Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immunohistochemical techniques were applied to rheumatoid synovium in order to detect components of coagulation and fibrinolysis pathways within these tissues. These techniques revealed an intact coagulation pathway and plasminogen activator inhibitor-2 associated with macrophage-like cells that were present throughout these tissues, especially in subsurface areas. Cell-associated thrombin generation appeared to account for conversion of abundant fibrinogen to fibrin. Occasional macrophage-like cells also stained for urokinase but tissue-type plasminogen activator and plasminogen activator inhibitor-1 were restricted to vascular endothelium. Intense synovial fibrin deposition (with the limited evidence for associated fibrinolysis) may contribute to local inflammation and explain certain clinical features of rheumatoid arthritis. These findings suggest novel treatment hypotheses for this disease.
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PMID:Pathways of coagulation activation in situ in rheumatoid synovial tissue. 161 17

To explore mechanisms of coagulation activation in adenocarcinoma of the prostate, the occurrence and distribution of components of coagulation and fibrinolysis pathways in situ were studied by means of immunohistochemical techniques applied to frozen sections of fresh malignant and benign hyperplastic prostatic tissue obtained at transurethral resection. Fibrinogen was distributed throughout the perivascular and tumor connective tissue in both malignant and benign disease but was not present in adjacent areas of normal prostate. Antibodies specific for fibrin and D-dimer crosslink sites stained vascular endothelium focally in both malignant and benign tissues. Both neoplastic cells and benign hyperplastic glandular epithelial cells stained weakly and in a patchy distribution for tissue factor and focally for low-molecular-weight urokinase-type plasminogen activator. Focal staining of vascular endothelium was also observed for tissue plasminogen activator and plasmin-antiplasmin complex neoantigen. By contrast, no tissue staining was observed for factor VII, factor X, factor XIII "a" subunit, high-molecular-weight urokinase-type plasminogen activator, plasminogen activator inhibitors 1 to 3, protein C, and protein S. Thus, the similarity in findings between benign hyperplastic and neoplastic prostate tissue, the lack of either an intact tumor cell-associated coagulation pathway or fibrin formation, and the presence of fibrin on vascular endothelium are consistent with the concept that coagulation activation in prostatic cancer may not be due to a direct effect of the tumor cells on the clotting mechanism. Rather, such activation may be induced by a soluble tumor product that activates procoagulant activity on certain host (for example, vascular endothelial) cells. These findings, together with the lack of effect of warfarin anticoagulation on the clinical course of patients with prostatic cancer, contrast with findings in certain other tumor types and suggest that coagulation activation may not contribute to progression of adenocarcinoma of the prostate.
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PMID:Fibrin formation on vessel walls in hyperplastic and malignant prostate tissue. 170 19

Tumor necrosis factor (TNF) may be involved in the disturbance of the procoagulant-fibrinolytic balance in septicemia, leading to microvascular thrombosis. To assess the dynamics of the fibrinolytic response to TNF in humans, we performed a crossover saline-controlled study in six healthy men, investigating the effects of a bolus intravenous injection of recombinant human TNF (50 micrograms/m2) on the stimulation and inhibition of plasminogen activation as well as on plasmin activity and inhibition. TNF induced a brief fourfold increase in the overall plasma plasminogen activator (PA) activity peaking after 1 h (p less than 0.0001), which was associated with rises in the antigenic levels of urokinase-type plasminogen activator (p less than 0.0001) and tissue-type plasminogen activator (p less than 0.0001). Plasminogen activator inhibitor type I antigen remained unchanged in the first hour, but showed a rapid eightfold increase thereafter (p less than 0.0001), which coincided with the decrease in PA activity. Generation of plasmin activity in the first hour was signified by an 11-fold rise in D-dimer levels (p less than 0.0001); inhibition of plasmin was reflected by a 36-fold rise in plasmin-alpha 2 antiplasmin complexes (p less than 0.0001), as well as by a transient 16% decrease in alpha 2-antiplasmin activity (p less than 0.01). In conclusion, TNF induced an early activation of the fibrinolytic system becoming maximal in 1 h, with a rapid inhibition thereafter. Earlier observations in the same subjects showed sustained coagulation activation for 6-12 h. The observed disbalance between the procoagulant and fibrinolytic mechanisms after TNF injection confirms the in vivo relevance of the effects of TNF on vascular endothelium in vitro and may explain the tendency towards microvascular thrombosis in septicemia.
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PMID:Fibrinolytic response to tumor necrosis factor in healthy subjects. 171 36

Previous studies have suggested that the plasminogen activator (PA)/plasmin system has important roles in the pathogenesis of epithelial defects and stromal ulceration. The current studies were performed to localize PA species and identify them as tissue-type PA (tPA) or urokinase-like PA (uPA) as the two have distinct regulatory properties potentially related to the mechanisms of defect formation and ulceration. To determine the locations and types of PA species, antibodies to tPA or to uPA or the drug amiloride (a drug that inhibits uPA but not tPA) were incorporated into fibrin/fibronectin (Fn) clots overlying frozen sections to block regional fibrinolysis. Normal rabbit eyes showed tPA activity in association with corneal epithelium, corneal endothelium, and ciliary body/iris. After epithelial scrape or alkali burn, corneal tPA activity was detected initially in the defect zone colinear with fibrin/Fn and was symmetrical to resurfacing epithelium. The observation that initial fibrinolysis occurs in the defect zone, known to contain fibrin/Fn, suggests that tPA from blood (limbal vascular endothelium) and/or from corneal epithelium has become bound to (and activated on) the fibrin/Fn. PA activity was also associated with the leading edges of migrating epithelium post-scrape and post-burn and was not inhibited by antibodies to either tPA or uPA but was inhibited by amiloride. After complete closure of the primary defect post-scrape, only tPA appeared to be associated with the epithelium in that all PA activity was inhibited by antibodies to tPA. The observation that leading edge activity post-burn, in correlation with the formation of secondary defects, continues to be inhibitable by amiloride but not by antibodies to tPA suggests that uPA remains abnormally on the leading edge, and that sustained uPA activity in that location results in inappropriate degradation of subepithelial fibrin/Fn to result in a defect. Successful regulation of uPA activity at the leading edge of corneal epithelium post-burn would be expected to be useful therapeutically in the healing of epithelial defects and the prevention of stromal ulceration.
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PMID:Pathogenesis of corneal epithelial defects: role of plasminogen activator. 190 16

Components of coagulation and fibrinolysis reactions were identified in situ by immunohistochemical staining in fresh frozen sections of small cell carcinoma of the lung tissue. Tumor cells stained positively for tissue factor, a protein that is capable of activating the extrinsic pathway of coagulation (the components of which have been seen within small cell carcinoma of the lung [SCCL] tissue), and for proteins C and S antigens. Fibrin was seen in a focal distribution at the host-tumor interface, indicating that thrombin had acted upon the fibrinogen found throughout the tumor stroma. Staining with a neoepitope-specific antibody, which does not discriminate between fibrinogen fragment D and fibrin fragment D-dimer, was similar to that of the fibrin antibody. High molecular weight urokinase-type and tissue-type plasminogen activators were seen in vascular endothelium, but neither existed within the tumor. Low molecular weight urokinase was found in rare isolated foci of tumor cells primarily adjacent to areas of necrosis. Plasminogen activator inhibitor-3 occurred in tumor cell cytoplasmic blebs and in necrotic tumor cells, but plasminogen activator inhibitors 1 and 2 were not seen. Our data suggest a mechanism for thrombin generation and fibrin formation within SCCL tissues that could support cell proliferation, stroma formation, and preservation. These features could be conductive to perpetuation of this tumor and conceivably could form the basis of the beneficial effects of antithrombotic therapy seen in SCCL.
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PMID:Abnormal regulation of coagulation/fibrinolysis in small cell carcinoma of the lung. 215 29

Primary cultures of human hepatocytes and the human hepatocellular cell line Hep G2 are shown to produce fast-acting inhibitors of tissue-type plasminogen activator (tPA) and urokinase. The tPA inhibitory activities in conditioned medium of these liver cell types are very similar to those present in human endothelial cell conditioned medium. They are stable at pH 2.5, have similar dissociation constants with tPA (1.5 to 5 pmol/L), and are similar in thermostability. Addition of tPA to conditioned medium of Hep G2 and endothelial cells that has been depleted of tPA and urokinase reveals a 100 kilodalton tPA-inhibitor complex. The fast-acting tPA inhibitory activity in human plasma has comparable properties, and may originate from the liver or the vascular endothelium or both. After sodium dodecyl sulfate-polyacrylamide gel electrophoresis of conditioned medium from hepatocytes, Hep G2, and endothelial cells, additional fibrinolytic inhibition at 52 kilodaltons was visualized. This was not found with human plasma.
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PMID:Inhibition of plasminogen activators by conditioned medium of human hepatocytes and hepatoma cell line Hep G2. 298 82

Human saphenous veins were analyzed for presence of plasminogen activators (t-PA) in the endothelium of the vessel walls by immunohistochemical techniques. We used a polyclonal rabbit antihuman t-PA antibody, a monoclonal mouse-antihuman t-PA and a goat antibody to low molecular weight urokinase. To demonstrate presence of antigen we used FITC conjugated anti-IgG or the Biotin-Avidin technique. Both monoclonal and polyclonal anti-t-PA demonstrated positive fluorescence in the endothelial layer. Tests for urokinase were negative. The present study thus demonstrated that t-PA was present in the vascular endothelium. This is in accordance with data from earlier histochemical studies for detection of PA activity.
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PMID:Immunohistochemical localization of plasminogen activators in human saphenous veins. 308 70

Oral administration of clinical-type high molecular weight urokinase (HMW-UK) in a single dose of 30,000-60,000 International Units (IU) in enteric-coated capsules, in a group of normal human subjects, induced a plasma fibrinolytic state suggesting transport of HMW-UK across the intestinal tract. Other groups of human subjects were given a single dose of 120,000 IU daily of pure HMW-UK for 1 d and 7 d together with a placebo dose, all of the ingredients except urokinase (UK), daily for 7 d. UK-type proteins were isolated from the plasma of blood samples drawn 6 h after administration of the final dose, by a sequential two-step affinity chromatography method first with [N alpha-(epsilon-aminocaproyl)-DL-homoarginine hexylester]-Sepharose and second with a specific rabbit anti-HMW-UK-IgG-Sepharose. The yield of UK-type proteins from the 7-d group, 0.79 mg/dl, was approximately twofold greater than that obtained from either the placebo or 1-d groups. The specific plasminogen activator activity of the 1-d and 7-d groups were similar, 508 and 537 IU/mg protein, respectively; negligible plasminogen activator activity could be detected in the placebo group. The kinetics of activation parameters of human Glu-plasminogen of the UK-type protein, isolated from the 1-d group, were similar to those obtained with urinary HMW-UK. The UK-type proteins isolated only from the 7-d group showed, in sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis, a major protein band of molecular weight 53,000 in the same position as HMW-UK. In addition, two other major protein bands of approximately 140,000 and approximately 120,000 mol wt were found in the 7-d placebo-, and 1-d groups, and also in the 7-d group. The 53,000 mol wt protein, about 50% of the total protein in the 7-d group, was further purified by preparative SDS-polyacrylamide gel electrophoresis, and found to be a two-chain protein with a specific activity of 1,241 IU/mg protein. The protein showed common antigenic determinants with urinary HMW-UK. The oral administration of 120,000 IU HMW-UK to human subjects for 7 d stimulated the synthesis of a UK-type protein of 53,000 mol wt, probably the zymogen, from either the liver or vascular endothelium, which was released into the circulation, and converted into active UK by circulating plasmin. The induction of the fibrinolytic state produced the conversion of native circulating Glu-plasminogen into the degraded Lys-plasminogen form, which was found in large amounts in the plasma of the 7-d group. The new plasma components, e.g., the 53,000-mol wt UK-zymogen and Lys-plasminogen, could play an important role in clot resolution of the fibrin-thrombus in thromboembolic diseases. Oral administration of HMW-UK has been shown to be clinically effective in patients with cerebral thrombosis in a multicenter double blind study.
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PMID:Transport of urokinase across the intestinal tract of normal human subjects with stimulation of synthesis and/or release of urokinase-type proteins. 392 68

In an attempt to elucidate the mechanism of fibrinolytic enhancement by orally administered urokinase, studies on the intestinal transport of urokinase were carried out, using 125I-labeled human high mol wt urokinase, administered intraduodenally in the experimental dog model with a saphenous vein thrombus. Using the plasma sample obtained from blood 45 minutes after intraduodenal administration of the urokinase, protein fractions were isolated by a sequential two-step affinity chromatography method, first with [N alpha-(epsilon-aminocaproyl)-DL-homoarginine hexylester]-Sepharose followed by a specific anti-human low mol wt urokinase rabbit IgG-Sepharose (adsorbed-eluted and unadsorbed). Each of the isolated protein fractions was further purified by gel filtration on Sephacryl S-300. The proteins isolated by the two-step affinity chromatography method were transported human urokinase with radioactivity in the adsorbed-eluted fraction, and newly synthesized and/or released dog plasminogen activators, probably urokinase-type and tissue-activator type, without radioactivity. In an antibody quenching assay, dog urokinase and the immuno-affinity unadsorbed fraction were not neutralized, but the immuno-affinity adsorbed-eluted fraction was completely neutralized by the specific anti-urokinase IgG antibody. Proteins isolated from control plasma (after administration of saline) by the two-step affinity chromatography method in the unadsorbed fraction had negligible amounts of activator activity. In these studies, we were able to show that synthesis of plasminogen activators was stimulated, with the activators being released, from either the liver or the vascular endothelium. Also we showed that urokinase is transported across the intestinal tract in the dog model.
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PMID:The transport of 125I-labeled human high molecular weight urokinase across the intestinal tract in a dog model with stimulation of synthesis and/or release of plasminogen activators. 403 58

The effects of urokinase on ADP breakdown by vessel-wall, platelet aggregation and the related prostaglandin system "in vitro" were investigated. It is confirmed that urokinase does not induce platelet aggregation both in humans and rabbits "in vitro". Conversely, in high concentrations, urokinase inhibits ADP-induced platelet aggregation in human and rabbit platelet-rich plasma. No effects were observed on rabbit platelet thromboxane A2 release and on rat vascular prostacyclin production, both measured by radioimmunoassay of thromboxane B2 and 6-keto-F1 alpha prostaglandin, respectively. Moreover, the incubation of urokinase with vascular endothelium resulted in an increased disappearance rate.
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PMID:"In vitro" activity of urokinase on platelet function and on ADP degradation by vascular tissue. 675 93


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