UNIPROT:P43026 - FACTA Search

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Query: UNIPROT:P43026 (lipopolysaccharide)
62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intra-alveolar fibrin deposition accompanies many forms of inflammatory lung injury. Appropriate clearance of this fibrin matrix is important for normal healing and remodeling. The local generation of plasmin by the action of plasminogen activators (PAs) represents a pivotal step in the fibrinolytic process. To investigate whether the alveolar epithelium plays a role in the modulation of intra-alveolar fibrinolysis, we have studied PA regulation by rat pulmonary alveolar epithelial cells. We have found large quantities of PA activity both in conditioned media and cell lysates from epithelial monolayers in culture. Casein-plasminogen zymography reveals that this PA activity migrates as a tight doublet with an apparent mol wt of 45 kD, clearly distinct from rat tissue-type PA (tPA, greater than 68 kD). Analysis of freshly isolated type II alveolar epithelial cells demonstrates readily measurable PA activity in cell lysates, as well as expression of urokinase-type PA (uPA) mRNA on Northern blot analysis. Upregulation of PA activity occurs progressively with time in culture as the alveolar epithelial cells lose type II cell characteristics and become more flattened. Stimulation of alveolar epithelial cell monolayers with lipopolysaccharide or tumor necrosis factor increases levels of secreted PA activity. The relative abundance of uPA mRNA was shown to change in parallel with PA activity during in vitro differentiation or after exposure to inflammatory mediators. Thus, alveolar epithelial cells are likely an important source of uPA in the lung, the expression of which is influenced by the state of cellular differentiation as well as the presence of inflammatory mediators.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression of urokinase-type plasminogen activator by rat pulmonary alveolar epithelial cells. 212 Nov 71

Plasminogen activator inhibitor 2 (PAI-2) plays an essential role in the regulation of localized extracellular proteolysis by its inactivation of urokinase. Using probes derived from a cDNA we isolated from lipopolysaccharide (LPS)-stimulated human peripheral blood monocytes, we have mapped, isolated, and determined the molecular organization of the gene for PAI-2 (PLANH2). In situ hybridization of the cDNA to normal metaphase chromosomes has confirmed our prior assignment of the gene for PAI-2 to chromosome 18 and further localized it to the long arm at 18q21.2-18q22. We have isolated nine independent genomic clones, two of which were found to contain the entire PAI-2 transcriptional unit of approximately 16.4 kilobase pairs (kbp). Analysis of the gene organization by restriction enzyme mapping, Southern blotting, and DNA sequencing revealed that the cDNA sequence is divided among eight exons interrupted by seven introns, the junctions of which all conform to the "GT-AG" consensus rule. In common with the arrangement found throughout, the serpin superfamily, of which PAI-2 is a member, the first intron is located just 5' to the initiator methionine residue, and the 3' untranslated region (UTR) is not interrupted by a splice junction. Determination of the transcription initiation site by primer extension analysis of monocytic mRNA indicated that our PAI-2 cDNA was, at most, only three nucleotides short of full length, yielding a primary PAI-2 transcript with a 66-bp first exon. A promoter "TATAAAbox" is located 30 bp upstream of the "cap" site.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Chromosomal organization and localization of the human urokinase inhibitor gene: perfect structural conservation with ovalbumin. 230 56

Cultured bovine aortic endothelial cells (BAEs) synthesize and secrete type 1 plasminogen activator inhibitor (PAI-1), an Mr 50,000 glycoprotein which inhibits both urokinase and tissue-type plasminogen activators. The synthesis of PAI-1 in BAEs is positively regulated by a variety of agents. To elucidate the mechanisms which govern expression of the PAI-1 gene, total cytoplasmic RNA was prepared from BAEs and analyzed by Northern blotting using a 1.3-kilobase (kb) human PAI-1 cDNA probe. Hybridization under conditions of high stringency revealed two bovine PAI-1 RNA species, 3.0 and 1.6 kb in length. The ratio of the two species was approximately 4:1. The 3.0-kb mRNA was bound by oligo(dT)-cellulose, whereas the 1.6-kb form was not, suggesting that the latter form lacked a poly(A) terminus. Treatment of BAEs with transforming growth factor beta (TGF-beta), bacterial lipopolysaccharide (LPS), or tumor necrosis factor alpha (TNF-alpha) markedly enhanced the steady-state levels of both RNA species. In each case, increases were detectable within 1 h, and maximal effects (i.e. greater than 30-fold increase) were observed between 6 and 18 h of treatment, followed by a decline to near-basal levels by 48 h. The response to each of these agents was dose-dependent, with maximal induction observed at concentrations of 10 ng/ml TGF-beta, 10 ng/ml LPS, and 25 ng/ml TNF-alpha. Induction of PAI-1 mRNA by these agents was not blocked by the protein synthesis inhibitor cycloheximide, suggesting that de novo protein synthesis was not required. In fact, treatment with cycloheximide (2 micrograms/ml) alone also increased PAI-1 mRNA levels. Treatment with cycloheximide in combination with TGF-beta, LPS, or TNF-alpha further enhanced the accumulation of PAI-1 mRNA. Nuclear transcription run-on experiments indicated that these agents elevated the rate of PAI-1 gene transcription 20-30-fold and that gene template activity was temporally correlated with the accumulation of PAI-1 mRNA. These data are consistent with the conclusion that the observed increases in PAI-1 steady-state mRNA levels result from primary effects of these agents on the rate of PAI-1 gene transcription.
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PMID:Regulation of type 1 plasminogen activator inhibitor gene expression in cultured bovine aortic endothelial cells. Induction by transforming growth factor-beta, lipopolysaccharide, and tumor necrosis factor-alpha. 249 79

The effect of lipopolysaccharide (LPS) on the production of fibrinolytic inhibitor by human endothelial cells was determined because results of previous experiments have shown us that it is possible to stimulate this synthesis with muramyl dipeptide. Treatment of these cells with LPS resulted in a marked enhancement of fibrinolytic inhibitor, as estimated in a urokinase-induced fibrinolysis assay. A dose-response curve was obtained for LPS concentrations ranging from 10 to 1,000 ng/ml, thus demonstrating the great sensitivity of these cells. This inhibitor did not reduce plasmin activity and formed complexes with high- and low-molecular-weight urokinase as visualized by fibrin enzymography on sodium dodecyl sulfate-polyacrylamide electrophoretic gels. The molecular weight of this inhibitor was estimated to be 54 to 58 kilodaltons. These findings led us to conclude that LPS stimulates formation of a plasminogen antiactivator. This LPS effect could be suppressed by polymyxin B and colimycin. The stimulatory effect of muramyl dipeptide required doses which were at least 1,000 times greater than those of LPS and was not decreased by polymyxin B. These results show the possibility of independent modulation of plasminogen antiactivator production at the endothelial level, which could be important in endotoxemia. Under these conditions colimycin might have an additional advantage for clinical use because of its ability to prevent fibrinolytic inhibition.
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PMID:Effect of polymyxin B and colimycin on induction of plasminogen antiactivator by lipopolysaccharide in human endothelial cell culture. 301 72

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

Experimental thrombosis which developed exclusively in glomerular capillary walls was induced in rats by the combined injection of nephrotoxic antiserum (0.2 ml of pooled material) as a preparatory agent and 20 micrograms or more of lipopolysaccharide as a provoking agent. Effects of some antiplatelet and anticoagulant drugs on the glomerular lesions were tested in this experimental glomerular thrombosis. With administration of 2000 units/kg or more of heparin at the time of provoking injection, coagulation time was prolonged for over 5 hr, and the glomerular thrombosis was adequately prevented. Prolongation of prothrombin time (PT) for over 60 sec to prevent thrombosis required warfarin, but with this drug there was only a narrow margin between an effective dose and that which produced a fatal hemorrhage. Low levels of fibrinogen (less than 50 mg/dl) induced by batroxobin seemed to protect partially and high doses of urokinase did not seem to protect from glomerular thrombosis. OP-41483, a derivative of prostacyclin which is about five times more active than PGE1 in inhibiting platelet aggregation, and other anti-platelet drugs except for ticlopidine were not effective in preventing glomerular thrombosis. These findings were in accordance with the fact that thrombocytopenia induced by antiplatelet antiserum did not prevent glomerular thrombosis. Ticlopidine may have a unique and valuable therapeutic potential for the control of this condition.
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PMID:Effect of drug administration on experimental renal glomerular thrombosis. 328 90

Human peripheral blood mononuclear cells (PBM) respond to lipopolysaccharide (LPS) with increased release of a plasminogen activator (PA) inhibitor. This response is dose dependent and parallels the LPS-induced expression of PBM tissue factor activity. The PA inhibitors of control and LPS-stimulated PBMs appear identical as both are identified by antibodies to PA inhibitor type 2 of human placenta, but not by antibodies to type 1 inhibitor of bovine aortic endothelial cells. The PA inhibitor is specific for urokinase type PA as determined by the 125I-fibrin plate assay, and direct cleavage of 125I-plasminogen; it does not effectively inhibit tissue-type PA. The inhibitor forms an active site-dependent complex with 125I-urokinase, which then demonstrates an increase in mol wt from 33 kd to 68 kd on reduced sodium dodecyl sulfate (SDS) polyacrylamide gels. PBMs neither secrete nor express active PA. Hence, the exposure of PBMs to LPS results in conditions highly favorable to fibrin deposition and persistence: increased procoagulant and antifibrinolytic activities, accompanied by no measurable PA. Such modulation of these effectors may be important in the pathogenesis of fibrin characteristically found in tissue lesions of endotoxin-initiated processes.
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PMID:Increased release of plasminogen activator inhibitor type 2 accompanies the human mononuclear cell tissue factor response to lipopolysaccharide. 334 43

Human milk was shown to contain prostaglandin E2 (PGE2) and plasminogen activator (PA) at variable concentrations depending on the time of lactation after delivery. Milk PA was functionally and immunologically identical to urokinase. A follow-up study showed that the maximum PGE2 concentrations occurred during the second week while the maximum PA concentration was observed at the end of the first week of lactation. Milk macrophages cultured in vitro were able to secrete both PGE2 and PA. When cells were activated by concanavalin A (ConA) or E. coli lipopolysaccharide (LPS), PGE2 secretion increased dramatically while PA secretion did not. The ability of activated macrophages to secrete PGE2 was at its highest shortly after delivery. It then progressively decreased during lactation. The possible physiological role of PGE2 and PA on the gastrointestinal tract of breast fed infants is discussed.
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PMID:Prostaglandin E2 and plasminogen activators in human milk and their secretion by milk macrophages. 346 15

Endotoxin producing bacteria cause disseminated intravascular coagulation (DIC); however, the mechanism of endotoxin action in man is still unclear. Impairment of the fibrinolytic system has been suggested as a contributing mechanism. A single injection of Escherichia coli lipopolysaccharide in rabbits resulted in a marked and prolonged increase of the levels of a fast-acting inhibitor of plasminogen activator (PA-inhibitor) in plasma (from 3.9 +/- 0.7 to 41 +/- 13.2 U/ml after 3 h). Gel filtration studies indicated that inhibition of human tissue-type plasminogen activator (t-PA) by rabbit plasma is accompanied by a change in the elution profile of the activator compatible with the formation of an enzyme-inhibitor complex with an apparent molecular weight of 100,000. Injection of human t-PA (1,500 IU/kg body wt) in endotoxin treated animals resulted in very fast inhibition of t-PA and formation of a similar complex. The half-life of circulating PA-inhibitor activity in rabbits was about 7 min as estimated by donor receiver plasma transfusion experiments. Stimulation of cultured human endothelial cells with endotoxin resulted in enhanced rate of accumulation of PA-inhibitor activity in the culture medium (two- to sevenfold increase). In five patients with septicemia, markedly increased levels of PA-inhibitor (14.3 +/- 15.5 U/ml) as compared with control subjects (1.3 +/- 0.7 U/ml) were observed in plasma. A very strong correlation (r = 0.98) was found between inhibition of t-PA and of urokinase in all conditions, suggesting that this fast-acting inhibitor reacts with both plasminogen activators. These data suggest that the appearance of this fast-acting PA-inhibitor is very sensitive to endotoxin stimulation. The marked increase in the level of PA-inhibitor in blood may contribute to the pathogenesis of DIC in septicemia.
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PMID:Generation in plasma of a fast-acting inhibitor of plasminogen activator in response to endotoxin stimulation. 392 Feb 45

Human peripheral monocytes stimulated by either muramyl dipeptide [N-acetyl-muramoyl-L-alanyl-D-isoglutamine], bacterial lipopolysaccharide or lymphokine-containing supernatants of human lymphocytes, could be shown to produce and secrete appreciable activities of a 52 000-Mr plasminogen activator. This enzyme was suppressed in control and stimulated cultures by dexamethasone (0.1 microM). Monocyte plasminogen activator could only be assayed under conditions of low ionic strength and had no detectable activity at 0.15 M NaCl. Intracellular enzyme was present as a proenzyme, requiring activation by preincubation with plasminogen containing traces of plasmin, before its activity could be seen on sodium dodecyl sulphate/polyacrylamide gel electrophoresis by a fibrin overlay method. Secreted enzyme was in the active form. Further incubation of lysate or supernatant plasminogen activator with plasminogen did not produce any active enzyme species of Mr 36 000, unlike incubations of urokinase with plasminogen. Moreover, comparisons with other plasminogen activators of Mr 52 000 from transformed cell lines showed that the monocyte activator was unique in its resistance to monocyte minactivin, a specific inactivator of urokinase-type plasminogen activators, and in its sensitivity to human alpha 2-macroglobulin. It was therefore concluded that human monocyte plasminogen activator, although sharing an Mr of 52 000 in common with other such activators, is not identical to the high Mr form of urokinase or the plasminogen activators of transformed cells. On present evidence it is the least likely of these enzymes to be active extracellularly under normal physiological conditions.
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PMID:Novel properties of human monocyte plasminogen activator. 619

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