Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Lysates of rat (Rattus norvegicus, Wistar strain) peritoneal macrophages selected by adherence were analysed for procoagulant activity (PCA) and plasminogen activator activity (PAA). 2. PCA is expressed following in vitro stimulation by lipopolysaccharide and in vivo (respectively 118 +/- 19.1 and 147.2 +/- 45.2 mUnits/10(6) M phi) very early after the intraperitoneal injection of thioglycollate. 3. PAA present in 24 hr thioglycollate stimulated cells (79.5 +/- 26.1 mI.U./10(6) M phi), disappears in a time dependent fashion after in vitro lipopolysaccharide stimulation. 4. Our findings indicate that rat peritoneal macrophages regulate their coagulolytic activities in a specific manner. 5. Rat peritoneal cavity may be proposed as a model for the study of inflammatory reaction with PCA and PAA as its indexes.
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PMID:Rat peritoneal macrophage procoagulant and fibrinolytic activities. An expression of the local inflammatory response. 167 89

Vascular endothelial cells undergo morphological and functional changes at sites of cell-mediated immune responses which may serve to promote the pathogenesis of inflammation. These changes, described as "endothelial cell activation" can be invoked by a variety of cytokines which include interleukin I (IL-1), tumor necrosis factor (TNF), and lipopolysaccharide (LPS). We report here on the regulation of the plasminogen activator (PA) proteolytic system by human recombinant TNF alpha in short term cultures (less than 4 passages) of human umbilical vein endothelial cells (HUVECs). TNF alpha treatment of HUVECs enhanced the production of 55 kDa urokinase (u) PA activity and uPA antigen by fourfold, in a concentration dependent manner (5-100 U/ml), following a 24 h treatment as determined by PA zymography and micro-ELISA assays, respectively. This response was specific for uPA since, no change in extracellular tissue type PA activity and tPA antigen levels were noted under analogous conditions. A similar 4-fold increase in the de novo synthesis of [35S]-methionine radiolabeled uPA was observed by immunoprecipitation following a 24 h TNF treatment. The induction of uPA by TNF was inhibited by actinomycin D and cycloheximide implying the necessity of RNA and protein synthesis, respectively. The effect of TNF could not be prevented by the addition of IL-1 neutralizing antibodies. Therefore, it is unlikely that TNF acts through the induction of IL-1 secretion. Time course studies using PA zymography indicate that within 8 h after TNF exposure, a 2-fold increase in uPA activity above untreated basal levels was observed. Upregulation of extracellular uPA production in HUVECs following TNF treatment suggests yet a new aspect of cellular and interstitial PA regulation in endothelium during inflammation and angiogenesis.
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PMID:Tumor necrosis factor induction of urokinase-type plasminogen activator in human endothelial cells. 180 6

Granulocyte-macrophage colony-stimulating factor (GM-CSF) raised the plasminogen activator (PA) activity of cultured human monocytes. This activity was characterized to be urokinase-PA (u-PA) by incubation with specific IgG and by sodium dodecyl sulfate-polyacrylamide gel electrophoresis zymography. Increased u-PA activity reflected GM-CSF-induction of u-PA mRNA levels. The stimulatory properties of GM-CSF for monocyte PA activity differed from those of interleukin-4, which induced monocyte tissue-type PA (t-PA) activity, and of interferon-gamma (IFN-gamma), which alone was not stimulatory but augmented lipopolysaccharide-induced t-PA activity. GM-CSF alone did not stimulate detectable monocyte t-PA activity but combined with IFN-gamma to promote this activity. Plasmin formation arising from GM-CSF-induced u-PA in monocytes may contribute to the matrix turnover involved in, eg, cell migration and inflammation, and may explain some of the pathology seen in GM-CSF transgenic mice.
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PMID:Activation of human monocytes by granulocyte-macrophage colony-stimulating factor: increased urokinase-type plasminogen activator activity. 189 23

The type of plasminogen activator (PA) produced by bovine milk macrophages has been determined. Macrophages produce a PA protein with molecular weight of 28,000 and isoelectric point of 8.5, and with enzymatic activity independent of fibrin. These characteristics are identical to those reported for bovine urokinase-PA. Although blood monocytes and milk macrophages produce PA after stimulation with lipopolysaccharide, mammary macrophages are clearly limited in their ability to release PA. At maximal stimulation, 78% of the PA produced by milk macrophages remained cell-associated. In marked contrast, blood monocytes released 76% of the PA produced into the culture medium. Macrophages isolated from mastitic quarters produced higher (2.5 times) amounts of PA, compared with those produced by macrophages isolated from healthy quarters. However, in both cases, macrophages were unable to secrete the protein already produced. The limited PA secretion by milk macrophages might be a residual function of a differentiated macrophage population.
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PMID:Plasminogen activator production by bovine milk macrophages and blood monocytes. 192 1

Tumor necrosis factor (TNF) induced by bacterial lipopolysaccharide (LPS) was shown to have an important role in precipitation of septic shock and disseminated intravascular clotting (DIC). At the endothelial level TNF down-regulates thrombomodulin (thus preventing protein C formation) and inhibits the production of tissue plasminogen activator (t-PA), thus impairing anticoagulant mechanisms. On the other hand, TNF up-regulates the production of procoagulant factors such as t-PA inhibitor (PAI), tissue factor and platelet activating factor (PAF). These effects create an imbalance between procoagulant and anticoagulant mechanisms, in favor of the former. TNF also activates polymorphonuclears (PMNs), and increases their chemotaxis and adherence to endothelial surfaces by up-regulation of specific endothelial (ELAM-1) and PMN (CDw18) adherence proteins. The damage inflicted by activated PMN to the endothelial cell promotes tissue factor exposure and PAI release, with initiation of the characteristic explosive coagulation process of DIC, facilitated by the dissociation between pro- and anticoagulant mechanisms induced by TNF. These newly discovered mechanisms precipitating septic shock and DIC enable consideration of new treatments for this condition as anti-TNF antibodies or TNF inhibitors, anti-ELAM-1 antibodies anti-tissue factor antibodies, administration of activated factor C, etc. These therapeutic approaches may revolutionize the treatment of septic shock and DIC in the next decade.
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PMID:Role of tumor necrosis factor in the pathogenesis of intravascular coagulopathy of sepsis: potential new therapeutic implications. 199 4

Immunogold EM was employed to compare the distribution of type 1 plasminogen activator inhibitor (PAI-1) on the surface of agonist-activated human umbilical vein endothelial cells (HUVECs) with that of control, unactivated cells. As previously observed, (Schleef, R.R., T.J. Podor, E. Dunne, J. Mimuro, and D.J. Loskutoff. J. Cell Biol. 110:155-163), analysis of cross-sections of nonpermeabilized control HUVEC monolayers stained first with affinity-purified rabbit antibodies to PAI-1 and then with gold-conjugated goat anti-rabbit IgG, revealed the presence of relatively few gold particles (less than 1-2% of the total) on the apical cell surface. The majority of gold particles were detected primarily in the extracellular matrix between the culture substratum and the cell membrane. In contrast, treatment of HUVECs with tumor necrosis factor alpha (TNF alpha; 200 U/ml, 24 h) or with lipopolysaccharide (LPS; 10 micrograms/ml, 24 h) resulted in an increased staining of PAI-1 not only in the extracellular matrix, but also on the apical cell surface (10-fold increase). Immunoabsorption of the rabbit anti-PAI-1 with purified PAI-1, or treatment of HUVECs with tissue-type plasminogen activator (2.5 micrograms/ml, 2 h, 4 degrees C) reduced the amount of staining both on the apical surface and in the extracellular matrix of agonist-activated HUVECs by 80-95%. The topographical location of PAI-1 on the cell surface was examined further by coupling immunogold staining with high resolution surface replication. Transmission EM of surface replicas from TNF alpha- or LPS-activated HUVECs revealed a general increase in PAI-1 staining both on planar regions and within indentations of the apical cell surface. Nonactivated HUVECs revealed PAI-1-specific immunogold particles only in areas of exposed extracellular matrix between the cells and occasionally at regions of cell-cell contacts. Analysis of activated bovine aortic endothelial cells by immuno-electron microscopy, immunologic assays, and flow cytometry revealed similar increases in surface PAI-1. These increases in surface PAI-1 could be detected by 3 h and continued over a 24-h period. The expression of PAI-1 on the luminal surface of endothelial cells during immune or inflammatory reactions could reduce endothelial fibrinolytic activity, thus, promoting the localized, pathologic formation of intravascular thrombi.
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PMID:Immunoelectron microscopic localization of type 1 plasminogen activator inhibitor on the surface of activated endothelial cells. 204 19

It has been reported that omental fat tissue is a good source of human microvascular endothelial cells. By characterization we demonstrate that the epitheloid cells isolated from omental tissue are not endothelial cells, but mesothelial cells. They contain abundant cytokeratins 8 and 18, which are absent in endothelial cells, and vimentin. No staining with the endothelial-specific antibodies EN-4 and PAL-E is observed. A faint and diffuse staining of von Willebrand factor (vWF) is seen in mesothelial cells, whereas microvascular endothelial cells from subcutaneous fat display vWF in distinct granular structures. Human peritoneal mesothelium produces plasminogen activator-dependent fibrinolytic activity, which is essential in the resolution of fibrous exudates and may therefore be important in preventing the formation of fibrous peritoneal adhesions. This fibrinolytic activity is plasminogen activator-dependent, but has not been fully characterized. We report here that human omental tissue mesothelial cells in vitro produce large amounts of tissue-type plasminogen activator (t-PA), together with type 1 and 2 plasminogen activator inhibitor (PAI-1 and PAI-2). PAI-1 is predominantly secreted into the culture medium, whereas the major part of PAI-2 is found in the cells. No urokinase-type plasminogen activator is detected. On stimulation with the inflammatory mediator tumor necrosis factor (TNF), at least a threefold decrease in t-PA antigen is observed, together with an increase in both PAI-1 and PAI-2. TNF also induces a marked change in cell shape. Whereas TNF and bacterial lipopolysaccharide (LPS) have similar effects on the production of PA inhibitor by human endothelial cells, LPS has no or only a relatively small effect on the fibrinolytic properties of mesothelial cells. The decreased fibrinolytic activity induced by the cytokine TNF may impair the natural dissolution of fibrin deposits at the peritoneum in the presence of an inflammatory reaction.
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PMID:Characterization and fibrinolytic properties of human omental tissue mesothelial cells. Comparison with endothelial cells. 210 84

Plasma levels of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI) and the in vitro ability of platelets to aggregate and of monocytes to express procoagulant (tissue factor) activity (PCA) were evaluated in five patients who are homozygous for familial hypercholesterolemia (FH) before and after a single and a regular 5-month cholesterol removal by low density lipoprotein (LDL) apheresis. The biweekly procedure resulted in a 25% to 30% reduction (approximately 150 mg/dl) in total and LDL cholesterol (both were greater than 550 mg/dl at the beginning of the study). The basal levels of t-PA antigen and fibrinolytic activity before and after 10 minutes of venous stasis, basal PAI activity, and PAI-1 antigen were comparable to controls and were not affected by LDL apheresis. Likewise, regardless of the cholesterol removal, the PCA of freshly isolated monocytes and that of monocytes incubated with lipopolysaccharide did not differ from control values. Finally, the pre-apheresis sensitivity of platelets to adenosine diphosphate, arachidonic acid, and collagen was 1.5 to 2 times the normal value. This ratio was unchanged throughout the 5-month procedure. We conclude that fibrinolysis and monocyte PCA are normal in FH patients, whereas platelet aggregation is abnormally high, and none of these parameters is significantly affected by a 25% to 30% reduction in total and LDL cholesterol by LDL apheresis. Furthermore, our data suggest that removal of cholesterol from plasma by LDL apheresis is important for gaining insight into the mechanisms involved in the ischemic complications of arteriosclerosis in FH patients.
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PMID:Hemostatic variables in homozygous familial hypercholesterolemia. Effect of regular plasma cholesterol removal by low density lipoprotein apheresis. 212 91

To identify factors responsible for the decline of plasma tissue-type plasminogen activator (t-PA)-specific activity that we have observed after infusions of the activator and to define the potential usefulness of selected variants of t-PA in obviating them in patients with infarction, serial plasma samples from patients (n = 4) and rabbits (n = 15) given t-PA were assayed for total t-PA antigen, t-PA activity, and free as opposed to type-1 plasminogen activator inhibitor (PAI-1)--complexed t-PA. In patients, attenuation of t-PA specific activity after infusions was evident with concentrations of total t-PA antigen that were as much as sevenfold greater than pretreatment values (62 compared with 9 ng/ml). Attenuation of t-PA activity corresponded with the disappearance of free t-PA from plasma and was associated with persistence of complexes of t-PA with PAI-1. In normal rabbits (n = 4) given wild-type t-PA by bolus injection, PAI-1 activity was 4 +/- 1 arbitrary units/ml. Attenuation of t-PA activity was not evident until 60 minutes after injection at a time when total plasma t-PA antigen concentration was as low as 13 +/- 8 ng/ml. Under these conditions, plasma t-PA was composed predominantly of free t-PA. In rabbits (n = 5) given lipopolysaccharide to increase plasma PAI-1 activity to 193 +/- 84 arbitrary units/ml, the specific activity of t-PA was attenuated as early as 15 minutes after injection at a time when total t-PA antigen concentration was as high as 164 +/- 79 ng/ml. As was the case with samples from patients, attenuation was associated with the disappearance of free t-PA and the persistence of complexes of t-PA with PAI-1. A genetically engineered variant of t-PA with comparable specific activity and a comparable rate constant of association with PAI-1 but designed to persist in the circulation manifested prolonged clearance from plasma of normal rabbits (n = 3) (t1/2 = 24.6 +/- 1.6 minutes compared with an alpha phase t1/2 of 1.9 minutes for wild-type t-PA). The variant lacked the epidermal growth factor and kringle one domains and contained a duplicated kringle two domain.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Dependence of fibrinolytic activity on the concentration of free rather than total tissue-type plasminogen activator in plasma after pharmacologic administration. 249 4

We have examined the effects of bacterial lipopolysaccharide (endotoxin) on the fibrinolytic activity of bovine pulmonary artery endothelial cells. Endotoxin suppressed the net fibrinolytic activity of cell extracts and conditioned media in a dose-dependent manner (threshold dose, 0.1 ng/ml; maximal dose, 10-100 ng/ml). The effects of endotoxin required at least 6 h for expression. Cell extracts and conditioned media contained a 44-kDa urokinase-like plasminogen activator. Media also contained multiple plasminogen activators with molecular masses of 65-75 and 80-100 kDa. Plasminogen activators in extracts and media were unchanged by treatment of cells with endotoxin. Diisopropyl fluorophosphate (DFP) abolished fibrinolytic activity of extracts and conditioned media. DFP-treated samples from endotoxin-treated but not untreated cells inhibited urokinase and tissue plasminogen activator, but not plasmin. Inhibitory activity was lost by incubation at pH 3 or heating to 56 degrees C for 10 min. These treatments did not affect inhibitory activity of fetal bovine serum. Incubation of 125I-urokinase with DFP-treated medium from endotoxin-treated cells produced an inactive complex with an apparent molecular mass of 80-85 kDa. The complex could be detected by chromatography on Sephadex G-100, but not by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. These findings suggest that low doses of endotoxin suppress fibrinolytic activity in endothelial cells by stimulating the production or expression of a fast-acting, relatively labile inhibitor of plasminogen activator.
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PMID:Endotoxin induction of an inhibitor of plasminogen activator in bovine pulmonary artery endothelial cells. 307 53


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