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At least 775 records · Page 43Linked to original sources
PubMed1988

Cytokine activation of vascular endothelium. Effects on tissue-type plasminogen activator and type 1 plasminogen activator inhibitor.

Regulation of the fibrinolytic system of cultured human umbilical vein endothelial cells (HUVECs) by recombinant interleukin 1 beta (rIL-1 beta) and tumor necrosis factor alpha (rTNF alpha) was investigated. Functional and immunologic assays indicated that both cytokines decreased HUVEC tissue-type plasminogen activator (tPA) and increased type 1 plasminogen activator inhibitor (PAI-1) in a dose- and time-dependent manner. Maximal effects (50% decrease in tPA antigen; 300-400% increase in PAI-1 activity) were achieved with 2.5 units/ml rIL-1 beta and 200 units/ml rTNF alpha. Combinations of rIL-1 beta and rTNF alpha were not additive at these maximal concentrations. After a 24-h pretreatment with rIL-1 beta, HUVECs secreted tPA at one-quarter of the rate of control cells and released PAI-1 at a rate that was 5-fold higher than controls. Neither the basal rate of PAI-1 release nor the increased rate of release of PAI-1 in response to rIL-1 beta was affected by subsequently treating the cells with secretagogues (e.g. phorbol myristate acetate) suggesting that PAI-1 is not contained within a rapidly releasable, intracellular storage pool. Northern blot analysis using a PAI-1 cDNA probe indicated that the cytokines increased the steady-state levels of the 3.2- and 2.3-kb PAI-1 mRNA species, but with a preferential increase in the larger mRNA form. The fact that both rIL-1 beta and rTNF alpha act in a similar manner strengthens the hypothesis that the local development of inflammatory/immune processes could reduce endothelial fibrinolytic activity.

Calcimycin↗
PubMed1988

Prognostic significance of antithrombin III, plasminogen and proactivator of plasminogen activity in viral hepatitis.

Antithrombin III/AT III/, plasminogen (Plg) and proactivator of plasminogen [PPlg] activity were studied in 663 patients with various liver diseases and 547 healthy subjects. Parallel analysis of AT III, Plg and PPlg gives a very valuable prognostic information concerning the forthcoming evolution of viral hepatitis [v.h] and acute liver failure. The prognosis of v.h. in the cases with normal Plg activity is independent from the AT III activity in 98% of the cases it is associated with clinical improvement. The combination with low Plg and elevated AT III activity suggested clinical improvement in 65-90% of the patients. Most critical is the combination between low Plg and low AT III activity. This combination suggests clinical aggravation and danger of hepatic coma. The existence of 4 patterns of AT III activity is shown: elevated, normal in physiological condition, normal in pathological condition and decreased activity.

Antithrombin III↗
PubMedDate not supplied

Plasminogen and plasminogen proactivator in liver diseases.

The behaviour of plasminogen (PLg) and plasminogen proactivator (PPLg) and some currently employed enzyme parameters were prospectively studied in 1047 subjects, of whom: 748 patients with liver diseases and jaundice; 52 tumor patients and 247 healthy persons. The patients with parenchymal liver diseases showed significantly reduced PLg and PPLg activity in direct relation with the severity and the stage of diseases. In patients with obstructive jaundice the activity of the fibrinolytic enzymes was usually normal, rarely increased. Other parameters such as: ALAT, LAP, G--GT and bilirubin were elevated most often in patients with viral hepatitis as well as in patients with obstructive jaundice. Quick time was found less affected during acute viral hepatitis and acute liver failure. It seems possible to recommend PLg and PPLg as liver function tests in association with the other function tests.

Hepatitis, Viral, Human↗
PubMed1984

Plasminogen activator and plasminogen activator inhibitor associated with granulomatous inflammation: a study with murine leprosy.

Plasminogen activator that is associated with the development of hypersensitivity granulomas (gPA) was partially purified from a saline soluble fraction of murine lepromas elicited in "resistant" mice, C57BL/6N. The gPA was shown to consist of two subspecies (23,000 and 48,000 in molecular weight) with essentially identical enzymologic properties. The gPA was found to be a relatively heat stable weakly alkaline serine proteinase with trypsin-like characteristics in the specificity for synthetic substrates and proteinase inhibitors. It showed a high affinity for H-D-Ile-Pro-Arg-pNA (Km = 1.4 X 10(-4) M) H-D-Val-Leu-Lys-pNA (Km = 5.2 X 10(-4) M), and L-pyroGlu-Gly-Arg-pNA (Km = 9.3 X 10(-4) M). The gPA did not demonstrate antigenic cross reaction with urokinase-type or tissue-type plasminogen activator. Two distinct enzymatic regulators of the gPA were also demonstrated in the saline soluble fraction of the hypersensitivity granulomas. The gPA and its regulation are assumed to be correlated with macrophage activation in the hypersensitivity granulomas.

Animals↗
PubMed1995

Hormonal regulation of tissue-type plasminogen activator and plasminogen activator inhibitor type-1 in cultured monkey Sertoli cells.

Sertoli cells play a central role in the control and maintenance of spermatogenesis. Isolated Sertoli cells of mouse and rat testes have been shown to secrete plasminogen activator (PA) and a plasminogen activator inhibitor type-1 (PAI-1) in culture. In this study, we have investigated the hormonal regulation of PA and PAI-1 activities in cultured monkey Sertoli cells. Sertoli cells (5 x 10(5) cells/well) isolated from infant rhesus monkey testes were preincubated at 35 degrees C for 16 h in 24-well plates precoated with poly(D-lysine) (5 micrograms/cm2) in 0.5 ml McCoy's 5a medium containing 5% of fetal calf serum and further incubated for 48 h in 0.5 ml serum-free medium with or without various hormones or other compounds. PA as well as PAI-1 activities in the conditioned media were assayed by fibrin overlay and reverse fibrin autography techniques respectively. The Sertoli cells in vitro secreted only tissue-type PA (tPA), no detectable amount of urokinase-type PA (uPA) could be observed. Monkey Sertoli cells were also capable of secreting PAI-1. Immunocytochemical studies indicated that both tPA and PAI-1 positive staining localized in the Sertoli cells, spermatids and residual bodies of the seminiferous epithelium; Northern blot analysis further confirmed the presence of both tPA and PAI-1 mRNA in monkey Sertoli cells. Addition of follicle-stimulating hormone (FSH) or cyclic adenosine monophosphate (cAMP) derivatives or cAMP-generating agents and gonadotrophin-releasing hormone (GnRH) agonist or phorbol ester (PMA) to the cell culture significantly increased tPA activity.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗
PubMed1994

Comparative thrombolytic properties of tissue-type plasminogen activator and of a plasminogen activator inhibitor-1-resistant glycosylation variant, in a combined arterial and venous thrombosis model in the dog.

rt-PA-K, a variant of recombinant tissue-type plasminogen activator (rt-PA) with substitution of amino acids 296 to 299 with alanine (KHRR296-299AAAA) has increased fibrin-specificity and reduced sensitivity to plasminogen activator inhibitor-1; rt-PA-T, with threonine 103 replaced by asparagine has an additional glycosylation site and a reduced clearance; and rt-PA-N, with asparagine 117 mutagenized to glutamine lacks the high mannose carbohydrate side chain. We have investigated whether combination of these properties in a single molecule might yield an improved thrombolytic agent. The thrombolytic potency and fibrin-specificity of the combination mutant rt-PA-TNK was compared with that of rt-PA in a combined venous whole blood clot model and platelet-rich arterial eversion graft thrombosis model in dogs given intravenous heparin and aspirin. Infusion of 0.125 to 1.0 mg/kg over 60 min in groups of 4 to 5 dogs produced dose-dependent fibrin-specific venous clot lysis. The thrombolytic potency (percent lysis per mg compound administered per kg body weight) of rt-PA-TNK was significantly higher than that of rt-PA as evidenced by a higher maximal rate of lysis of 480 +/- 100% versus 140 +/- 40% within the 2 h observation period per mg of compound administered per kg body weight (mean +/- SEM, p = 0.004) and a significantly lower dose of 0.08 +/- 0.01 versus 0.21 +/- 0.04 mg/kg body weight at which the maximal rate of lysis was obtained (p = 0.004).(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1994

Low density lipoprotein receptor-related protein is necessary for the internalization of both tissue-type plasminogen activator-inhibitor complexes and free tissue-type plasminogen activator.

Tissue-type plasminogen activator (t-PA) is used as a thrombolytic agent in treatment of myocardial infarction. However, large doses of this agent must be administered in treatment to maintain a thrombolytic state because t-PA is cleared rapidly from circulation. We designed specific ligands to distinguish between two major mechanisms by which t-PA is taken into cells and degraded. One of these mechanisms involves internalization of complexes between t-PA and its cognate inhibitor plasminogen activator inhibitor type-1 (PAI-1); the other mechanism is independent of PAI-1. Using specific inhibitors for low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor (LRP), we show that the degradation by hepatocytes of both free t-PA and t-PA.PAI-1 complexes involve the receptor LRP. We demonstrate that fibroblasts degrade both free t-PA (PAI-1-independent) and t-PA complexed with its specific inhibitor PAI-1 (PAI-1-dependent), whereas genetically altered fibroblasts that do not express LRP neither internalize nor degrade these ligands. We also show that a PAI-1-independent, t-PA ligand can inhibit the degradation of both free t-PA and t-PA.PAI-1 complexes. We propose LRP is the receptor for both PAI-1-independent and PAI-1-dependent t-PA ligands.

Amino Acid Sequence↗
PubMed1994

The role of plasminogen activator inhibitor type 1 in the clearance of tissue-type plasminogen activator by rat hepatoma cells.

The role of plasminogen activator inhibitor type 1 (PAI-1) in the clearance of tissue-type plasminogen activator (t-PA) by hepatocyte-like cells was studied. Rat (Novikoff) hepatoma cells were able to bind and degrade t-PA in a PAI-1 independent fashion, but PAI-1 markedly increased the rate of degradation and t-PA/PAI-1 was a more efficient inhibitor of 125I-t-PA or of 125I-t-PA/PAI-1 degradation than free t-PA. Competition studies revealed that the effect of PAI-1 is unlikely to involve determinants located on the PAI-1 part of the complex: 1) an excess of free PAI had no effect on the rate of degradation of 125I-t-PA/PAI-1.2) Complexes of PAI-1 with urokinase-type PA or with a t-PA mutant lacking the finger and growth factor domains were unable to compete for the binding and degradation of free or PAI-1-complexed 125I-t-PA.3) t-PA KHRR296-299AAAA, a mutant which reacts 2 orders of magnitude slower with PAI-1 than wild type t-PA, behaved similar to wild type t-PA. The clearance via both the PAI-1-dependent and the PAI-1-independent mechanisms was inhibited by the receptor-associated protein, a general inhibitor of clearance mediated by the LDL receptor-related protein. We conclude that t-PA can be cleared by rat hepatoma cells in a PAI-1 independent fashion, but after complex formation with PAI-1, binding of t-PA to the cells is increased and clearance accelerated. Both mechanisms seem to involve the same receptor.

Animals↗
PubMed1993

[Effects of guan-mai-shu on tissue-type plasminogen activator and plasminogen activator inhibitor in the plasma of patients with coronary heart disease].

Effects of Guan-Mai-Shu (GMS), a traditional Chinese medicine preparation, on tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI) in the plasma of patients with coronary heart disease were studied. It was found that those patients had a significant decrease in t-PA activity (P < 0.05) and a significant increase in PAI activity (P < 0.01) compared to healthy subjects. After treatment of GMS, t-PA activity significantly increased (P < 0.001), while PAI activity decreased (P < 0.001). These results indicated that GMS could raise t-PA activity and reduce PAI activity in the plasma of patients with coronary heart disease.

Adult↗
PubMed1993

The role of type-1 plasminogen activator inhibitor in failure of thrombolytic therapy with recombinant tissue plasminogen activator.

We investigated the possible role of type-1 plasminogen activator inhibitor (PAI-1) on success or failure of thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA) in 10 responders and 10 non-responders with acute myocardial infarction and early initiation of therapy within 2 h of onset using the common infusion scheme (100 mg rt-PA over 3 h). We determined plasma levels of t-PA (activity and antigen) as well as PAI-1 (activity and antigen) in samples obtained before, during and after thrombolytic treatment and compared the course of each of those parameters between responders and non-responders to therapy. Success or failure of treatment was determined by a combination of noninvasive methods and proven by coronary angiography within 5 days of initiation of thrombolysis. Thirty, 60, 90, and 120 min after initiation of rt-PA infusion, specific t-PA activities in plasma of responders were 0.62, 0.63, 0.62, and 0.57 (IU/ng/ml), respectively, as compared to 0.42, 0.42, 0.40, and 0.32 (IU/ng/ml) in nonresponders (p < 0.001). Between 4 and 8 h after initiation of therapy, a time span known to be critical for thrombotic reocclusion, specific activities were still significantly elevated in responders as compared to non-responders (p < 0.01). PAI-1 activity levels, which were not detectable during rt-PA infusion in either group, recovered to pre-treatment values 2 h earlier in non-responders.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1993

[Evaluation of tissue plasminogen activator and plasminogen activator inhibitor-1 in blood obtained from patients of idiopathic central serous chorioretinopathy].

It is postulated that idiopathic central serous chorioretinopathy (ICSC) may be induced by a variety of underlying choroidal diseases capable of producing initially alterations in the permeability of the choriocapillaries. A history of unusual emotional stress frequently accompanies the onset of visual complaints. We have reported that alterations of serum lipids may exert a powerful effect on tissue plasminogen activator (t-PA) levels acting as a risk factor of variable cardioangiopathies. In this study, we evaluated the levels of t-PA activity, t-PA antigen and plasminogen activator inhibitor-1 (PAI-1) in blood from the patients with central serous chorioretinopathy, and compared them with the levels of total cholesterols (TCH), triglycerides (TG), and high-density lipoprotein cholesterol (HDL). t-PA activity levels and HDL were lower than in standard controls but t-PA antigen, PAI-1 antigen, and TG were higher. These facts may be associated with the pathogenesis or pathophysiological features of ICSC.

Adult↗
PubMed1993

Cytokine regulation of the synthesis of plasminogen activator inhibitor-2 by human vascular endothelial cells. Comparison with plasminogen activator inhibitor-1 synthesis.

Plasminogen activators are inhibited by plasminogen activator inhibitors-1 (PAI-1) and -2 (PAI-2). We describe the synthesis of PAI-2 by human vascular endothelial cells (EC) cultured from umbilical vein, saphenous vein and foreskin microvasculature in response to interleukin-1 alpha (IL-1 alpha) and tumour necrosis factor alpha (TNF alpha) and compare it with that of PAI-1. Both PAI-2 and PAI-1 were quantitated by ELISAs. PAI-2 was cell-associated while PAI-1 was secreted by EC. IL-1 alpha and TNF alpha increased the synthesis of PAI-2 and PAI-1 by EC in a dose-dependent manner. IL-1 alpha was a stronger stimulus for PAI-2 synthesis than TNF alpha, while both cytokines were equally effective for PAI-1. Northern blot analysis revealed similar changes in mRNA levels to those in antigen levels. PAI-2 synthesis by cytokine-stimulated EC may be important in thrombus formation and inflammation.

Cells, Cultured↗
PubMed1995

Diagnostic efficacy of plasma urokinase-type plasminogen activator and plasminogen activator inhibitor-2 in differentiation of hepatocellular carcinoma from cirrhosis.

We determined the plasma antigen levels of urokinase-type plasminogen activator(u-PA) and plasminogen activator inhibitor 2(PAI-2) in 41 patients with hepatocellular carcinoma and 28 patients with different stages of liver cirrhosis. No significant differences of u-PA and PAI-2 levels were calculated between the two groups of tumor patients (HCC) and liver cirrhosis without tumor (non-HCC). Within both study groups, no significant differences were found in u-PA and PAI-2 levels of the different Child categories. Discriminative functions of both u-PA and PAI-2 (total error count estimates of 43.1% and 43.6%, respectively), were low compared to that (29.0%) of alpha-fetoprotein (AFP). The combinations of AFP and u-PA lowered the total error rate (21.9%) more than that of each marker alone. However, whether plasma u-PA and PAI-2 may be considered as a risk factor further investigation was needed and our findings raise the question as to whether these markers could be considered as useful screening markers for earlier detection of HCC in liver cirrhosis because discriminant functions of u-PA and PAI-2 were not significant. Sensitivities and specificities of u-PA and PAI-2 were also not high enough, resulting in the ranges of total diagnostic efficiency from 43% to 50%, and, from 49% to 63%, respectively, at different cut-off values. No direct relationship was detected between AFP and u-PA, between AFP and PAI-2, and between u-PA and PAI-2.

Adult↗
PubMed1995

von Willebrand factor, soluble P-selectin, tissue plasminogen activator and plasminogen activator inhibitor in atherosclerosis.

Tissue plasminogen activator antigen (tPA), plasminogen activator inhibitor antigen (PAI-1), soluble P-selectin and von Willebrand factor antigen (vWf) were measured by ELISA in 41 patients with peripheral vascular disease (PVD), 41 with ischaemic heart disease (HD) and in 46 age and sex matched asymptomatic controls. Increased vWf was found in patients with IHD (p = 0.0002) and in patients with PVD (p = 0.0011) relative to the controls but levels did not differ between the two patients groups. Raised tPA found in both PVD (p = 0.0006) and IHD (p = 0.0061) compared to the controls also failed to differentiate the two groups of patients. Soluble P-selectin was also raised in both groups (p = 0.003 in IHD and p = 0.0102 in PVD) with no difference between the groups. There were no differences in levels of PAI-1 between the groups. In the subjects taken as a whole, there were significant Spearman's correlations between tPA and vWf (r = 0.37, p < 0.001), tPA and triglycerides (r = 0.38, p < 0.001), tPA and P-selectin (r = 0.19, p = 0.032), vWf and age (r = 0.25, p = 0.005) and inversely between vWf and HDL (r = -0.25, p = 0.006). These data support the concept that increased levels of tPA may be important in atherosclerosis, and indicate that soluble P-selectin may be useful in further analysis of the role of platelets and the endothelial cell in this disease.

Aged↗
PubMed1995

Characterization of the interaction of a complex of tissue-type plasminogen activator and plasminogen activator inhibitor type 1 with rat liver cells.

The present study was undertaken in order to determine the recognition site for tissue-type plasminogen activator-plasminogen activator inhibitor type 1 [t-PA-PAI-1] complexes in rat liver in vivo and in vitro. After intravenous injection into rats t-PA-PAI-1 complexes were rapidly removed from the plasma and the liver took up 80% of the injected dose. Within the liver parenchymal and endothelial liver cells contributed mainly to the uptake of t-PA-PAI-1, and were responsible for 62% and 24% of the liver uptake, respectively. The interaction of t-PA-PAI-1 with isolated rat parenchymal liver cells was of high affinity (Kd 17 nM). A well-known antagonist of the alpha 2-macroglobulin receptor (alpha 2MR/low-density lipoprotein receptor-related protein (LRP), GST-39kDa protein (GST-39kDaP) efficiently inhibited the binding (IC50 0.7 nM) of t-PA-PAI-1 to rat parenchymal liver cells. The interaction of t-PA-PAI-1 with LRP on rat parenchymal liver cells was not Ca2(+)-dependent and is most probably mediated by a specific determinant on PAI-1, since an anti-PAI-1 monoclonal antibody inhibited the binding of t-PA-PAI-1, where as free t-PA did not. The binding of t-PA-PAI-1 to rat hepatocytes could not be inhibited by a complex of plasmin and alpha 2-antiplasmin nor by various other ligands of LRP like beta-VLDL and lactoferrin. Binding of t-PA-PAI-1 to rat parenchymal liver cells was followed by internalization and subsequent degradation in the lysosomal compartment. It is concluded that parenchymal and endothelial liver cells mediate the removal of t-PA-PAI-1 complexes from the circulation. LRP on rat parenchymal liver cells is responsible for the uptake and degradation of t-PA-PAI-1 and may therefore be important for the regulation of the t-PA levels in the circulation.

Animals↗
PubMed1995

Comparative study of four extraction procedures for urokinase type plasminogen activator and plasminogen activator inhibitor-1 in breast cancer tissues.

The urokinase type plasminogen activator (u-PA) and the plasminogen activator inhibitor-1 (PAI-1) are among the best second-generation prognostic tissue factors in breast cancer. However, different extraction procedures and assay kits are used in different laboratories. A total of 79 breast tumour tissues stored in liquid nitrogen were analysed in this study. We compared u-PA and PAI-1 levels determined with the American Diagnostics (AD) kit after various extraction procedures. The median cytosolic extraction yield in the presence of 0.4 mol/l KCl, calculated relative to extraction in the presence of 10 ml/l Triton X100 when adapted to standard laboratory working hours (incubation for 2 h instead of 12 h) was 74.4% for u-PA and 85.8% for PAI-1. In addition, the correlations were acceptable. Cytosolic extracts prepared with KCl could permit optimal u-PA and PAI-1 assays while also enabling hormone receptors to be determined with the same specimens. Further studies with clinical data are now necessary to determine the prognostic relevance of this extraction procedure.

Breast Neoplasms↗
PubMed1996

Production of tissue-type plasminogen activator (t-PA) and type-1 plasminogen activator inhibitor (PAI-1) in mildly cirrhotic rat liver.

We have studied the production of tissue-type plasminogen activator (t-PA) and type-1 plasminogen activator inhibitor (PAI-1) in liver of normal rats and in rats with mild cirrhosis induced by carbon tetrachloride inhalation, to demonstrate the production of these fibrinolytic components and their pathophysiologic role in the liver in vivo. Immunohistochemical study of paraffin-embedded liver sections and fibrin autography of frozen sections showed that the normal rat liver produces very little t-PA or PAI-1. On the contrary, striking t-PA activity and both t-PA and PAI-1 antigens were observed in the cirrhotic liver. Both t-PA and PAI-1 in plasma were also markedly increased in the cirrhotic rats. Because the hepatocyte can internalize t-PA or PA/PAI-1 complexes from circulation, Northern blot analysis of the total liver RNA was performed to demonstrate the endogenous synthesis of t-PA and PAI in the liver. Although the normal liver hardly expresses either t-PA or PAI-1 mRNA, striking t-PA and PAI-1 mRNA expression was observed in the liver of rats with mild cirrhosis. These data demonstrate that t-PA and PAI-1 production is strongly upregulated in the liver in rats with mild cirrhosis. These fibrinolytic components, whose production is closely associated with liver failure, may play important roles in the regulation of hepatocyte proliferation and liver regeneration in vivo.

Animals↗
PubMed1996

Regulation of tissue-type plasminogen activator and plasminogen activator inhibitor type-1 in cultured rat Sertoli and Leydig cells.

New data are provided to show that (i) rat Sertoli cells produce two types of plasminogen activators, tissue type (tPA) and urokinase type (uPA), and a plasminogen activator inhibitor type-1 (PAI-1); (ii) both tPA (but not uPA) and PAI-1 secretion in the culture are modified by FSH, forskolin, dbcAMP, GnRH, PMA and growth factors (EGF and FGF), but not by hCG and androstenedione (delta 4); (iii) in vitro secretion of tPA and PA-PAI-1 complexes of Sertoli cells are greatly enhanced by presence of Leydig cells which produce negligible tPA but measurable PAI-1 activity; (iv) combination culture of Sertoli and Leydig cells remarkably increases FSH-induced PAI-1 activity and decreases hCG- and forskolin-induced inhibitor activity as compared with that of two cell types cultured alone. These data suggest that rat Sertoli cells, similar to ovarian granulosa cells, are capable of secreting both tPA and uPA, as well as PAI-1. The interaction of Sertoli cells and Leydig cells is essential for the cells to response to hormone stimulation for tPA and PAI-1 secretion.

Animals↗