Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In a quantitative model of thrombolysis, consisting of rabbits with a 125I-fibrin labeled blood clot in the jugular vein, simultaneous intravenous infusion over 4 hours of t-PA and scu-PA or of t-PA and urokinase had a significantly greater (p less than 0.01) thrombolytic effect than could be anticipated on the basis of the added effects of each agent alone. In order to further investigate the mechanism of this in vivo synergism, recombinant t-PA (rt-PA) and scu-PA in synergistic amounts were infused: 1) simultaneously over 4 hours, 2) rt-PA over 1 hour, then 15 min later scu-PA over 2 hours and 3) scu-PA over 1 hour, than 15 min later rt-PA over 2 hours. Simultaneous infusion of 0.1 mg/kg rt-PA and 0.2 mg/kg scu-PA gave 48 +/- 2 percent thrombolysis (mean +/- SEM, n = 5) and of 0.2 mg/kg rt-PA and 0.4 mg/kg scu-PA 67 +/- 5 percent (n = 5). When these infusions were given sequentially, rt-PA followed by scu-PA gave 32 +/- 5 (n = 4) and 49 +/- 8 (n = 4) percent lysis, but scu-PA followed by rt-PA yielded only 14 +/- 1 (n = 4) and 21 +/- 1 (n = 4) percent lysis, indicating that synergism occurs when rt-PA is followed by scu-PA but not when scu-PA is followed by rt-PA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Synergistic effect on thrombolysis of sequential infusion of tissue-type plasminogen activator (t-PA) single-chain urokinase-type plasminogen activator (scu-PA) and urokinase in the rabbit jugular vein thrombosis model. 312 88

The thrombolytic efficacy of recombinant single-chain urokinase-type plasminogen activator (rscu-PA) was studied in an open-chest canine model of coronary artery thrombosis. Dogs (n = 16) were anesthetized, a left thoracotomy performed, and a two cm segment of the left circumflex coronary artery was isolated and instrumented with an electromagnetic flow probe, an intracoronary stimulation electrode, and an adjustable mechanical occluder. Anodal direct current (100 microA) was applied to the stimulation electrode until thrombosis occurred (n = 14). After 30 min of thrombotic occlusion, rscu-PA was administered intravenously. Dogs were sacrificed either 6 h after thrombolysis or 6.5 h after initiation of rscu-PA when thrombolysis did not occur. In group A (30-50 micrograms/kg bolus rscu-PA + 20-40 micrograms/kg/min infusion rscu-PA for 30 min, n = 5) thrombolysis occurred in one case (20%) and this artery reoccluded. In group B (250 micrograms/kg bolus rscu-PA + 25 micrograms/kg/min infusion rscu-PA for 30 min, n = 6) all reperfused and only one reoccluded (16.6%). In group C (200 micrograms/kg bolus rscu-PA + 100 micrograms/kg/min rscu-PA infusion for 30 min, n = 2) both reperfused and neither reoccluded. Infarct size, determined as a percentage of left ventricle, was smaller when thrombolysis was followed by persistent reperfusion (n = 7), than when reperfusion did not occur (n = 4): 16.9 +/- 3.7% vs 31.3 +/- 2.2%, respectively (mean +/- SEM, p less than 0.02). If thrombolysis was followed by reocclusion, infarct size was 27.0 +/- 10.0%. In this study thrombolysis occurred when changes in prothrombin time, partial thromboplastin time, fibrinogen and fibrin split products were suggestive of systemic finbrinogenolysis. In conclusion, effective thrombolysis with rscu-PA appears to limit infarct size and to be accompanied by evidence of systemic fibrinolysis.
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PMID:Recombinant single-chain urokinase-type plasminogen activator (rscu-PA) induces thrombolysis and systemic fibrinolysis in a canine model of coronary artery thrombosis. 313 91

Increased production of the serum protease plasminogen activator is associated with tissue damage. The in vitro production of plasminogen activator by alveolar macrophages obtained by bronchoalveolar lavage was studied in 22 normal subjects and 28 patients with interstitial lung disease to determine whether plasminogen activator is produced by normal alveolar macrophages and whether this is increased in patients with interstitial lung disease. Plasminogen activator activity, measured with an iodine-125 labelled fibrin release assay, was found to be dependent on time, effector cell numbers, and plasminogen concentration. Plasminogen activator production by alveolar macrophages from 14 normal non-smokers and eight normal smokers was similar and the mean value was 0.78 (SEM 0.16) urokinase (UK) units x 10(-8)/cell/hour. Alveolar macrophages from the seven patients with cryptogenic fibrosing alveolitis and six patients with histiocytosis-X produced more plasminogen activator (1.89 (0.25) and 4.54 (1.3) x 10(-8) UK units/cell/hour respectively) than macrophages from normal subjects (p less than 0.05), whereas those from 15 patients with sarcoidosis did not (1.09 (0.2) x 10(-8) UK units/cell/hour). Exposure of normal alveolar macrophages to immune complexes enhanced plasminogen activator production to 2.07 (0.27) x 10(-8) UK units/cell/hour, whereas exposure to products of activated T cells and to purified gamma interferon reduced plasminogen activator production (to 0.38 (0.11) and 0.62 (0.11) x 10(-8) UK units/cell/hour respectively). These studies show that plasminogen activator is produced by normal human alveolar macrophages and that its production is increased in patients with cryptogenic fibrosing alveolitis and histiocytosis-X.
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PMID:Production of plasminogen activator by alveolar macrophages in normal subjects and patients with interstitial lung disease. 321 49

Coronary thrombolysis was induced by infusion of highly purified human pro-urokinase isolated from a transformed kidney cell line (ACHN) or by infusion of urokinase of urinary origin in anesthetized dogs with 1-hr-old clots in the left anterior descending coronary artery. The clots were induced with a copper coil and thrombolysis was detected by repeat coronary angiography. Intravenous infusion of pro-urokinase at a rate of 10 micrograms/kg/min for 30 min in two dogs did not induce thrombolysis, which was only obtained after 8 and 15 min of its subsequent intracoronary administration. Intravenous infusion of pro-urokinase at a rate of 20 micrograms/kg/min for 30 min in four dogs induced coronary thrombolysis within 23 +/- 2 min (mean +/- SEM). This was not associated with systemic fibrinolytic activation because the alpha 2-antiplasmin and fibrinogen levels did not decrease. Intravenous infusion of urokinase at a rate of 10 micrograms/kg/min for 30 min elicited thrombolysis in four of seven dogs within an average of 19 +/- 2 min. In the other three dogs thrombolysis was only obtained within 11 +/- 3 min of its subsequent intracoronary infusion. Administration of urokinase was associated with systemic fibrinolytic activation as evidenced by a decrease of alpha 2-antiplasmin to about 10% and of fibrinogen to 43 +/- 13% of the preinfusion value. It is concluded that intravenous infusion of pro-urokinase at a sufficiently high rate produces coronary thrombolysis without systemic fibrinolysis in dogs.
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PMID:Coronary thrombolysis in dogs with intravenously administered human pro-urokinase. 392 37

A simple venous thrombosis model in rabbits was used for the quantitative evaluation of the thrombolytic effect of human extrinsic (tissue-type) plasminogen activator as compared with urokinase.A thrombus was formed in an isolated segment of the jugular vein from a mixture of (125)I-labeled fibrinogen, whole rabbit blood, and thrombin. In order to immobilize the thrombus during lysis, it was formed around a woolen thread introduced longitudinally in the lumen of the vein. Thrombotic extension of the clot was prevented by subcutaneous injection of heparin. The extent of thrombolysis was measured as the difference between the radioactivity introduced in the clot and that recovered in the vein segment at the end of the experiment. In control animals the extent of thrombolysis was 5.6+/-1.4% (n = 5) after 6 h, 14.5+/-1.7% (n = 10) after 30 h, 16.0+/-1.5% (n = 11) after 78 h, and 48.1+/-2.7% (n = 10) after 174 h (mean+/-SEM). Extrinsic (tissue-type) plasminogen activator, highly purified from the culture fluid of a human melanoma cell line, was administered systemically or locally over a time period of 4 h and the percent thrombolysis measured 2 h after the end of the infusion. One- and two-chain extrinsic plasminogen activator had very similar thrombolytic potency. Systemic infusion resulted in a dose-dependent degree of thrombolysis. The activator-induced thrombolysis, after infusion of 100,000 IU ( congruent with1 mg protein), was approximately 75% for fresh clots, 35% for 1-d-old clots, 30% for 3-d-old clots, and 50% for 7-d-old clots. The thrombolytic activity of urokinase was more than five times lower than that of extrinsic plasminogen activator: Infusion of 500,000 IU resulted in approximately 40% lysis of fresh clots and 25% of 1-3-d-old clots, while 7-d-old clots appeared to have become resistent to urokinase. Local infusion resulted in a 5-10 times higher thrombolytic effect of both extrinsic plasminogen activator and urokinase. Thrombolysis with extrinsic plasminogen activator was not associated with systemic activation of the fibrinolytic system as evidenced by unaltered plasma levels of fibrinogen, plasminogen, and alpha(2)-antiplasmin. Systemic infusion of urokinase resulted in significant thrombolysis only at doses that were associated with disseminated plasminogen activation. Local infusion of urokinase required a 5-10-fold higher dose than extrinsic plasminogen activator to obtain a similar degree of thrombolysis, which also occurred in the absence of systemic activation of the fibrinolytic system. It is concluded that the extent of thrombolysis by extrinsic plasminogen activator is mainly determined by the dose of activator and its delivery in the vicinity of the thrombus and much less by the age of the thrombus or the molecular form of the activator. Extrinsic plasminogen activator appears to be superior to urokinase because of its higher (5-10-fold) specific thrombolytic activity and the absence of systemic activation of the fibrinolytic system, which results in defibrinogenation and a bleeding tendency.
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PMID:Thrombolysis with human extrinsic (tissue-type) plasminogen activator in rabbits with experimental jugular vein thrombosis. Effect of molecular form and dose of activator, age of the thrombus, and route of administration. 668 15

Extrinsic (tissue-type) plasminogen activator (plasminogen activator) was isolated either as a single-chain or as a two-chain molecule from the culture medium of a human melanoma cell line. The thrombolytic activity of both molecular forms of activator was investigated in beagle dogs with an experimental femoral vein thrombosis and compared with that of urokinase. The 125I-fibrinogen-labeled thrombus was formed in an isolated 4-cm segment of the vein, aged for 30 min, and the thrombolytic substances were infused over a 4-h period. The degree of thrombolysis was measured 2 h later as the difference between the injected and recovered 125I. In six control animals with a saline infusion the extent of thrombolysis was 16.3 +/- 3.8% (mean +/- SEM), in five dogs receiving 100,000 IU urokinase, 17.4 +/- 3.7% (P less than 0.4) and in four dogs with 1,000,000 IU urokinase 40.6 +/- 4.8% (P less than 0.001). Infusion of 100.000 IU single-chain plasminogen activator in five dogs resulted in 3.5 +/- 7.8% lysis (P less than 0.05) and of 100,000 IU two-chain plasminogen activator in five dogs in 60.1 +/- 10.8% (P less than 0.001). Infusion of 300,000 IU one-chain plasminogen activator yielded 57.5% lysis and of the same amount of two-chain plasminogen activator 72.9%. Significant activation of plasminogen, consumption of alpha 2-antiplasmin, and fibrinogen breakdown in plasma was only observed in animals receiving the high doses of urokinase but not in the saline, plasminogen activator, or the low-dose urokinase groups. It is thus concluded that in this thrombosis model human extrinsic plasminogen activator has a higher specific thrombolytic effect that urokinase. Plasminogen activator also appears to induce thrombolysis without systemic fibrinolytic activation and fibrinogen breakdown.
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PMID:Thrombolysis with human extrinsic (tissue-type) plasminogen activator in dogs with femoral vein thrombosis. 719 39

Urokinase-type plasminogen activator (u-PA) is a 54-kd enzyme shown to participate in tissue degradation under certain normal and pathological conditions, including cancer invasion and metastasis. Increased u-PA expression has been found in cancers of the breast, lung, colon, and prostate, and correlated with worse outcome in patients with lung and breast cancer. We examined the correlation between u-PA expression in gliomas and patient survival. Seventy-seven gliomas from 41 men and 36 women (ages 2 to 73) were immunostained for u-PA using monoclonal antibody 394 directed against human urokinase. The tumors included 32 grade 4, 16 grade 3, and 20 grade 2 astrocytomas (Daumas-Duport scale), and 9 pilocytic astrocytomas. Strong cytoplasmic staining was found in tumor cells of all grade 4, most of the grade 3, and a few of the lower grade tumors. Adjacent normal brain tissue showed faint staining associated with subpial cell processes and white matter fibers. The fiber staining was stronger in brain tissue infiltrated by tumor cells. Cytoplasmic u-PA staining in tumor cells was scored from 0 (no staining) to 6 (strong and widespread staining). The mean u-PA scores were 5.08 +/- 0.19 (mean +/- SEM) for grade 4, 3.97 +/- 0.46 for grade 3, 1.65 +/- 0.39 for grade 2, and 1.22 +/- 0.60 for pilocytic astrocytomas. The statistical analysis was based on cytoplasmic staining only. Analysis of variance revealed significant differences between the mean u-PA scores of different grades (P < 0.02 between grades 4 and 3, and P = 0.0001 between grades 4 or 3 and 2, and between grades 4 or 3 and pilocytic), except between grade 2 and pilocytic astrocytomas. Univariate analysis indicated that u-PA score > or = 4 (P = 0.0001), tumor grade 4 (P = 0.01), and age > 50 (P < 0.001) were all significant predictors for shorter disease survival. A three-way interaction model by multivariate analysis indicated that u-PA score > or = 4, tumor grade 4, and age > 50, taken together, were significant factors for shorter patient survival (P < 0.02). We conclude that u-PA may be used as a prognostic tool in conjunction with tumor grade and patients' age in predicting survival for patients with gliomas.
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PMID:Prognostic role of urokinase-type plasminogen activator in human gliomas. 760 73

The evaluation of porcine small intestine submucosa (SIS) in a microsurgical model was conducted using an interpositional graft in the rat femoral artery. The SIS grafts were fabricated from processed porcine material that was wrapped around a glass tube and oversewn longitudinally to produce a tubular structure. Of the 42 animals studied, 7 received grafts of untreated SIS (group I), 7 of the grafts were presoaked (PSH) in heparin (Group II), 7 animals were treated with systemic heparin prior to implantation of PSH-SIS (group III), 7 animals received SIS grafts crosslinked to heparin (group IV), 7 animals received SIS grafts crosslinked to urokinase (group V), and 7 animals received untreated autologous epigastric vein grafts (group VI). Patency was assessed postoperatively and selected grafts were evaluated by histology. All SIS grafts failed to maintain patency beyond the first postoperative hour. Histologic examination of the thrombosed graft surfaces revealed a smooth luminal surface with a thick layer of attached fibrin and platelets with a central occluding thrombus. The thickness of the induced fibrin layer appears to narrow intraluminal space significantly at the microvascular level. While having excellent success at vessel diameters greater than 3 mm, and in a variety of nonporcine animal models without xenographic rejection, SIS in this model was thrombogenic despite a favorable surface morphology as demonstrated by SEM. Even with use of heparin and urokinase SIS graft thrombosis occurred.
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PMID:Experimental evaluation of small intestinal submucosa as a microvascular graft material. 783 May 42

The localization of proteases to cell surfaces via receptors may facilitate cell migration, invasion, and matrix degradation. Since vascular smooth muscle cell (SMC) migration may be an important event in atherosclerosis and in intimal thickening after vascular injury, we studied the cell surface expression of a receptor for urokinase-type plasminogen activator (u-PAR) in cultured human vascular SMC. Using immunofluorescence microscopy, we demonstrated several staining patterns of SMC u-PAR: at the periphery of the cell membrane, at the leading edge, and at cell-cell contact sites. When migration experiments were performed using a wound assay, one-third of the SMC at the wound edge demonstrated polarization of cell surface u-PAR toward the leading edge of the cell membrane (32 +/- 2%, +/- SEM, n = 7). A similar pattern was seen with an antibody to caveolin, a transmembrane protein found in caveolae, but not with an antibody to 5'-nucleotidase, another cell surface glycophosphatidylinositol-anchored protein, which was homogeneously expressed on the cell surface. Low-density lipoprotein receptor-related protein, which mediates internalization of u-PAR bound ligands, was distributed in a diffuse punctate pattern, not polarized to the leading edge. Double immunofluorescent studies demonstrated codistribution of SMC u-PAR with vinculin and caveolin in migrating SMC at the leading edge in a wound assay. Polarization of cell surface u-PAR was not observed in either nonwounded or subconfluent cultures, despite random migratory behavior. These studies suggest that in response to wounding, human vascular SMC polarize and concentrate cell surface u-PAR to their leading edge, perhaps facilitating directional migration.
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PMID:Migrating vascular smooth muscle cells polarize cell surface urokinase receptors after injury in vitro. 786 16

Endothelial release of tissue plasminogen activator (t-PA) may initiate fibrinolysis. Fibrinolysis and coagulation were investigated in 12 patients undergoing elective coronary artery bypass surgery. Cardiopulmonary bypass (CPB) was 108 +/- 7 min (mean +/- SEM), the time of cold, crystalloid, retrograde cardioplegia 53 +/- 5 min. Arterial and coronary sinus blood were sampled concomitantly before cardioplegia and after release of the aortic cross-clamp, for measurement of t-PA antigen (Ag) and activity, plasminogen activator inhibitor (PAI-1) Ag and activity, t-PA/PAI-1 complex, single chain urokinase (sc-uPA) and urokinase (uPA) plasminogen activators, the fibrin split product D-dimer, thrombin-antithrombin complex (TAT), and the prothrombin split product F 1 + 2. Cardiopulmonary bypass significantly increased t-PA Ag and activity, t-PA/PAI complex, D-dimer, TAT, and F 1 + 2, and decreased PAI-1 Ag and activity in arterial blood; uPA and sc-uPA were unchanged. The tissue plasminogen activator antigen was higher in coronary sinus than arterial blood after 1 (39 +/- 5 vs 24 +/- 4 ng/ml, P < 0.003), 4 (P < 0.003), and 10 min (P < 0.004) reperfusion. Tissue plasminogen activator activity and t-PA/PAI complex increased, PAI-1 activity decreased, while all other parameters were unchanged across the coronary circulation. In conclusion, CPB induces fibrinolysis and coagulation. Cold cardioplegia induces t-PA release in the coronary circulation, denoting a postischemic antithrombotic function of the coronary endothelium. Tissue plasminogen activator may be used to evaluate endothelial stimulation or injury induced by CPB, or by different regimens of myocardial protection.
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PMID:Fibrinolysis during cardiac surgery. Release of tissue plasminogen activator in arterial and coronary sinus blood. 808 78


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