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)

The accumulation of excessive extracellular matrix (ECM) following tubular injury likely represents an imbalance between ECM production and degradation. We assessed the temporal relationship between the accumulation of ECM, cell adhesion molecules, matrix degrading proteinases, and their inhibitors in a rat model of anti-tubular basement membrane (TBM) antibody-associated tubulointerstitial nephritis (TIN) by the RNase protection assay and immunohistochemistry. There was an increase in the steady state expression of fibronectin (FN) and alpha 2(IV) collagen mRNAs beginning on day 7 with the onset of neutrophil infiltration. An increase in alpha 1(III) collagen and alpha 1-integrin did not occur until days 9 and 10, respectively, at which time mononuclear leukocytes were the predominant infiltrating cell. Increased levels of FN, alpha 1(III), alpha 2(IV) and alpha 1-integrin mRNAs occurred through day 14. By immunohistochemistry, increased accumulation of collagen IV, heparan sulfate proteoglycan, and laminin were detected along the thicken TBM; collagens I and III were immunolocalized within the tubulo-interstitium, while FN was present in both the TBM and interstitium in rats with TIN on day 14. The increase in matrix accumulation was associated with little or no increase in proteinases. u-PA transcripts fell beginning on day 8, with recovery to control values by day 12. Transin mRNA was found at low levels only on days 8 and 9, and the protein could not be detected by Western blotting. In contrast, these changes were associated with an increase in proteinase inhibitors, so that TIMP and PAI-1 mRNAs increased beginning on day 7 and persisted through day 14.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Extracellular matrix accumulation in immune-mediated tubulointerstitial injury. 800 77

Subendothelial collagen is one of the main triggers of platelet-dependent thrombus formation in arteries. The antithrombotic effects of rabbit polyclonal inhibitory antibodies to rat collagen type I-III and of murine non-inhibitory monoclonals to human recombinant single-/two-chain urokinase-type plasminogen activator (rscu-/rtcu-PA), cross-reacting with rat scu-/tcu-PA and their chemically synthesized conjugate, were studied both in vitro and in vivo. Anticollagen antibodies and bispecific conjugate inhibited human platelet adhesion, aggregation and formation of thrombus-like structures induced by rat collagen immobilized on the polystyrene surface in a condition mimicing a high shear rates in the large elastic arteries. Monoclonals to human rscu-/rtcu-PA did not block the collagen-induced platelet activation in vitro. The short-term treatment of the collagen-soaked silk thread by the collagen antibodies suppressed the platelet-dependent thrombus formation in the arterio-venous shunt in rats by 56 +/- 4% (P < 0.05). Bispecific conjugate, directed to collagen and endogenous rat scu/tcu-PA inhibited thrombus formation by the same factor as anticollagen antibodies. The treatment of collagen-adsorbed conjugate by human rtcu-PA did not increase the antithrombotic effect. The present results suggest, that the local administration of the anticollagen antibodies to the site of vascular injury can be an efficient tool for prophylaxis of platelet-dependent thrombus formation in arteries at thrombolysis or percutaneous transluminal coronary angioplasty.
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PMID:Collagen-targeted antibodies inhibit platelet-dependent thrombosis in vivo. 808 34

The enzymatic activities of uPA, and a collagenase-like proteinase in the post-nuclear fraction of cell homogenates of a metastatic carcinomatous cell line following X-ray irradiation were examined by the use of chromogenic substrates and by casein- or gelatin-containing zymographies and electrophoretic gel stained with avidin-conjugated peroxidase. Enhanced activities were observed in these cells, while those of 5'nucleotidase and Na(+)-K(+)-ATPase were attenuated. A partial purification and characterization of the collagenase showed that it was able to hydrolyze the heat-denatured type-I collagen more efficiently than the native one. The activation of both uPA and collagenase enables an efficient degradation of matrix barrier proteins. These findings suggest that following a certain dose range of X-ray irradiation, tumor cells may increase their ability to migrate and invade through the enhancement of uPA and collagenase activities.
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PMID:The concomitant augmentation of urokinase-type plasminogen activator and collagenase-like proteinase activities in X-ray irradiated cells of a human metastatic carcinomatous line. 809

This study examines the long-term clinical success and complications of thrombolysis-angioplasty (TLA) of failed arterial grafts performed in 17 patients (group 1) and matched with 21 patients (groups 2) who had intra-arterial thrombolysis (IAT) followed by graft revision. TLA consists of alternating thrombolysis with percutaneous transluminal angioplasty (PTA) in the treatment of occlusive arterial disease. Failed grafts consisted of 21 vein grafts, 6 ovine collagen grafts, 6 polytetrafluorethylene (PTFE) prostheses, 3 human umbilical veins and 2 polyurethane vascular grafts. All bypasses were below the knee, of which 13 were to the tibial level. Thrombolytic agents used were urokinase in 21 cases, tissue plasminogen activator in 13 cases and streptokinase in 4 cases. Following successful thrombolysis, PTA was performed with a 3 mm to 5 mm balloon catheters. Nine tandem lesions were corrected. In all 24 stenoses were treated: 14 anastomotic stenoses, 4 graft strictures and 5 peripheral stenotic lesions. The combined cumulative patency rate of both groups was 36% (SE 10.8%) at 3 years. The initial technical success rate in group 1 was 70% (12 of 17 grafts). The cumulative patency rate, as revealed by life-table analysis, was 35.6% (SE 10.2%) at one year and 21.3% (SE 9.6%) at 2 years. In all, 10 grafts failed at follow-up and in 6 of these cases secondary intervention was unsuccessful. Mid-graft and isolated lesions responded better than did anastomotic and tandem lesions. In group 2 the cumulative patency rate was 60.4% (SE 5.7%) at one year and 50.3% (SE 12.9%) at 2 years.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Thrombolysis combined with angioplasty for failed femorodistal arterial grafts. 814 Aug 40

EMT6 is a transplantable mouse mammary tumor cell line that has been utilized widely as a model system to study the effects of various treatments on local tumor growth and pulmonary metastasis. In this study, we examined the cellular mechanisms by which scatter factor (SF), a fibroblast-derived cytokine that stimulates epithelial cell motility, may contribute to tumor-cell dissemination, using the EMT6 model system. In vitro, SF stimulated EMT6 cell motility, invasiveness and cell-surface expression of urokinase (an enzyme required for cell migration through tissue). SF differentially stimulated EMT6 cell adhesion to and migration onto surfaces coated with collagen I and laminin. EMT6 cells treated in vitro with SF and injected i.v. into isogeneic BALB/c-Rw mice showed a small but significant increase (1.7-fold) in lung colony formation as compared with control cells. For EMT6 cells in vitro, SF had no effect on DNA synthesis, cell proliferation, cell size distribution, or in vitro colony-forming ability. Thus, the increase in lung colonization may be due to enhanced ability of SF-treated cells to adhere to subendothelial basement membrane or to invade through tissue. Studies of the tissue distribution of SF in BALB/c-Rw mice demonstrated high levels of active factor in the lung. Thus, the presence of endogenous pulmonary SF may have reduced the degree to which SF treatment stimulated EMT6 lung colonization. Significant SF activity was also found in extracts of EMT6 tumors. Cultured EMT6 cells did not produce SF, but did produce high titers of a soluble low-molecular-weight protein activity that is capable of stimulating SF production in human fibroblasts 3- to 5-fold. EMT6 tumor extracts contained high titers of a similar SF-inducing activity. These observations suggest that SF may contribute to the invasive and metastatic phenotype of EMT6 cells via a paracrine mechanism in which tumor cells induce the production of SF in stromal fibroblasts.
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PMID:Scatter factor modulates the metastatic phenotype of the EMT6 mouse mammary tumor. 819 80

Pharmacokinetics of two doses of the recombinant single-chain urokinase-type plasminogen activator (r-scu-PA) saruplase (40 and 20 mg) and its effect on fibrinolytic and haemostatic parameters were studied in six healthy male subjects using a randomized, double-blind, placebo-controlled, cross-over study. Special precautions were taken to prevent artefactual in vitro effects on fibrinolytic activity. The clearance of saruplase ranged from 310 to 862 ml/min and the apparent volume of distribution of the central compartment was about 8 1. Both doses of saruplase caused alpha 2-antiplasmin consumption, indicating some systemic fibrinolytic activation. However, the 20 mg dose caused no detectable fibrinogen breakdown and only a small increase in total fibrin/fibrinogen degradation products (TDP) (from 0.16 microgram/ml [range 0.14 to 0.19] to 0.78 microgram/ml [range 0.56 to 1.26]), while the 40 mg dose produce a fibrinogen breakdown to an average value of 44% (range 19 to 60%) and TDP increased from 0.12 microgram/ml (range 0.11-0.12) to 2.29 micrograms/ml (range 0.45 to 5.55). The breakdown of fibrinogen was related to the quantity of saruplase converted to active two-chain u-PA (tcu-PA) in vivo (6 to 22% conversion). There were no important effects of saruplase on overall blood coagulation (activated partial thromboplastin time) and platelet function (collagen induced platelet aggregation, urinary [2,3-dinor]-thromboxane B2 excretion and plasminogen activator inhibitor 1 [PAI-1] release from platelets). Saruplase is cleared rapidly from the plasma and a variable amount is converted to tcu-PA. This two-chain form of u-PA probably causes the dose-dependent systemic fibrinolytic activation.
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PMID:Pharmacokinetics of saruplase, a recombinant unglycosylated human single-chain urokinase-type plasminogen activator and its effects on fibrinolytic and haemostatic parameters in healthy male subjects. 823 42

Using immunohistochemistry and in situ hybridization, we have characterized the expression and localization of components of the plasminogen activator proteolytic cascade in an organotypic coculture system which consists of a "dermal" portion (human dermal fibroblasts throughout a collagen matrix) and a stratified, well-differentiated epidermal portion. Specifically, the following components were examined: the enzymes urokinase-type plasminogen activator and tissue-type plasminogen activator and their type 1 and type 2 inhibitors. Urokinase plasminogen activator mRNA and antigen were found predominantly in the least differentiated, basal keratinocytes; in some fields there was also faint deposition of antigen beneath the basal cells. The distribution of plasminogen activator inhibitor type 1 was similar to that of urokinase, except that inhibitor type 1 antigen deposition beneath the basal cells appeared more intense and uniform. In contrast to the results with urokinase plasminogen activator and inhibitor type 1, tissue plasminogen activator mRNA and antigen were localized focally in the suprabasal, i.e. more differentiated, keratinocytes. Plasminogen activator inhibitor type 2 mRNA and antigen were detected in most epidermal layers, but were more intense suprabasally and often spared the basal layer. These studies demonstrate that the same type of cell, i.e. the keratinocyte, can express different components of the plasminogen activator cascade depending on its state of differentiation. The change in expression of plasminogen activator cascade components with keratinocyte differentiation suggests distinct epidermal functions for these components, related to cell-matrix interaction and epidermal differentiation.
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PMID:Differential expression of plasminogen activators and their inhibitors in an organotypic skin coculture system. 827 Jun 42

The use of first generation plasminogen activators, urokinase, streptokinase and tissue plasminogen activator has revolutionized thrombolytic therapy for myocardial infarction and ischaemia, and potentially stroke. However, thrombolytic therapy employing these activators is limited by reocclusion of the very arteries being opened, which follows in a small but significant number of patients. The development of second generation plasminogen activators, e.g. staphylokinase and anisoylated plasminogen streptokinase activator complex, has not alleviated the problems encountered with classical plasminogen activators. It is now widely recognized that aberrant platelet aggregation induced primarily by thrombin, rather than plasmin, is one of the major causes of recurrent thrombosis following pharmacologic thrombolysis. Agents that (a) inhibit enzymatic and/or coagulant activity of thrombin, (b) block binding of thrombin to its receptor, and (c) interfere with the generation of thrombin by the prothrombinase complex may compromise haemostasis resulting in haemorrhage. We recently demonstrated that thrombin-induced platelet aggregation is accompanied by cleavage of aggregin, a putative ADP-receptor on the platelet surface, and that these events are indirectly mediated by intracellularly activated calpain expressed on the surface. In this review, we discuss the known mechanisms of thrombin-induced platelet aggregation and suggest relative advantages of potential pharmacological agents, being developed in our laboratory, over those that have been previously developed and tested. These inhibitors selectively prevent aggregation of platelets induced by thrombin by inhibiting calpain expressed on the surface. Moreover, one of these inhibitors which blocks thrombin-induced platelet aggregation does not interfere with other platelet responses mediated by thrombin or platelet aggregation induced by other agonists, such as, ADP, collagen, phorbol myristate acetate and thromboxane A2 mimetics. This selectivity could reduce the chances of perturbing the formation of a haemostatic plug.
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PMID:Reocclusion after thrombolytic therapy: strategies for inhibiting thrombin-induced platelet aggregation. 832 74

Decreased expression of the cell-cell adhesion molecule, E-cadherin, promotes dedifferentiation and invasiveness of human carcinoma cells, whereas this process can be reversed by reexpression of E-cadherin (U. H. Frixen et al., J. Cell Biol., 113: 173-185, 1991; J. H. Schipper et al., Cancer Res., 51: 6328-6337, 1991). In this work we studied the involvement of extracellular matrix-degrading proteases in E-cadherin-dependent tumor cell invasion. When T47D and MCF-7 human differentiated breast carcinoma cells were treated with the E-cadherin antibody DECMA (decompacting monoclonal antibody) the cells dissociated from each other and lost their epithelioid morphology, paralleled with a rise in the secretion of urokinase-type plasminogen activator (uPA) into the extracellular milieu as determined by zymography. The stimulation of uPA required protein and RNA synthesis. Furthermore, when DECMA-treated T47D cells were cultured on artificial collagen matrices the induced invasiveness correlated with accumulation of uPA in the culture medium, and uPA antibodies inhibited this invasion process. Actin filaments which are thought to be associated with the cytoplasmic part of E-cadherin were disrupted after treatment of T47D cells with DECMA. These results suggest a link between cell-cell adhesion, the integrity of actin filaments, and the regulation of uPA biosynthesis.
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PMID:Stimulation of urokinase-type plasminogen activator expression by blockage of E-cadherin-dependent cell-cell adhesion. 833 68

Plasmin is thought to be involved in the pericellular proteolysis of the human epidermis under physiological and pathological conditions. Plasmin is provided by activation of the proenzyme plasminogen. We have explored in vitro whether plasminogen is bound and activated at the keratinocyte surface, a possible mechanism for providing plasmin in the pericellular space. Plasminogen and plasmin could be eluted from the surface of keratinocytes grown in serum-containing medium. When plasminogen was added to cultured keratinocytes it was activated by cell-associated urokinase-type plasminogen activator. The activation required plasminogen binding to the cell surface. Plasminogen binding by keratinocytes was saturable and proceeded in a time- and concentration-dependent manner. Surface-bound plasmin was rapidly displaced from the surface into the culture supernatant. When compared to plasmin in solution surface-bound plasmin was relatively protected from interaction with the specific inhibitor alpha 2-antiplasmin. Addition of exogenous plasmin or plasmin generation by the keratinocyte-associated plasminogen activators was ensued by the detachment of adherent keratinocytes in culture. Along the same line, plasmin counteracted keratinocyte adhesion to fibrin-coated but not to collagen-coated culture plates. The findings indicate that plasmin may be generated in the pericellular space of keratinocytes and may interfere with the adhesion to particular extracellular substrates.
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PMID:Binding and activation of plasminogen at the surface of human keratinocytes. 835 16


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