Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The role of nitric oxide (NO) in ischaemia-reperfusion injury to the heart continues to be debated. 2. The role of NO released during endotoxemia on myocardial reperfusion injury was examined in rats given saline or lipopolysaccharide (LPS, 10 mg. kg-1). 3. Aortic rings from LPS-treated rats showed a markedly decreased contractile response to both noradrenaline (NA) and U46619, and a diminished relaxation response to acetylcholine, thrombin and aggregating platelets. Treatment of rat aortic rings from LPS-treated rats with the NO synthesis inhibitor N omega-nitro-L-arginine (L-NOARG) reversed the diminished contractile response to NE and U46619. 4. Before ischaemia-reperfusion, baseline force of cardiac contraction (FCC) and coronary perfusion pressure (CPP) were lower and coronary flow was higher in hearts from LPS-treated rats (all P < 0.05 vs. saline-treated group). Treatment of hearts from LPS-treated rats with L-NOARG increased baseline FCC and CPP. 5. After ischaemia-reperfusion, hearts from saline-treated rats showed a 36 +/- 5% fall in FCC, a 38 +/- 6% rise in CPP and a 38 +/- 5% fall in coronary flow, whereas hearts from LPS-treated rats revealed only a 16 +/- 9% fall in FCC, a 10 +/- 3% rise in CPP and a 20 +/- 4% fall in coronary flow (all P < 0.05 vs. changes in saline-treated group). Fewer hearts from LPS-treated rats developed reperfusion arrhythmias (6% vs. 60% hearts from saline-treated rats, P < 0.02). Myocardial superoxide dismutase activity was higher in the LPS-treated group (P < 0.05). 6. NO synthesis, measured as formation of nitrite, was higher (P < 0.05) in cardiac and aortic tissues from LPS-treated rats. Prostacyclin (PGI2) release in coronary effluent was greater in LPS-treated rat hearts (P < 0.05 vs. saline-treated rats). 7. Thus LPS-treated hearts demonstrate a basal decrease in FCC and coronary vascular resistance. These hearts demonstrate a modest protection from reperfusion injury. Induction of NO synthesis, and possibly PGI2 release, may underlie cardioprotection from ischaemia-reperfusion.
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PMID:Reperfusion injury in the endotoxin-treated rat heart: reevaluation of the role of nitric oxide. 911 24

Tissue factor (TF) is a transmembrane receptor that serves as a cofactor for factor VIIa and initiates the extrinsic pathway of blood coagulation. Under normal physiological conditions, TF is expressed in extravascular and perivascular cells but not in vascular endothelial cells and monocytes. TF can be induced in these cells by inflammatory regulators and other stimulators, such as LPS, thrombin, oxidized lipoproteins, and certain growth factors. An earlier study showed that growing primary cultures of human umbilical vein endothelial cells (HUVECs) with endothelial cell growth supplement (ECGS) and heparin had impaired the ability of monolayers to express surface membrane TF activity after perturbation. The mechanism by which ECGS suppressed TF activity was not known. In the present study, we investigated the effect of recombinant acidic and basic fibroblast growth factors (aFGF and bFGF) on the induction of TF in a HUVEC cell line and a fibroblast cell line. Both aFGF and bFGF suppressed the phorbol myristate acetate-induced expression of TF in endothelial cells but not the serum-induced expression of TF in fibroblast cells. Diminished expression of the cell surface TF activity observed in endothelial cells grown with aFGF or bFGF was due to the accumulation of a lower number of TF mRNA transcripts. TF mRNA stability was not altered in HUVECs grown with aFGF or bFGF. Nuclear run-on experiments revealed that the transcription of TF and several other genes that play an important role in inflammation and angiogenesis was reduced in the endothelial cells that were cultured with aFGF or bFGF. The diminished expression of TF may be part of a generalized response of endothelial cells to FGF that facilitates migration of endothelial cells during angiogenesis.
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PMID:Acidic and basic fibroblast growth factors suppress transcriptional activation of tissue factor and other inflammatory genes in endothelial cells. 915 59

Alveolar macrophages (AM) play pivotal roles in the defense mechanism and the regulation of inflammatory processes in the airways. Macrophages express receptors for thrombin on their surfaces, and thrombin induces the chemotaxis and the proliferation of macrophages. Thrombin acts on vascular endothelial cells to synthesize endothelin (ET)-1. AM have been known to express prepro ET-1 mRNA. Thus, we hypothesized that thrombin stimulates AM so as to synthesize ET. Surgically resected human lungs were irrigated by saline to remove intravascular blood, then saline was instilled into the bronchus, and the fluids were recovered. AM were separated by Percoll density centrifugation (density, 1.060 g/ml). AM were resuspended in culture medium without FCS in the presence or absence of thrombin. ET was synthesized by thrombin in a concentration-dependent manner, and the amounts of ET synthesized by thrombin (10 U/ml) were equivalent to those by LPS (10 microg/ml). Dexamethasone (10(-6)-10(-10) M), IL-4 (100 U/ml), and TGF-beta (10 ng/ml) significantly suppressed the ET synthesis by thrombin (p < 0.05). In contrast, 1,25-dihydroxyvitamin D3 (10(-8)-10(-10) M) enhanced the ET synthesis up to approximately 300%. The analysis using high pressure liquid chromatography revealed that AM-derived ET consists of ET-1, ET-2, and ET-3. Major constituents were ET-2 and ET-1, and the ratio of ET-2/ET-1 was 1.7 +/- 0.4 (mean +/- SE). These results indicate that thrombin is a potent agonist for AM to synthesize ET.
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PMID:Human alveolar macrophages synthesize endothelins by thrombin. 916 66

Monocytes, macrophages and foam cells are central to atherogenesis. We have examined the potential ability of monocytes, macrophages and foam cells to affect the stability of deposited fibrin, characteristic of the atherosclerotic plaque, by their production of plasminogen activators and their inhibitors. Monocytes respond to thrombin and LPS by up-regulation of PAI-2 synthesis, and PAI-2 is their major product among the plasminogen activators/inhibitors. In contrast, macrophages and foam cells, while they did produce PAI-2, did not respond to thrombin and LPS by an increase in its synthesis. All PAI-2 produced by macrophages and foam cells was accumulated intracellularly, whereas monocytes also secreted PAI-2. Secreted PAI-2 was active as an inhibitor of u-PA, whereas intracellular PAI-2 required detergent treatment to generate activity. Thus monocytes, but not macrophages or foam cells, produce and secrete active PAI-2, thus potentially affecting fibrin stability in the local environment.
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PMID:Regulation, location and activity of plasminogen activator inhibitor 2 (PAI-2) in peripheral blood monocytes, macrophages and foam cells. 924 52

Binding activity for nuclear factor kappa B (NFkappaB) consensus probes was studied in nuclear extracts from peripheral blood mononuclear cells of 15 septic patients (10 surviving and 5 not surviving). Nonsurvivors could be distinguished from survivors by an increase in NFkappaB binding activity during the observation period (P < 0.001). The increase in NFkappaB binding activity was comparable to the APACHE-II score as a predictor of outcome. Intravenous somatic gene transfer with an expression plasmid coding for IkappaBalpha was used to investigate the role of members of the NFkappaB family in a mouse model of endotoxemia. In this model, increased NFkappaB binding activity was present after injection of LPS. Intravenous somatic gene transfer with IkappaBalpha given before LPS attenuated renal NFkappaB binding activity and increased survival. Endothelial cells and monocytes/macrophages were the major target cells for somatic gene transfer, transfected with an average transfection efficiency of 20-35%. Tissue factor, a gene under regulatory control of NFkappaB, was induced by LPS. Somatic gene transfer with a reporter plasmid containing the functional tissue factor promoter demonstrated NFkappaB-dependent stimulation by LPS. Intravenous somatic gene transfer with IkappaBalpha reduced LPS-induced renal tissue factor expression, activation of the plasmatic coagulation system (decrease of thrombin-antithrombin III complexes) and renal fibrin/fibrinogen deposition. Somatic gene transfer with an expression plasmid with tissue factor cDNA in the antisense direction (in contrast to sense or vector alone) also increased survival. Furthermore, antisense tissue factor decreased renal tissue factor expression and the activation of the plasmatic coagulation system.
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PMID:Role of NFkappaB in the mortality of sepsis. 927 14

IFN-gamma plays a role in immune regulatory functions as well as in viral defense. We show in this study that IFN-gamma treatment down-regulates the induction by a viral mimetic, polyinosinic-polycytidylic acid (poly(I:C)), of the endothelial cell-specific leukocyte adhesion protein, E-selectin. The inhibitory effect of IFN-gamma on poly(I:C)-induced E-selectin was concentration and time dependent and was specific for dsRNA, in that the induction of E-selectin by TNF-alpha, IL-1 beta, thrombin, or LPS was not inhibited significantly by this pretreatment. IFN-gamma pretreatment reduced poly(I:C)-induced E-selectin mRNA in a protein synthesis-independent manner. Poly(I:C)-induced E-selectin mRNA t1/2 was reduced slightly by IFN-gamma treatment, while the message for VCAM-1 was stabilized. Transient transfection of endothelial cells with an E-selectin promoter-driven reporter gene construct revealed that poly(I:C) stimulation of E-selectin promoter activity was decreased significantly by IFN-gamma pretreatment. Poly(I:C)-induced nuclear factor-kappa B activation following IFN-gamma pretreatment was unaffected, as shown by electrophoretic mobility shift analysis. These results indicate a novel role for IFN-gamma in the regulation of E-selectin gene expression in response to dsRNA by a transcriptional mechanism independent of nuclear factor-kappa B, as well as by a minor decrease in message stability.
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PMID:IFN-gamma inhibits double-stranded RNA-induced E-selectin expression in human endothelial cells. 937 88

Psoriatic arthritis (PA) is an inflammatory rheumatic disease that can concomitantly occur in patients with psoriasis vulgaris. Psoriatic synovitis shows alterations of the synovial microvasculature. Inflammatory cells adhere to endothelial cells (EC) and migrate through the vascular wall of postcapillary venules located in the subintimal layer of the synovial membrane. The aim of our study was to investigate, first, the phenotype of lymphocytes (LC) of PA patients using flow cytometry (FC) with regard to activation antigens and adhesion molecules; second, the adhesion of LC of PA patients on cultivated resting or activated (with thrombin, LPS, IFN-gamma, or TNF-alpha) human umbilical vein endothelial cells (HUVEC) by counting the Feulgen-stained nuclei of both adherent LC and HUVEC using image analysis; and third, the synthesis of IL-6 and IL-8 in both LC and HUVEC 24 hr after cell contact. These cytokines were determined qualitatively by immunofluorescence and quantitatively at the single-cell level by FC as well as in the supernatants of the cultures using commercial cytokine ELISAs. Fourth, we investigated whether or not the LC adhesion on HUVEC as well as the cytokine production could be inhibited by monoclonal antibodies against LC- or EC-specific adhesion molecules. In contrast to controls PA patients showed an increased surface expression of CD11a, b, and c as well as of CD44 but a reduced surface expression of CD49d/CD29, and CD49e/CD29, and cell-bound fibronectin on CD3+ LC. The activation markers CD25 and HLA-DR were found to be slightly enhanced in PA. The cell adhesion was generally enhanced in PA patients vs controls. It could be reduced with monoclonal antibodies (MoAbs) against CD11a and CD18 on IFN-gamma- or TNF-alpha-activated HUVEC but was generally enhanced after treatment of HUVEC with MoAbs against CD54, CD62E, or CD106. Due to LC adhesion on HUVEC IL-6 and IL-8 were produced in significantly higher amounts in PA patients compared to controls. This effect occurred already in resting but was enhanced in activated HUVEC. While IL-6 is mainly produced by HUVEC but also in smaller quantities by LC, IL-8 is synthesized only by HUVEC and could be modified by preincubation with MoAbs against LC- or EC-specific adhesion molecules in parallel to the cell adhesion. The experiments show that the main adhesion pathway in LC homing of PA patients is the interaction of the LC adhesion molecule CD11a/CD18 with CD54 on EC followed by an enhanced synthesis of proinflammatory and chemotactic cytokines. These results favor the hypothesis that the pathological alterations of the microvasculature in PA patients are generated by altered homing processes.
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PMID:Interactions of lymphocytes from patients with psoriatic arthritis or healthy controls and cultured endothelial cells. 940 Jun 30

We investigated the effects of human inter-alpha-inhibitor (I alpha I) on hemodynamics, oxygenation, and coagulation parameters in a porcine model of endotoxic shock. Four groups of six animals were studied: (1) control, (2) I alpha I group receiving 30 mg/kg I alpha I over 30 min, (3) LPS group receiving 5 micrograms.kg/min Escherichia coli endotoxin over 30 min, and (4) LPS + I alpha I group receiving 30 min after endotoxin 30 mg/kg/30 min I alpha I. We measured hemodynamic and oxygenation parameters, usual coagulation markers and plasma levels of thrombin-antithrombin complexes, antithrombin III activity, plasminogen activator tissue type, plasminogen activator inhibitor type 1, von Willebrand factor, tumor necrosis factor-alpha, and I alpha I at baseline and at 30, 60, 90, 120, 180, 240, and 300 min. In the I alpha I group, plasma I alpha I levels reached 447 +/- 23 mg/L just after injection and 287 +/- 39 mg/L at 300 min. I alpha I half-life was 7.3 +/- 1.9 h. In the IPS + I alpha I group, I alpha I plasma levels decreased more rapidly, reaching 260 mg/L at 300 min. Compared with the LPS group, administration of I alpha I normalized the mean arterial pressure and cardiac index, improved the LPS-induced pulmonary hypertension, and resulted in the blunted increase in blood lactate and oxygen extraction ratio. A significant decrease in thrombin-antithrombin complexes and plasminogen activator inhibitor type 1 levels were observed. There was no significant difference in plasma tumor necrosis factor-alpha levels. We concluded that in this hypodynamic model of endotoxin shock, I alpha I administration resulted in a marked improvement in the hemodynamic, oxygenation, and coagulation parameters.
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PMID:Effects of inter-alpha-inhibitor in experimental endotoxic shock and disseminated intravascular coagulation. 941 62

During vascular injury, such as observed in atherosclerosis, restenosis, vasculitides, transplantation, or sepsis, vascular smooth muscle cells (SMC) can be exposed to platelets or platelet products. Under these conditions proliferation or cytokine production of SMC stimulated by platelets or platelet products may contribute to regulation of vascular pathogenesis. Thus, we investigated interleukin-6 (IL-6) and IL-8 production as well as proliferation of SMC in response to platelets or platelet lysates. Platelets not already preactivated by thrombin induced IL-6 (10- to 50-fold) or IL-8 production of unstimulated SMC in a cell number dependent fashion. Preactivation of platelets with thrombin potently increased the platelet-mediated IL-6 (50- to 1,000-fold) and IL-8 production of SMC. Hirudin specifically inhibited the activation of platelets with thrombin. Isolated platelets cultured in the absence of SMC did not contain detectable IL-6 or IL-8. Prestimulation (4 hours) of SMC with pathophysiologically relevant substances (lipopolysaccharide [LPS], tumor necrosis factor-alpha [TNF-alpha], or IL-1alpha) further increased the platelet-induced cytokine production. The platelet-derived SMC stimulatory activity was IL-1, since IL-1 receptor antagonist (IL-1-Ra) inhibited the platelet-induced cytokine production of SMC. Anti-platelet-derived growth factor (PDGF)-antibody did not further reduce this activity. Thrombin itself stimulated expression of IL-6 and IL-8 to some degree and induced IL-6 production of SMC synergistically with IL-1. Platelets also induced proliferation of SMC, however, anti-PDGF antibodies, rather than IL-1-Ra blocked this response. These data show that platelet-derived IL-1 stimulates cytokine production of vascular smooth muscle cells, indicating that platelet-derived IL-1 may contribute to regulation of local pathogenesis in the vessel wall by activation of the cytokine regulatory network.
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PMID:Platelet-derived interleukin-1 induces cytokine production, but not proliferation of human vascular smooth muscle cells. 941 77

Thrombomodulin (TM) is a cell-surface receptor that plays a critical role in endothelial cell anticoagulant activity through its cofactor role in the thrombin-catalyzed activation of human protein C. In this study, we examined the effect of vascular endothelial growth factor (VEGF), a potent angiogenic factor, on surface anticoagulant activity and thrombomodulin expression. We show that thrombin-dependent activation of human protein C, measured on the endothelial cell surface, increased from 50 to 80% following exposure of cells to VEGF for 24 h. The effect was concentration dependent with the half-maximal stimulatory effect at approximately 100 pM. This increase in thrombin-dependent aPC generation correlated with a proportional and concentration-dependent increase in the level of cell-surface TM antigen. Both the total cellular TM antigen and the total cellular TM mRNA levels increased approximately 2.5-fold in VEGF-treated cells suggesting that most if not all of the regulation was at the message level. We further show that VEGF blocked IL-1 beta-induced suppression of both TM surface antigen and mRNA and was similarly capable of antagonizing the down-regulation of TM by TGF-beta and from cell activation by LPS. Our data suggest that VEGF regulation of TM may contribute to mechanisms that would maintain local hemostasis during angiogenesis and revascularization and could play a role in minimizing loss of vessel anticoagulant function during inflammatory processes.
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PMID:Thrombomodulin-dependent anticoagulant activity is regulated by vascular endothelial growth factor. 945 83


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