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)

Tissue and urokinase-type plasminogen activators are serine proteases with highly restricted specificity, their best characterised role being to release the broad specificity protease plasmin from inactive plasminogen. It has frequently been suggested that these, and similar proteases, are involved in axonal growth and tissue remodelling associated with neural development. To help define what this role might be, we have studied the expression of the plasminogen activators in developing rat nervous tissue. Urokinase-type plasminogen activator mRNA is strongly expressed by many classes of neurons in peripheral and central nervous system. We have analysed its appearance in spinal cord and sensory ganglia, and found the mRNA is detectable by in situ hybridisation very early in neuronal development (by embryonic day 12.5), at a stage compatible with it playing a role in axonal or dendritic growth. Tissue plasminogen activator mRNA, on the other hand, is expressed only by cells of the floor plate in the developing nervous system, from embryonic day 10.5 and thereafter. Immunohistochemical and enzymatic analysis showed that active tissue plasminogen activator is produced by, and retained within, the floor plate. A mechanism is suggested by which high levels of tissue plasminogen activator produced by the stationary cells of the floor plate could influence the direction of growth of commissural axons as they pass through this midline structure.
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PMID:The expression of tissue and urokinase-type plasminogen activators in neural development suggests different modes of proteolytic involvement in neuronal growth. 128 56

Measurements were made of the nature and levels of plasminogen activator in human tears using, as a model of inflammation, patients undergoing cataract surgery. Tissue plasminogen activator (t-PA) but not urokinase plasminogen activator (u-PA) was found in tears. A wide variation in the range of t-PA in pre-operative tears was found. In those patients not receiving per-operative subconjunctival betamethasone a significant rise in t-PA was found in tears on the first post-operative day over pre-operative levels. A significant fall was noted in those receiving per-operative subconjunctival betamethasone.
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PMID:Plasminogen activator in human tears. 128 46

Tissue plasminogen activator (t-PA), urokinase plasminogen activator (u-PA) and plasminogen activator inhibitors (PAI) are elevated in late pregnancy with t-PA and u-PA remaining so at 6 weeks postnatal. PAI-2 remains at postpartum but was absent by 6 weeks postnatal unlike PAI activity which was absent at postpartum and returned to nonpregnant level at postnatal. The potential fibrinolytic response to stress is much reduced in pregnancy thus increasing the risk of thromboembolism.
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PMID:Plasminogen activators and inhibitors in normal late pregnancy, postpartum and in the postnatal period. 134 96

Fibrin gels form within the alveolar and interstitial compartments of the injured lung, and fibroblasts invade and facilitate organization of these transitional gels. We studied the effects of transforming growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha) on fibrinolytic and procoagulant activities of human lung fibroblasts (HLF) to determine their capacity to regulate pulmonary fibrin deposition. Fibrinolytic activity of cell lysates and media (n = 6 HLF cultures) were uniformly depressed by TGF-beta or TNF-alpha. In dose and time-course studies, HLF plasminogen activator inhibitor-1 (PAI-1) was increased by TGF-beta, whereas TNF-alpha induced release of PAI-1 into the media. HLF and media urokinase concentrations were depressed by TGF-beta, whereas urokinase was unchanged or increased by TNF-alpha. Tissue plasminogen activator was mainly cell associated and unchanged by TGF-beta or TNF-alpha. HLF antiplasmin activity was not detected. Plasma recalcification times of HLF media were decreased by TNF-alpha but unchanged by TGF-beta. These studies suggest that TGF-beta and TNF-alpha impair the ability of HLF to degrade fibrin by disturbing the balance of HLF plasminogen activators and PAI and that these cytokines concurrently leave unchanged or increase the capacity of HLF to initiate fibrin formation. Cytokines likely to occur in the injured lung induce abnormalities of fibrinolysis in HLF from adults; such abnormalities favor extravascular fibrin deposition, a characteristic feature of alveolitis.
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PMID:Mechanisms of fibrin formation and lysis by human lung fibroblasts: influence of TGF-beta and TNF-alpha. 141 27

We established that plasmin (10(-10) M to 10(-6) M) caused neutrophils (PMN) to aggregate using an in vitro assay. Plasminogen had no PMN aggregatory activity even at a concentration of 2 microM. However, plasminogen caused PMN to aggregate when incubated with plasminogen activators [tissue plasminogen activator (25-200 U/ml) or urokinase (5-500 U/ml)]. Tissue plasminogen activator and urokinase alone had no PMN aggregatory activity. Analysis of these incubation mixtures indicated that plasmin was generated in the process and that the time course of plasmin generation correlated with the aggregation response. Active-site-inhibited plasmin did not induce PMN aggregation, indicating that a functional catalytic site was required for the response. Pretreatment of PMN with either active-site-inhibited plasmin or tranexamic acid prevented PMN aggregation by plasmin, indicating that both binding of plasmin to the cell surface via the lysine binding sites and catalysis were required for the response. The generation of plasmin during activation of fibrinolysis may play a pro-inflammatory role by mediating aggregation of PMN.
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PMID:Plasmin generation induces neutrophil aggregation: dependence on the catalytic and lysine binding sites. 153 99

Therapy for thrombo-occlusive disease of the cerebral venous sinuses remains controversial. Although several thrombolytic agents, such as urokinase and anticoagulants, are recommended for treatment, major significant risks include cerebral hemorrhage, especially in patients with venous infarction. Tissue plasminogen activator (tPA) has shown a high affinity for fibrin-bound plasminogen, while exhibiting a low affinity for circulating plasminogen. The purpose of this study was to evaluate this drug for use in cerebral sinus thrombo-occlusive disease. Eleven adult male rabbits were chosen as experimental animals. All animals underwent microsurgical dissection of their major dural venous sinuses. Direct compression was used to form a thrombus within the sinus. The presence of significant venous thrombosis was confirmed radiographically by iohexol sinography. Subsequently, tPA was delivered systemically via the marginal ear vein at a dose of 3000 units/h; the result was total lysis of the clot documented by a sinogram 1 hour after the drug was administered. Postmortem pathological examination confirmed total lysis in seven of eight animals. One animal showed partial retained clot fragments. No significant coagulopathic state was observed. In three control animals, saline was infused without clot lysis. We conclude that tPA is a highly effective agent for the lysis of acute induced venous sinus thrombosis in an experimental model.
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PMID:Efficacy of tissue plasminogen activator in the lysis of thrombosis of the cerebral venous sinus. 210 40

The mechanism of coagulation activation in renal cell carcinoma was investigated using immunohistochemical techniques applied to fresh frozen sections of resected primary tumors. Tissue factor antigen was detected in the endothelium of vascular channels within the tumors. Fibrinogen and factor V were distributed diffusely in the perivascular tumor connective tissue. Fibrin was readily detected in a linear pattern along the edges of nodules of viable tumor indicating that thrombin had formed from the interaction of coagulation factors demonstrated previously in renal cell carcinoma tissue. Tissue plasminogen activator was detected in the endothelium of blood vessels in the vicinity of the tumor and urokinase in areas of necrosis but neither were associated with viable tumor cells. These results indicate that thrombin is formed locally in renal cell carcinoma tissue that transforms fibrinogen to fibrin. There also appears to be a net deficit in fibrinolysis in situ in this tumor. We postulate that these conditions might contribute to stabilization and progression of renal cell carcinoma and that clinical trials of antithrombotic agents are justified in this tumor type.
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PMID:Fibrinogen-fibrin transformation in situ in renal cell carcinoma. 211 16

Thrombotic thrombocytopenic purpura (TTP) is characterized by widespread occluding and persistent microthrombotic lesions. Evidence for both endothelial damage and primary platelet aggregation as possible pathogenetic mechanisms has been produced. Persistence of microthrombi has not been explained satisfactorily. In patients with TTP we studied plasma fibrinolysis and protein C. Tissue plasminogen activator (t-PA) activity levels, measured functionally, were low or unmeasurable in 11 of 12 patients; t-PA antigen levels, measured immunochemically, were normal in all six observed. The level of potent inhibitor of plasminogen activation directed against both t-PA and urokinase was elevated significantly in all 12, whereas the alpha 2-antiplasmin level was elevated in only two. Protein C antigen levels were low in three of six patients observed. Fibrinolysis levels in patients in remission did not differ from those in patients with acute disease. Plasma exchange resulted in temporary reversal of the abnormalities, but achievement of clinical remission was not associated with permanent normalization of fibrinolysis. Inasmuch as all 12 patients had severely depressed fibrinolytic mechanisms it is possible that a defect in the fibrin-clearing system permits thrombus formation to occur and proceed in an unchallenged fashion, thereby contributing to the complex events leading to arterial ischemia in vital organs.
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PMID:Fibrinolysis in health and disease: abnormal levels of plasminogen activator, plasminogen activator inhibitor, and protein C in thrombotic thrombocytopenic purpura. 243 36

Recognition that myocardial infarction is caused by coronary thrombosis has stimulated a search for a safe, rapidly acting, and effective thrombolytic regimen. Tissue plasminogen activator (t-PA) can provide relatively clot-selective thrombolysis, but one quarter of patients fail to achieve reperfusion, lysis speed is not optimal, and higher doses have been associated with an increased incidence of hemorrhagic stroke. We report the results of a multicenter study of pro-urokinase, a second naturally occurring plasminogen activator that has structural similarities to t-PA but has a different mechanism of action. Pro-urokinase was administered 3.9 +/- 1.1 hours after the onset of chest pain to 40 patients with acute myocardial infarction with angiographically confirmed complete coronary occlusion (TIMI grade 0). After a 90-minute intravenous infusion of pro-urokinase (4.7-9 million units, 36-69 mg) 51% (20 of 39) of the patients demonstrated reperfusion (TIMI grade 2 or 3) occurring 64.8 +/- 22.3 minutes after initiation of therapy. Fibrinogen levels fell only 10 +/- 17% from baseline, confirming the fibrin specificity of pro-urokinase. As with t-PA, however, this specificity was only relative. alpha 2-Antiplasmin decreased to 39% and plasminogen decreased to 64% of initial values. Fibrinogen degradation products increased 63% and the fibrin-specific D-dimer increased 8.7-fold. Thus, pro-urokinase produces relatively clot-selective coronary thrombolysis similar to that produced by t-PA, but the use of either pro-urokinase or t-PA alone in higher doses would be likely to produce more nonspecific effects.
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PMID:Clot-selective coronary thrombolysis with pro-urokinase. 249 4

The ability of streptokinase and urokinase to lyse intravascular fibrin-based clots is firmly established. However, there is a lack of enthusiasm for these agents because of serious haemorrhagic complications and a lack of controlled randomized studies indicating their efficacy. Thrombolytic therapy is suitable in only 15 per cent of patients with acute deep venous thrombosis. It restores the venous circulation to normal in up to 95 per cent of these patients if therapy is instituted within 5 days of the onset of symptoms. These patients have significantly fewer symptoms on follow-up than patients treated with heparin although the ability of thrombolytic therapy to preserve venous valvular function and to prevent the post-phlebitic syndrome is now in question. Thrombolytic therapy is as effective as heparin in preventing pulmonary embolism and may be superior in its treatment. Pulmonary haemodynamics are rapidly improved, diffusion capacity is restored and, although the evidence is inconclusive, long-term pulmonary hypertension may be prevented. Although the mortality rate is not decreased, controlled studies show that thrombolytic therapy may be beneficial in massive pulmonary embolism with clinical shock. Thrombolytic therapy is indicated for acute arterial and acute bypass graft occlusion when the surgical alternative is associated with a higher morbidity and mortality. Partial thrombolysis is achieved in up to 90 per cent of cases and the need for further therapeutic intervention is eliminated in one-third of the patients treated. New thrombolytic agents with greater specificity and potentially greater efficacy and fewer complications are being developed. Tissue plasminogen activator has been successfully used. Prourokinase, fibrin-seeking urokinase and acetylated streptokinase-plasminogen complex may expand the role of thrombolytic therapy in surgical practice.
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PMID:The role of thrombolytic therapy in surgical practice. 265 13


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