Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In a previous study, we found particular proteases which degrade myelin basic protein (MBP) in a conditioned medium of cultured rat brain microglia. The MBP degrading activity in microglial-conditioned medium (Mic-CM) increased markedly in the presence of plasminogen. By Sephadex G-150 column chromatography, plasminogen-dependent MBP degrading activity was eluted at the position of about 47 kDa and 28 kDa. Furthermore slight plasminogen-dependent protease activity in the presence of fibrin (tissue plasminogen activator activity) was detected at a molecular weight of about 68 kDa. The two molecular forms (47 kDa and 28 kDa) of plasminogen-dependent protease were demonstrated by casein-zymography, and it was suggested that they were urokinase type-plasminogen activators (uPA). This suggestion was confirmed by immunoblotting using anti-uPA antiserum. The unique 28 kDa type was considered to be produced from the 47 kDa form by limited proteolysis. Secretion of PA from microglia was demonstrated by cell zymography. In contrast, significant secretion of plasminogen activator inhibitor could not be detected in the Mic-CM. In addition, lipopolysaccharide significantly decreased the secretion of PA from microglia, while interleukin-1 and basic fibroblast growth factor enhanced the secretion.
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PMID:Microglia isolated from rat brain secrete a urokinase-type plasminogen activator. 137 34

Peripheral blood monocytes are essential participants in processes that require pericellular plasminogen activation, a regulated proteolytic pathway that is greatly influenced by the relative concentrations of urokinase-type plasminogen activator (profibrinolytic) and plasminogen activator inhibitor type 2 (PAI-2) (anti-fibrinolytic). Monocyte synthesis of these molecules is inducible by bacterial lipopolysaccharide (LPS) although PAI-2 production is regulated over a much wider concentration range than is urokinase-type PA. The PAI-2 response of LPS-stimulated monocytes was investigated and found to be biphasic, with a peak of mRNA at 4-6 h after stimulation, a decrement in mRNA levels at 8-10 h, and a secondary increase at 16 h. The primary (early phase) response was studied in detail wherein PAI-2 protein production was found to depend on the levels of PAI-2 mRNA. The profiles of steady-state PAI-2 mRNA levels and PAI-2 protein production were parallel with respect to LPS concentration, time of exposure to LPS, and persistence of the response. PAI-2 mRNA accumulation was inducible by cycloheximide but prevented by actinomycin D. The increase in steady-state PAI-2 mRNA was mediated both by an increase in gene transcription and by stabilization of the mRNA once formed. Therefore, the initial phase of PAI-2 production by LPS-stimulated monocytes is determined by the amount of PAI-2 mRNA in these cells; levels of PAI-2 mRNA are controlled by several mechanisms, allowing for rapid variations in production of this molecule.
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PMID:Regulation of plasminogen activator inhibitor mRNA levels in lipopolysaccharide-stimulated human monocytes. Correlation with production of the protein. 155 15

The second messengers and protein kinases involved in the induction of type I plasminogen activator inhibitor (PAI-1) synthesis by various agents were evaluated in cultured bovine aortic endothelial cells. Phorbol myristate acetate (PMA) induced PAI-1 in these cells implicating the protein kinase C (PK-C) pathway. However, bradykinin, which also activates PK-C in bovine aortic endothelial cells, did not induce PAI-1. Moreover, when PK-C was down-regulated by PMA pretreatment, subsequent induction of PAI-1 by transforming growth factor beta (TGF beta) and tumor necrosis factor alpha (TNF alpha) was unaltered, and induction by lipopolysaccharide (LPS) was decreased by only 50%. LPS increased phospholipid second messengers which can activate PK-C but TGF beta and TNF alpha did not. Agents which increase cAMP, (e.g., forskolin and isobutylmethylxanthine) blocked the induction of PAI-1 synthesis by PMA, LPS, TGF beta and TNF alpha suggesting that induction may occur by lowering cAMP. This possibility seems unlikely since cAMP levels did not change in response to any of these agents. Moreover, somatostatin lowered cAMP but did not induce PAI-1. PAI-1 was not induced by treating the cells with cGMP, Na+/H+ ionophore and calcium ionophore or arachidonic acid.
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PMID:Regulation of type I plasminogen activator inhibitor synthesis by protein kinase C and cAMP in bovine aortic endothelial cells. 165 42

We wanted to determine the effects of WEB 2086, a platelet activating factor (PAF) antagonist, in lipopolysaccharide (LPS) shock in anesthetized pigs. In a randomized study, LPS from S. abortus equi, 2 micrograms/kg/h was given IV for six hours. Thirteen animals received LPS and WEB 2086, 10 mg/kg/h IV for 6.5 hours, beginning 30 minutes before LPS. Eleven septic controls received saline and LPS, three nonseptic controls received saline and WEB 2086, and three nonseptic controls received saline only. In six animals we investigated the effect of synthetic PAF in doses between 50 and 10,000 ng on arterial (AP) and pulmonary arterial (PAP) pressure before and during infusion of WEB 2086. The LPS-induced rise in PAP was reduced by WEB 2086 (p = 0.01) but not the decrease in AP. The LPS-induced leukopenia, hypoxia, increase in airway pressure, and release of plasminogen activator inhibitor were reduced by WEB 2086. Platelet activating factor produced an increase in PAP and a biphasic response in AP. All PAF dose response curves were shifted to the right by WEB 2086. Platelet activating factor was a pulmonary hypertensive agent and contributed to the LPS-induced respiratory alterations.
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PMID:A triazolodiazepine platelet activating factor receptor antagonist (WEB 2086) reduces pulmonary dysfunction during endotoxin shock in swine. 190 48

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

Transforming growth factor-beta (TGF beta) is a growth modulator that stimulates the growth of fibroblastic cells but inhibits the growth of cells of epithelial origin. TGF beta also influences the production of extracellular matrix proteins, and of proteases and the type 1 plasminogen activator inhibitor (PAI-1) by cultured cells. TGF beta appears also to have various immunoregulatory effects, suppressing both T- and B-cell activities. It has been proposed that it might increase the expression of interleukin-1 (IL-1) mRNA in cultured human monocytes, thus potentiating immune functions. To analyze the role of TGF beta in IL-1 production we have now quantitated the effect of this factor on the production of biologically active IL-1 as well as IL-1 beta mRNA expression. The effect of TGF beta on IL-1 production optimally activated with bacterial lipopolysaccharide (LPS) was also studied. It was found that IL-1 activity and mRNA levels were rapidly elevated by LPS but not by TGF beta. Culture fluids from monocytes treated with TGF beta alone or with TGF beta plus LPS inhibited the proliferation of the test thymocytes. After gel filtration, the media from TGF beta-treated cultures showed no activity in the molecular weight area of IL-1 (approx. 15 kD), while the supernatants from TGF beta plus LPS-induced cells contained IL-1 activity in these fractions, the magnitude of which was, however, at the same level as in the culture fluids derived from cells stimulated with LPS alone.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Transforming growth factor-beta does not alter interleukin-1 expression in cultured human macrophages. 247 Jul 67

Peripheral blood mononuclear cells (PBMs) produce both tissue factor and plasminogen activator inhibitor type 2 (PAI-2) in response to gram-negative bacterial lipopolysaccharide (LPS). The cellular roles in the tissue factor response have been previously elucidated, and we now report those roles in PAI-2 production. Monocytes are the only cells among LPS-stimulated PBMs that produce PAI-2 as assessed by measurement of PAI-2 activity and antigen. Concomitant immunohistochemistry demonstrated that monocytes contain PAI-2, with a greater number staining positively and more intensely after exposure to LPS. LPS-stimulated monocytes produced increased amounts of PAI-2 with or without addition of lymphocytes. Lymphocytes prestimulated with LPS and then washed did not induce PAI-2 production in monocytes to which they were added. Lipid X, a precursor in the biosynthetic pathway of lipid A and LPS, was able to inhibit LPS induction of monocyte PAI-2 in a dose-dependent manner. This inhibition was not due to cellular toxicity, the phospholipidlike nature of lipid X, interference with the PAI-2 assay, or monocyte production of a substance interfering with PAI-2. Lipid X was an effective inhibitor of PAI-2 production even when added up to 30 minutes after LPS.
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PMID:Endotoxin-induced production of plasminogen activator inhibitor by human monocytes is autonomous and can be inhibited by lipid X. 247 61

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


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