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)

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

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

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

An experimental disseminated intravascular coagulation (DIC) was induced in female CD rats by the intravenous administration of living bacteria (9.5 x 10(7) cfu Klebsiella pneumoniae), sublethal (5 mg/kg) or lethal (50 mg/kg) lipopolysaccharide (LPS), or tissue factor (1.5 micrograms/kg i.v. bolus or 0.4 micrograms/kg x hr i.v. infusion). We used a new fibrin monomer (FM) assay to follow the course of DIC. FM were detected by their ability to stimulate the tissue-type (t-PA) plasminogen activator dependent conversion of plasminogen to plasmin by a chromogenic assay. Miniplasminogen was used instead of plasminogen to avoid interference of the assay by alpha 2-antiplasmin. As a marker of DIC, elevated levels of FM were observed with all DIC-inducing agents (plasma levels were up to 90 micrograms/ml). The kinetics of FM formation were similar to the course of thrombin-antithrombin III (TAT) levels (maximal plasma levels 70 ng/ml); however, in the bacterial infection group, both parameters rose after a lag phase of about 1 hr. A 4 hr infusion of the highly specific thrombin inhibitor recombinant (rec.) hirudin (0.125 mg/kg x hr) resulted in a decrease of FM levels from 89.2 +/- 14.4 micrograms/ml in the LPS group (n = 10) to 27.4 +/- 11.2 micrograms/ml in the rec. hirudin group (n = 10; P < 0.001). The respective values for TAT levels were 73.1 +/- 19.7 micrograms/ml in the LPS group and 52.7 +/- 15.7 ng/ml in the rec. hirudin group (P < 0.001). Other coagulation parameters, such as platelets, fibrinogen, and fibrin(ogen) degradation products, were ameliorated accordingly.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Formation of fibrin monomers in experimental disseminated intravascular coagulation and its inhibition by recombinant hirudin. 805 64

Macrophage colony-stimulating factor (M-CSF or CSF-1) and granulocyte-macrophage CSF (GM-CSF) have been shown to increase human monocyte urokinase-type plasminogen-activator (u-PA) activity with possible consequences for cell migration and tissue remodeling; because monocyte u-PA activity is likely to be controlled in part also by the PA inhibitors (PAIs) made by the cell, the effect of M-CSF and GM-CSF on human monocyte PAI-2 and PAI-1 synthesis was investigated. To this end, elutriation-purified human monocytes were treated in vitro with purified recombinant human M-CSF and GM-CSF, and PAI-2 and PAI-1 antigen and mRNA levels measured by specific enzyme-linked immunosorbent assays and Northern blot, respectively. Each CSF could enhance the protein and mRNA levels of PAI-2 and PAI-1 at similar concentrations for each product. This similar regulation of monocyte PAI expression in response to the CSFs contrasted with that found for the effects of lipopolysaccharide, transforming growth factor-beta and a glucocorticoid. Therefore, PAIs may be modulating the effects of the CSFs on monocyte u-PA activity at sites of inflammation and tissue remodeling.
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PMID:Macrophage colony-stimulating factor and granulocyte-macrophage colony-stimulating factor stimulate the synthesis of plasminogen-activator inhibitors by human monocytes. 826 Jul

This study examined the effects of endogenous urokinase (uPA) on lipopolysaccharide (LPS)-stimulated tumor necrosis factor alpha (TNF-alpha) secretion in THP-1 mononuclear phagocytes. Anti-uPA monoclonal antibody (mAb) suppressed LPS-driven TNF-alpha secretion by 61.6 +/- 5.9% (P<.001), and PAI-1, a uPA inhibitor, suppressed it to 53.1 +/- 8.2% of the control value (P<.001). Up-regulation of TNF-alpha mRNA was suppressed in parallel with secreted TNF-alpha protein. TNF-alpha secretion was unaffected by depleting plasminogen or by aprotinin, a plasmin inhibitor. When endogenous uPA was displaced from the cell, exogenous high-molecular-weight (intact) uPA augmented LPS-driven TNF-alpha secretion. By contrast, a uPA fragment containing the catalytic domain was inhibitory, and the uPA receptor-binding domain had no effect. We conclude that endogenous uPA amplifies TNF-alpha neosynthesis of LPS-stimulated THP-1 mononuclear phagocytes. The effect requires intact uPA and is independent of plasmin activity. This represents a novel mechanism by which a mononuclear phagocyte-derived protease contributes to generating proinflammatory signals.
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PMID:Endogenously produced urokinase amplifies tumor necrosis factor-alpha secretion by THP-1 mononuclear phagocytes. 860 4

Binding of urokinase-type plasminogen activator (uPA) to a specific receptor (uPAR) on human lung fibroblasts enables it to regulate cellular proteolysis and remodeling of the extracellular matrix. Binding studies with radiolabeled uPA indicated that both normal and fibrotic lung fibroblasts express the receptor, but cells from fibrotic tissues bound significantly more uPA (P < 0.001). Phorbol myristate acetate, lipopolysaccharide, transforming growth factor-beta (TGF-beta), and tumor necrosis factor-alpha (TNF-alpha) increased uPA binding and plasminogen activation at the cell surface, with a greater maximal effect on fibrotic than on normal fibroblasts. Excess unlabeled uPA, specific antibody, or antisense oligonucleotides inhibited uPA binding. Ribonuclease (RNase) protection assays showed higher levels of uPAR messenger ribonuleic acid (mRNA) in each of the five fibrotic cell lines than in normal fibroblasts. uPA was mitogenic for normal as well as fibrotic fibroblasts, indicating that receptor binding concurrently localizes cellular proteolytic activity and stimulates mitogenesis. Morphometry and immunohistochemical analysis showed that uPAR, as well as uPA, was increased in fibroblasts in fibrotic lung tissue. Increased expression of uPAR by fibrotic lung fibroblasts and enhanced urokinase binding induced by proinflammatory cytokines suggest a novel mechanism by which fibroblast-mediated matrix remodeling and proliferation may be regulated in interstitial lung diseases.
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PMID:Differential expression of the urokinase receptor in fibroblasts from normal and fibrotic human lungs. 867 25

Most bacterial and fungal proteases excreted into infected hosts exhibit a wide range of pathogenic potentials ranging from pain, edema or even shock to translocation of bacteria from the site of infection into systemic circulation, thus resulting in septicemia. The basic mechanism or principle common to all these phenomena is explained by kinin generation, either directly from high- and/or low-molecular weight kininogens or indirectly via activation of the bradykinin generating cascade: i.e. Hageman factor-->activated Hageman factor-->prekallikrein-->kallikrein-->high-molecular weight kininogen-->bradykinin. Some bacterial proteases are also involved in activation of other host protease zymogens such as plasminogen, procollagenase (matrix metallo proteases) and proenzymes of the clotting system. Furthermore, most bacterial proteases are not only resistant to plasma protease inhibitors of the hosts, most of which belong to a group of serine protease inhibitors called serpins (serine protease inhibitors), but they also quickly inactivate serpins. Some bacterial proteases may also activate bacterial toxins thus rendering toxigenic pathogenesis. They are also capable of degrading immunoglobulins and components of the complement system and facilitate propagation of micro organisms. All in all, microbial proteases are very critical in enhancing pathogenesis of severe diseases. It is also noteworthy that bacterial cell wall components themselves, i.e. endotoxin (or lipopolysaccharide) of gram negative bacteria and teichoic/lipoteichoic acid of gram positive bacteria, are also able to activate the bradykinin generating cascade-involving activation of Hageman factor as mentioned above.
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PMID:Pathogenic mechanisms induced by microbial proteases in microbial infections. 873 87

We have evaluated the effect of plasminogen activators (t-PA and urokinase) on an experimental model of disseminated intravascular coagulation (DIC) in rabbits by injection of 20 micrograms/kg/h of E. coli lipopolysaccharide during 6 h t-PA (0.2 mg/kg and 0.7 mg/kg), urokinase (3000 U/kg/h) and saline (control) were given simultaneously with endotoxin. Results indicated that urokinase and low dose of t-PA significantly reduced the increase of plasminogen activator inhibitor (PAI) activity observed 2 h after endotoxin (p < 0.001). High t-PA dose also diminished the PAI levels at 6 h (p < 0.001). A significant reduction of fibrin deposits in kidneys was observed din both t-PA treated groups as compared with findings in the group of rabbits infused with saline solution (p < 0.005), whereas urokinase had no significant effect on the extent of fibrin deposition. Finally, the mortality rate in the control group (70%) was reduced to 50% in rabbits receiving high doses of t-PA. In conclusion, treatment with t-PA resulted in reduced PAI generation, fibrin deposits and mortality in endotoxin-treated rabbits.
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PMID:Endotoxin-induced intravascular coagulation in rabbits: effect of tissue plasminogen activator vs urokinase of PAI generation, fibrin deposits and mortality. 877 40


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