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 compared peritoneal dialysis effluents from 18 CAPD patients who had not suffered from peritonitis during the last 6 months (group 1) with the effluents from five patients with acute peritonitis (group 2), measuring activation markers of coagulation and fibrinolysis. These markers included prothrombin fragment F1 + 2 (F1 + 2), thrombin-antithrombin III complex (TAT), fibrin monomer (FM), and fibrin degradation products (FbDP). In the dialysate of group 1 we found remarkably high levels of F1 + 2, TAT and FM concomitant with a high concentration of FbDP, indicating a high rate of intraperitoneal fibrin turnover. The balance between peritoneal generation and degradation of fibrin was disturbed in untreated patients of group 2, who had significantly higher levels of coagulation markers and a higher ratio between FM and FbDP. Seven days after treatment with intraperitoneal administration of antibiotics and heparin, F1 + 2, TAT, FM and FbDP decreased significantly. To evaluate the role of mesothelial cells (MC) in the high peritoneal fibrin turnover we investigated the expression of tissue-type plasminogen activator (t-PA), urokinase-type plasminogen activator (u-PA), plasminogen activator inhibitor type-1 (PAI-1), and tissue factor in cultured human peritoneal MC under basal conditions and after exposure to tumour necrosis factor alpha (TNF alpha), interleukin-1 alpha (IL-1 alpha), or bacterial lipopolysaccharide (LPS). The exposure of MC to TNF alpha or to a lesser extent IL-1 alpha or LPS reduced their fibrinolytic activity by decreasing t-PA production and increasing PAI-1 synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Imbalance between intraperitoneal coagulation and fibrinolysis during peritonitis of CAPD patients: the role of mesothelial cells. 756 82

Plasminogen activator inhibitor-1 (PAI-1) is a primary endogenous inhibitor of tissue-type plasminogen activator (t-PA). In this study, we examined the effects of oversulfated fucoidan (OSF) derivatives and heparin on lipopolysaccharide (LPS)-induced release of PAI-1 antigen from cultured human umbilical vein endothelial cells (HUVEC). Addition of LPS (10 micrograms/ml) enhanced the release of PAI-1 by HUVEC but not of t-PA antigen. At 18 h, a 2.4-fold increase in the extracellular PAI-1 level was observed. The increased PAI-1 level was reduced to control level by the simultaneous addition of 10 micrograms/ml of OSF or heparin. The suppressive effect of native fucoidan was negligible. We also examined the molecular size effect of OSF, using 10-20, 20-40, and 40-60 kDa fragments. The result indicated that these fragments were effective as well as the 100-130 kDa form of OSF, hence suggesting an important role of the degree of sulfation. Interleukin-1 beta (IL-1 beta) is a potent inducer of PAI-1 in cultured HUVEC. Heparin, OSF, and its fragments did not suppress the IL-1 beta-induced release of PAI-1 antigen. Treatment of HUVEC with heparitinase or monoclonal antibody against heparin sulfate proteoglycan (HSPG) resulted in a complete loss of its ability to enhance PAI-1 release in response to LPS stimulation, while the chondroitinase ABC treatment hardly affected the PAI-1 production. These results suggest that HSPG is involved in the initial binding of LPS to HUVEC. The suppressive effects of OSF and heparin on LPS-induced PAI-1 release may result from the inhibition of LPS binding to the cell surface HSPG.
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PMID:Oversulfated fucoidan and heparin suppress endotoxin induction of plasminogen activator inhibitor-1 in cultured human endothelial cells: their possible mechanism of action. 757 76

The plasminogen activator (PA)-plasmin system is implicated in the degradation of the extracellular matrix in inflammation through activation of metalloproteases and prekallikrein. We examined the activation of the PA-plasmin system in human gingival fibroblast cells (Gin-1 cells) following treatment with lipopolysaccharide (LPS) from Campylobacter rectus, which is frequently detected at sites of periodontal disease. The C. rectus LPS stimulated the plasmin activity in the conditioned medium of Gin-1 cells in a time- and dose-dependent manner, and C. rectus LPS also stimulated the PA activity in the conditioned medium. The PA produced by Gin-1 cells was determined to be urokinase PA (uPA), as preincubation of Gin-1 conditioned medium with anti-uPA antiserum completely inhibited the PA activity while that with anti-tPA antiserum had no inhibitory effect. The concentration of PA inhibitor-1 (PAI-1) in the conditioned medium was decreased by the addition of C. rectus LPS. Therefore, the enhancement of plasmin activity in the conditioned medium was dependent on increased uPA activity via the decrease of the PAI-1 level of Gin-1 cells treated with C. rectus LPS. Furthermore, the conditioned medium of Gin-1 cells treated with C. rectus LPS showed significantly increased kallikrein activity, indicating the conversion of prekallikrein to kallikrein, which converts kininogen into kinin. These findings suggest that C. rectus LPS is a potent stimulator of inflammation of gingival tissue which acts through stimulation of the PA-plasmin system.
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PMID:Effect of Campylobacter rectus LPS on plasminogen activator-plasmin system in human gingival fibroblast cells. 777 54

The fibrinolytic potential of the endothelial cells gives important antithrombotic properties to the vascular wall. Thrombosis is a frequent complication to atherosclerosis and other conditions where inflammatory mediators are present in the vascular wall. Inflammatory agents like lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF alpha) have been demonstrated to modulate the expression of fibrinolytic factors in cultured endothelial cells. In the present study the expression of tissue-type plasminogen activator (t-PA), urokinase plasminogen activator (u-PA) and plasminogen activator inhibitors-1 and -2 (PAI-1 and PAI-2) antigen in conditioned medium from cultured human umbilical vein (HUVEC) and human saphenous vein (HSVEC) endothelial cells was investigated under basal conditions and after stimulation with LPS, TNF alpha, interferon-gamma (IFN-gamma) or interleukin-6 (IL-6) alone or in combinations. Stimulation with LPS or TNF alpha increased the expression of PAI-1, u-PA and PAI-2 in HUVEC and HSVEC, while the t-PA response differed between the two cell types. The effects of TNF alpha were modulated by IFN-gamma but not by IL-6. The increased expression of u-PA after stimulation with TNF alpha was reduced by IFN-gamma. In contrast, TNF alpha-induced expression of PAI-2 was synergistically increased by addition of IFN-gamma. These effects of IFN-gamma represent additional mechanisms by which inflammatory mediators may turn the fibrinolytic potential of the endothelium in a prothrombotic direction.
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PMID:Interferon-gamma modulates the fibrinolytic response in cultured human endothelial cells. 777 58

Healthy endothelium is a metabolically active interface between the blood and extravascular tissues. Its intimal surface is anticoagulant and antithrombotic, and it secretes a variety of molecules involved in regulating platelet function and blood coagulation. The rapid interactions between platelets, their secreted components, or thrombin and endothelial cells at sites of vessel damage ensure the local secretion of mediators such as prostacyclin and nitric oxide that limit the intravascular growth of the haemostatic plug. There is considerable evidence that a decreased ability of endothelial cells to synthesize NO contributes to the pathogenesis of arterial disease. Local deficiency of PGI2 synthesis has also been implicated in the thrombotic problems in haemolytic uraemic syndrome. Endothelium is also the source of circulating von Willebrand factor, important for efficient platelet adhesion. Chronically elevated plasma levels of vWF in a series of diseases where there is vascular pathology apparently reflect endothelial cell damage or activation, and may contribute to the prothrombotic tendency they exhibit. They may be compounded by decreased levels of the surface anticoagulant thrombomodulin, if the increased concentrations of the soluble forms of thrombomodulin detected in the circulation under similar conditions are a reflection of loss from the endothelium. Further alterations of function in a procoagulant/prothrombotic direction take place when endothelial cells are exposed to certain cytokines or lipopolysaccharide. Tissue factor synthesis is induced, thrombomodulin expression is decreased, and there is enhanced sensitivity of vWF secretion. In addition, the balance of tissue-type plasminogen activator and plasminogen activator inhibitor type I secretion is changed in favour of the latter. These processes are each likely to contribute to the occurrence of disseminated intravascular coagulation which can accompany septic shock.
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PMID:Endothelial cell function and thrombosis. 784 94

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

Renal glomerular microvascular endothelial cell damage is characteristic of Shiga toxin-associated hemolytic uremic syndrome (HUS). An impaired renal fibrinolysis may be responsible for renal microvascular fibrin accumulation during the course of HUS disease. This study examined the effect of Shiga toxin, bacterial lipopolysaccharide (LPS, endotoxin), and tumor necrosis factor (TNF) on the expression of fibrinolysis factors by human renal glomerular microvascular endothelial cells (HRMEC) in vitro. The results were compared to a previously better-characterized endothelial cell type, human umbilical vein endothelial cells (HUVEC). In HUVEC, the ratio of fibrinolysis antigens was antifibrinolytic, consisting of 55-fold more plasminogen activator inhibitor type 1 (PAI-1) than tissue-type plasminogen activator (tPA). Treatment of HUVEC with LPS or TNF accentuated this ratio by decreasing tPA and increasing PAI-1 expression. In contrast, HRMEC produced urokinase-type plasminogen activator (uPA) in a 24-fold excess to PAI-1 and were thereby profibrinolytic with regard to fibrinolysis antigen expression. LPS and TNF further decreased PAI-1 antigen expression by HRMEC. These results argue against a role for LPS or TNF in decreasing renal fibrinolysis at the level of fibrinolysis factor expression by renal endothelial cells. Nevertheless, HUVEC and HRMEC were responsive to the same LPS analogs in the same order of potency. Shiga toxin decreased fibrinolysis factor expression to a greater extent in HRMEC than in HUVEC. Since HRMEC fibrinolysis antigen expression was profibrinolytic, the Shiga toxin-mediated decrease in renal endothelial uPA synthesis may predispose renal microvasculature to thrombosis and may have implications for the development of HUS.
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PMID:Human renal microvascular endothelial cells as a potential target in the development of the hemolytic uremic syndrome as related to fibrinolysis factor expression, in vitro. 808 1

We have dissected the state of fibrinolytic balance in the C57/BL mouse macrophages, by means of immunotrap assays and zymography. We have monitored the individual changes of plasminogen activator (PA) and plasminogen activator inhibitor (PAI) activities of cellular lysates and secretions of these macrophages, after they were stimulated by various exogenous agents. The resident peritoneal macrophages were found to have very little PA but high level of PAI, and are therefore highly anti-fibrinolytic in nature. Upon stimulation by thioglycollate, PA activity increased and PAI activity decreased, thus raising the fibrinolytic balance in these macrophages. Upon incubation of resident or thioglycollate-activated macrophages by lipopolysaccharide (LPS), the PA level was depressed while the PAI level was increased, resulting in a large drop in the total fibrinolytic balance of the activated cells. When resident or thioglycollate-activated macrophages were incubated with the anti-inflammatory agent dexamethasone, the drug depressed both the expressions of PA and PAI, in the lysate and conditioned medium of both cell types. Thus cell-bound or secreted forms of macrophage PA and PAI activities were either increased or decreased in response to thioglycollate, LPS or dexamethasone challenge. The changes in PA and PAI resulted in different state of fibrinolytic balance in macrophages, and could be related to the different functions of these macrophages at different stages of their development.
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PMID:Modulation of the plasminogen activation system in murine macrophages. 845 67

Chemical modification of proteins is a common theme in their regulation. Nitrosylation of protein sulfhydryl groups has been shown to confer nitric oxide (NO)-like biological activities and to regulate protein functions. Several other nucleophilic side chains -- including those with hydroxyls, amines, and aromatic carbons -- are also potentially susceptible to nitrosative attack. Therefore, we examined the reactivity and functional consequences of nitros(yl)ation at a variety of nucleophilic centers in biological molecules. Chemical analysis and spectroscopic studies show that nitrosation reactions are sustained at sulfur, oxygen, nitrogen, and aromatic carbon centers, with thiols being the most reactive functionality. The exemplary protein, BSA, in the presence of a 1-, 20-, 100-, or 200-fold excess of nitrosating equivalents removes 0.6 +/- 0.2, 3.2 +/- 0.4, 18 +/- 4, and 38 +/- 10, respectively, moles of NO equivalents per mole of BSA from the reaction medium; spectroscopic evidence shows the proportionate formation of a polynitrosylated protein. Analogous reaction of tissue-type plasminogen activator yields comparable NO protein stoichiometries. Disruption of protein tertiary structure by reduction results in the preferential nitrosylation of up to 20 thus-exposed thiol groups. The polynitrosylated proteins exhibit antiplatelet and vasodilator activity that increases with the degree of nitrosation, but S-nitroso derivatives show the greatest NO-related bioactivity. Studies on enzymatic activity of tissue-type plasminogen activator show that polynitrosylation may lead to attenuated function. Moreover, the reactivity of tyrosine residues in proteins raises the possibility that NO could disrupt processes regulated by phosphorylation. Polynitrosylated proteins were found in reaction mixtures containing interferon-gamma/lipopolysaccharide-stimulated macrophages and in tracheal secretions of subjects treated with NO gas, thus suggesting their physiological relevance. In conclusion, multiple sites on proteins are susceptible to attack by nitrogen oxides. Thiol groups are preferentially modified, supporting the notion that S-nitrosylation can serve to regulate protein function. Nitrosation reactions sustained at additional nucleophilic centers may have (patho)physiological significance and suggest a facile route by which abundant NO bioactivity can be delivered to a biological system, with specificity dictated by protein substrate.
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PMID:Polynitrosylated proteins: characterization, bioactivity, and functional consequences. 864 72

Various growth factors released by macrophages and other cell types modulate normal hematopoiesis. The physiological mechanisms whereby these molecules interact with specific target cells are ill defined. Eicosanoids, the products of fatty acid metabolism, are known to regulate cell proliferation and differentiation. The release of membrane-bound phospholipid by phospholipase-A2 (PLA-2) is the first critical step in the initiation of membrane remodeling and eventually eicosanoid synthesis. We report here data that demonstrates how various cytokines exhibit a marked hydrolytic activity mediated through PLA-2 against both [1-14C] oleic acid- and [1-14C] arachidonic acid-labeled Escherichia coli (micelle) substrates. PLA-2 extracts were prepared from neutrophils elicited by injecting rats ip with 8% glycogen. The rate of hydrolysis of free fatty acids from the phospholipid substrate was found to be linear, rapid, and pH dependent and was calculated to be 30 nmoles of phospholipid/hr/mg protein lysate. Cytokines (i.e., interleukin-1 [IL-1, human and murine recombinant, alpha], mouse lung cell-derived colony-stimulating factor [L-CSF], granulocyte-macrophage colony-stimulating factor [murine recombinant GM-CSF], tumor necrosis factor [murine recombinant TNF-alpha], and granulocyte colony-stimulating factor [human recombinant, G-CSF] all induced PLA-2 activity with the release of free fatty acids above basal levels. In contrast, lipopolysaccharide (LPS), interleukin-2, (IL-2, human recombinant), and macrophage colony-stimulating factor (M-CSF) did not significantly activate PLA-2 hydrolysis. The activation of this membrane-bound enzyme-substrate complex by these growth factors may serve as a mechanism whereby the appropriate target cells expressing receptors respond through either direct or secondary signals leading to the formation of free fatty acids with the eventual synthesis of prostanoid or lipoxygenase products, resulting in cellular proliferation and differentiation.
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PMID:The regulation of phospholipase-A2 (PLA-2) by cytokines expressing hematopoietic growth-stimulating properties. 865 Feb 56


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