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)

Nitric oxide is a multifunctional regulator of the vascular system. In healthy blood vessels, nitric oxide is produced from L-arginine by the constitutive nitric oxide synthase in endothelial cells. In addition, vascular injury or inflammation cause the production of nitric oxide in most types of vascular cells, including vascular smooth muscle. This response to injury is due to the induction of a second type of nitric oxide synthase by cytokines such as interleukin-1 beta or tumor necrosis factor-alpha. Factors derived from blood (thrombin, plasmin) and from vascular cells (platelet-derived growth factor, transforming growth factor beta, insulin-like growth factor, epidermal growth factor and basic fibroblast growth factor), regulate the induction of nitric oxide synthesis in vascular smooth muscle cells. The endogenous production of nitric oxide by vascular smooth muscle at sites of injury may contribute to the local control of blood flow, vascular tone and blood fluidity. It may participate also to the remodeling of the injured blood vessel wall.
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PMID:Inducible nitric oxide synthase in vascular smooth muscle. 751 15

It is well known that granulocytes increase infarct size after reperfusion of the ischemic myocardium, and that monocytes promote atherogenesis. Those cells are also believed to play a contributory role in pathogenesis of coronary restenosis as response to arterial injury during balloon angioplasty. The adhesion of those leukocytes to the vascular endothelium is a prerequisite for their recruitment and accumulation in the lesion. Inflammatory mediators likely to occur under those conditions, e.g., histamine, thrombin, oxygen-derived free radicals (ODFR), interleukin (IL)-1, tumor necrosis factor (TNF)-alpha, and activated complement factors, induce in a distinct time course the (transient) expression of the leukocyte adhesion molecules P-selectin, E-selectin, intercellular adhesion molecule (ICAM)-1, and vascular cell adhesion molecule (VCAM)-1 on the endothelium. Only VCAM-1 is specific for monocytes; the others mediate the binding and subsequent extravasation of both monocytes and granulocytes. The response to the relevant inflammatory mediators, except for extracellularly produced ODFR, is coupled via specific receptors on the surface of the endothelium to specific signal transduction pathways and, except for P-selectin (early response), is directly dependent on protein synthesis (intermediate and late response). Protein kinase-C-induced phosphorylation of transcription factors is often shown to be involved. Protein synthesis is preceded by increased transcription of mRNA that is regulated in part by the transcription factor NF-kappa B. Indications have been obtained that intracellularly produced ODFR may be involved in the translocation of this transcription factor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Leukocyte adhesion molecules on the vascular endothelium: their role in the pathogenesis of cardiovascular disease and the mechanisms underlying their expression. 752 71

A number of cell types possess an L-arginine-nitric oxide (NO) pathway. We studied the presence of constitutive and inducible forms of NO synthase in human platelets. N omega-nitro-L-arginine, an inhibitor of NO synthase, potentiated thrombin-induced aggregation of washed human platelets, whereas L-arginine inhibited it. The direct evidence for the presence of constitutive form of NO synthase came from the observation of conversion of tritium-labeled L-arginine to tritium-labeled L-citrulline by washed platelets suspended in Ca(++)-rich but not in Ca(++)-free buffer. Incubation of washed platelets in Ca(++)-free buffer with cytokines (tumor necrosis factor-alpha and interferon-gamma) or cytokines plus lipopolysaccharide caused a marked increase in the conversion of [3H]L-arginine to [3H]L-citrulline, suggesting the presence of inducible form of NO synthase. Gel electrophoresis identified an approximately 130 kd protein band with NO synthase in the platelet cytosol, which on isolation converted [3H]L-arginine to [3H]L-citrulline. This 130 kd protein required the presence of Ca++, reduced nicotinamide adenine dinucleotide phosphate tetrahydro-L-biopterin, and flavin adenine dinucleotide for expression of NO synthase activity. Platelet sonicates demonstrated presence of nitrite, and its concentrations were lowered by preincubation of platelets with NG-nitro-L-arginine methyl ester and enhanced in cytokine-treated platelets. Reverse-transcription polymerase chain reaction demonstrated messenger RNA expression of the constitutive endothelial (but not brain) and inducible isoforms of NO synthase in platelets. These observations indicate that human platelet cytosol possesses both constitutive and inducible forms of NO synthase.
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PMID:Identification of constitutive and inducible forms of nitric oxide synthase in human platelets. 753 7

This study was undertaken to evaluate the relationship between serum tumor necrosis factor (TNF) and coagulopathy in patients with prostate cancer. TNF levels in 104 sera obtained from 101 prostate cancer patients were determined using an enzyme immunoassay. Serum levels of fibrin/fibrinogen degradation product E fragment (FDP) and plasma levels of fibrin degradation product D-dimer in patients with elevated serum TNF levels were 1221.95 +/- 375.94 ng/ml and 27.34 +/- 9.81 micrograms/ml, which were significantly higher than those (FDP, 94.35 +/- 13.17 ng/ml; D-dimer, 1.03 +/- 0.20 micrograms/ml) in patients with undetectable serum TNF levels (P < 0.01). In addition, patients with elevated serum TNF levels showed significant increases in plasma levels of thrombin-antithrombin-III complex and plasmin-alpha 2-antiplasmin inhibitor complex and a significantly higher incidence of positive plasma soluble fibrin monomer complex than did those with undetectable serum TNF levels. The percentage of prothrombin time was significantly decreased in the group with elevated serum levels of TNF. Serum levels of TNF were significantly elevated in patients with serum FDP levels of > or = 200 ng/ml than in those with serum FDP levels of < 200 ng/ml (3.91 +/- 0.45 versus 2.17 +/- 0.08 units/ml) and in patients with plasma D-dimer levels of > or = 2 micrograms/ml than in those with plasma D-dimer levels of < 2 micrograms/ml (3.82 +/- 0.48 versus 2.10 +/- 0.06 units/ml). These results suggest that TNF may be one of the pathogenetic factors that could explain the occurrence of coagulopathy in patients with prostate cancer.
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PMID:Tumor necrosis factor and coagulopathy in patients with prostate cancer. 758 24

The effects of tumor necrosis factor-alpha (TNF-alpha) on the production of the vasoactive substances nitric oxide (NO) and endothelin-1 (ET-1) were investigated in cerebrovascular cells in culture. Bovine cerebral endothelial cells (BCEC) stained positively for NADPH-diaphorase/NO synthase activity and spontaneously produced nitrite, a stable NO oxidation product, which accumulated in the culture medium in a linear way for 48 h. Low concentrations of TNF-alpha (0.5-2 ng/ml) significantly enhanced nitrite production after a 24-h incubation. Higher concentrations or longer exposure times resulted in a cytotoxic effect that altered cell morphology, released lactate dehydrogenase (LDH) to the culture medium, and reduced the protein content. Dexamethasone, but not the NO synthase inhibitor N-iminoethyl-L-ornithine (L-NIO), prevented the cytotoxic effect of TNF-alpha in BCEC. TNF-alpha also significantly enhanced nitrite production in bovine cerebral smooth muscle cells (BCSMC). The enhancement was detected at all times between 8 and 72 h and at all concentrations tested (2-100 ng/ml). Signs of cytotoxicity were not observed in BCSMC after incubation with TNF-alpha. ET-1 was constitutively secreted by BCEC. The production of ET-1 was stimulated by thrombin. TNF-alpha enhanced the release of ET-1 in BCEC, and this enhancement was not modified by the simultaneous addition of interferon-gamma (IFN-gamma). BCSMC did not produce ET-1, either spontaneously or in the presence of TNF-alpha, IFN-gamma, or of both together.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of TNF-alpha on the production of vasoactive substances by cerebral endothelial and smooth muscle cells in culture. 759 52

Platelet-activating factor (PAF) is known to modulate polymorphonuclear leukocyte (PMN) adhesion to endothelial cells cultured under static conditions and activated by thrombin. In contrast, there are no data on the role of PAF in PMN adhesion to cells exposed to flow conditions and activated by stimuli other than thrombin. Here we used the PAF receptor antagonist L-659,989 to evaluate PMN adhesion to human umbilical vein endothelial cells (HUVEC) in basal conditions or upon challenge with thrombin or tumor necrosis factor-alpha (TNF-alpha). Experiments were performed under dynamic flow using a parallel-plate flow chamber and a computer-based image analysis system. Rolling and adhesion of PMNs to endothelial cells significantly increased upon stimulation with thrombin. Thrombin-stimulated HUVEC also synthesized higher amounts of PAF than untreated cells. Pretreatment of PMNs with L-659,989 significantly reduced their rolling and adhesion to thrombin-activated HUVEC. Stimulation of HUVEC with TNF-alpha significantly increased the number of rolling and adherent PMNs as compared with untreated cells. Adhesion of PMNs to and migration across TNF-alpha-stimulated HUVEC were reduced by L-659,989, whereas cell rolling was unchanged. We conclude that PAF mediates leukocyte interaction under flow conditions with HUVEC activated by inflammatory stimuli.
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PMID:PAF mediates neutrophil adhesion to thrombin or TNF-stimulated endothelial cells under shear stress. 763 59

Administration of low doses endotoxin or tumor necrosis factor (TNF) in human experimental models for sepsis results in transient activation of both coagulation and fibrinolysis and subsequent inhibition of the fibrinolytic system by plasminogen activator inhibitor type 1 (PAI-1). We have investigated in a baboon model for sepsis, whether administration of a lethal or sublethal dose of living E. coli could induce similar activation patterns. Levels of thrombin-antithrombin III (TAT) complexes increased significantly to zeniths of 425 and 33 times the baseline values at t+360 in the lethal and sublethal group, respectively. Activation of fibrinolysis, as reflected by plasmin-alpha 2 antiplasmin (PAP) complexes, in the sublethal group was maximal at t+60 and was increasingly inhibited thereafter in spite of a sustained increase of tissue type plasminogen activator (t-PA) levels. In the lethal group PAP complexes increased to a zenith of 38 times the baseline values at t+240. PAI-1 levels increased to 15 times the baseline values at t+360 in the sublethal group, whereas in the lethal group they increased almost linearly to 20 times the baseline values at t+360. Despite high levels of PAI-1, effective inhibition of the fibrinolysis was not established until at T+240 in the lethal group. The difference in activation patterns of both mediator systems in the sublethal and lethal group of baboons indicate that extensive activation of coagulation contributes to the lethal complications in sepsis.
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PMID:Activation patterns of coagulation and fibrinolysis in baboons following infusion with lethal or sublethal dose of Escherichia coli. 768 56

Cardiopulmonary bypass for heart operations is associated with a whole body inflammatory reaction. The main factors involved in this reaction are the contact system and the complement system. The activation of the contact system is considered mainly responsible for impaired hemostasis because it affects platelet function. The activation of the complement system is considered the main cause for organ dysfunction, particularly of the lung, due to activation of leukocytes. This study in 10 neonates was undertaken to evaluate if there are effects of activation of the contact and the complement systems in neonatal extracorporeal life support comparable to those during cardiopulmonary bypass for cardiac operations. Two periods of blood activation during extracorporeal life support could be distinguished. The initial blood-material interaction at the onset of extracorporeal life support resulted in activation of both the contact and the complement systems. The contact activation was apparent by elevated factor XIIa-C1 esterase inhibitor complexes, decreased kallikrein inhibitory capacity, thrombin-antithrombin III formation, and moderate generation of fibrin(ogen) degradation products. The complement activation was characterized by elevated C3a, decreased leukocyte count, elastase release, and tumor necrosis factor-alpha production. This initial activation pattern subsided by 24 hours. A second activation period was observed 72 hours after the onset of extracorporeal life support, which was characterized only by increased clotting and fibrinolytic activity while no activation of the complement system was observed. We conclude that the initial activation pattern in extracorporeal life support is similar to that observed during cardiopulmonary bypass for cardiac operations. The contact activation that affects platelets might explain the continuous platelet consumption observed during extracorporeal life support. In this period, as in cardiopulmonary bypass, aprotinin given in the pump prime might be effective to prevent platelet consumption and impairment of hemostasis also in extracorporeal life support. The complement activation and leukocyte inflammatory reaction during the initial period are able to cause a capillary leak syndrome and might therefore explain the frequently observed temporary compromised lung function in extracorporeal life support. This reaction, as in cardiopulmonary bypass, might be reduced by the use of specific drugs or heparin coating also in extracorporeal life support. The cause of the second period of activation during extracorporeal life support requires further studies before adequate measures can be recommended.
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PMID:Blood activation during neonatal extracorporeal life support. 768 35

The activation of MAPKAP kinase 2 was investigated under heat-shock conditions in mouse Ehrlich ascites tumor cells and after treatment of human MO7 cells with tumor necrosis factor-alpha (TNF-alpha). MAPKAP kinase 2 activity was determined using the small heat-shock proteins (sHsps) Hsp25 and Hsp27 as substrates. In both cell types, about a threefold increase in MAPKAP kinase 2 activity could be detected in a time interval of about 10-15 min after stimulation either by heat shock or TNF-alpha. Phosphorylation of MAPKAP kinase 2, but not the level of MAPKAP kinase 2 mRNA, was increased after heat shock in EAT cells. It is further shown that activation of MAPKAP kinase 2 in MO7 cells is accompanied by increased MAP kinase activity. These data strongly suggest that increased phosphorylation of the sHsps after heat shock or TNF-alpha treatment results from phosphorylation by MAPKAP kinase 2, which itself is activated by phosphorylation through MAP kinases. Hence, we demonstrate that MAPKAP kinase 2 is responsible not only for phosphorylation of sHsps in vitro but also in vivo. The findings link sHsp phosphorylation to the MAP kinase cascade, explaining the early phosphorylation of sHsp that is stimulated by a variety of inducers such as mitogens, phorbol esters, thrombin, calcium ionophores, and heat shock.
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PMID:MAPKAP kinase 2 is activated by heat shock and TNF-alpha: in vivo phosphorylation of small heat shock protein results from stimulation of the MAP kinase cascade. 775 69

Lactoferrin is a prominent component of neutrophil secondary granules, and its blood concentration is increased in certain inflammatory diseases. In contrast to the well-described biochemical characterization of lactoferrin as an iron-binding protein, its physiologic role in the regulation of inflammation and other host defense mechanisms is unclear. In this report, we provide evidence that lactoferrin has a potent heparin-neutralizing activity during thrombin inhibition by the serine proteinase inhibitors (serpins) antithrombin and heparin co-factor II. Activated neutrophil supernatant, which contains lactoferrin and other heparin-binding proteins, could neutralize the heparin-dependent antithrombin-thrombin inhibition reaction. The addition of lactoferrin to plasma corrected the heparin-induced prolongation of blood plasma coagulation as measured by the activated partial thromboplastin time (aPTT). Treatment of whole blood with specific inflammatory mediators, fMLP, lipopolysaccharide (LPS), and tumor necrosis factor-alpha (TNF-alpha) increased the concentration of both plasma lactoferrin and platelet factor 4 while inhibiting the blood anticoagulant activity of heparin as measured by the aPTT. These results suggest that the prothrombotic sequelae of some inflammatory processes may be partly due to various agonists that release neutrophil lactoferrin, which can then neutralize glycosaminoglycan-dependent serpin-thrombin inhibition reactions.
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PMID:Neutralization of heparin activity by neutrophil lactoferrin. 781 95


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