a vasodilator peptide that has a variety of effects, including antithrombotic activities and resistant roles to lipopolysaccharide (LPS)-induced septic shock. During sepsis, LPS triggers the development of disseminated intravascular coagulation (DIC) via the tissue factor-dependent pathway of coagulation. It is unknown whether the antithrombotic activities of ADM contribute to its resistance to sepsis. In the present study, we investigated the effects of ADM on tissue factor pathway inhibitor (TFPI) (primary anticoagulant factor) expression in human umbilical vein endothelial cells (HUVECs) exposed to LPS, and the possible underlying mechanism for these effects. Exposure of HUVECs to LPS for 12 hours caused significant decrease of TFPI protein activities and mRNA expression. These effects were abolished by treatment with ADM (10(-10) to 10(-6) M), cAMP analogue and calcium antagonist. Accordingly, cAMP antagonist inhibited the counteraction effect of ADM on LPS in TFPI expression. Electrophoresis mobility shift assay (EMSA) and Western blot analysis showed that the protein level of GATA-2 and SP1 transcriptional factors and their binding to the corresponding regulatory sequences decreased by LPS treatment. And these effects of LPS were antagonized by ADM. Promoter-reporter assays and mutational analysis also confirmed the roles of GATA-2 and SP1 motifs from -1247 to -381 bp promoter sequence in TFPI inducible expression. Taken together, these results indicate that ADM antagonizes the effect of LPS on TFPI expression, which is mediated by affecting transcriptional factor GATA-2 and SP1 through cAMP and calcium signaling pathway.
 ...
PMID:Crucial roles of GATA-2 and SP1 in adrenomedullin-affected expression of tissue factor pathway inhibitor in human umbilical vein endothelial cells exposed to lipopolysaccharide. 1747 96

Pulmonary coagulopathy and hyperinflammation may contribute to an adverse outcome in sepsis. The present study determines the effects of natural inhibitors of coagulation on bronchoalveolar haemostasis and inflammation in a rat model of endotoxaemia. Male Sprague-Dawley rats were randomised to treatment with normal saline, recombinant human activated protein C (APC), plasma-derived antithrombin (AT), recombinant human tissue factor pathway inhibitor (TFPI), heparin or recombinant tissue plasminogen activator (tPA). Rats were intravenously injected with lipopolysaccharide (LPS), which induced a systemic inflammatory response and pulmonary inflammation. Blood and bronchoalveolar lavage were obtained at 4 and 16 h after LPS injection, and markers of coagulation and inflammation were measured. LPS injection caused an increase in the levels of thrombin-AT complexes, whereas plasminogen activator activity was attenuated, both systemically and within the bronchoalveolar compartment. Administration of APC, AT and TFPI significantly limited LPS-induced generation of thrombin-AT complexes in the lungs, and tPA stimulated pulmonary fibrinolytic activity. However, none of the agents had significant effects on the production of pulmonary cytokines, chemokines, neutrophil influx and myeloperoxidase activity. Natural inhibitors of coagulation prevent bronchoalveolar activation of coagulation, but do not induce major alterations of the pulmonary inflammatory response in rat endotoxaemia.
 ...
PMID:Natural anticoagulants limit lipopolysaccharide-induced pulmonary coagulation but not inflammation. 1753 62

Changes in plasma tissue factor (TF)-activated factor VII (FVIIa) and plasma tissue factor pathway inhibitor (TFPI) in type II diabetes mellitus are assessed, vascular complicated and noncomplicated patients compared, and whether these novel hemostatic activity markers predict vascular complications in diabetic patients, improving risk assessment, is determined. Fifty type II diabetic patients and 20 healthy controls (age, sex and body mass matched) underwent medical history and examination, fasting plasma glucose level, glycosylated hemoglobin (HbA1c), lipid profile, hemostatic parameters, plasma TF activity, and TFPI and TF expression on blood monocytes. Mean TF, TF activity, TFPI, and FVIIa significantly increased among hyperlipidemic compared with normolipidemic diabetic patients, and normolipidemic diabetic patients compared with controls. Mean percentage TF-positive monocytes with and without lipopolysaccharide, plasma TF activity, TFPI and FVIIa were significantly higher among complicated than noncomplicated diabetic patients. Mean percentage TF-positive monocytes without and with lipopolysaccharide, plasma TF activity, plasma TFPI and FVIIa were higher among diabetic patients with macrovascular compared with microvascular complications. High significant correlation occurred between HbA1c, triglycerides and percentage TF-positive monocytes with and without lipopolysaccharide stimulation, plasma TF activity and both FVIIa and TFPI. High activity levels of plasma TF and FVIIa with increased circulating TF-positive monocytes occurred in type II diabetic patients, especially with vascular complications. Results reflect high procoagulant activity possibly involved in diabetic vascular complications. Elevated TFPI levels were observed, but were not sufficient to balance high procoagulant activity. Correlation of procoagulant activity markers with HbA1c reinforces the importance of optimal glycemic control in type II diabetes.
 ...
PMID:Study of factor VII, tissue factor pathway inhibitor and monocyte tissue factor in noninsulin-dependent diabetes mellitus. 1818 Jun 9

Derangement of the blood clotting system contributes strongly to multiple organ failure in severe sepsis. In this review, we examine two microbial modulators of the clotting system: polyphosphates and omptins. Polyphosphates are linear polymers of inorganic phosphate that are abundant in the acidocalcisomes of prokaryotes and unicellular organisms as well as in the dense granules of human platelets. Polyphosphates modulate haemostasis by: (1) triggering clotting via the contact pathway; (2) accelerating the activation of coagulation factor V (a key cofactor in blood clotting) and (3) causing fibrin to form clots whose fibrils are thicker and more resistant to fibrinolysis. While polyphosphates are found in all prokaryotes, omptins have a more limited distribution among certain Gram-negative species. Omptins are outer membrane aspartyl proteases which were recently found to proteolytically inactivate tissue factor pathway inhibitor (TFPI), the main inhibitor of the initiation phase of blood clotting. Omptin activity against TFPI requires lipopolysaccharide without O-antigen (rough LPS) such as is found on the surface of Yersinia pestis, the etiologic agent of plague. Interestingly, expression of Pla, the Yersinia pestis omptin, has a demonstrated virulence role in converting plasminogen into the fibrinolytic enzyme plasmin, which would seemingly antagonize any procoagulant effect of TFPI inactivation. However, since the rate of TFPI inactivation is much higher than the rate of plasminogen activation, we suggest that Pla may have a dual function in supporting the bubonic form of plague which is unique to Yersinia pestis.
 ...
PMID:Polyphosphate and omptins: novel bacterial procoagulant agents. 1972 23


<< Previous 1 2 3 Next >>