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)

Endotoxemia promotes adhesive interactions between platelets and microvascular endothelium in vivo. We sought to determine whether endotoxin (lipopolysaccharide, LPS) modified platelet thrombus formation in mouse cremaster venules and whether Toll-like receptor 4 (TLR4) and neutrophils were involved in the response. Intravital videomicroscopy was performed in the cremaster microcirculation of pentobarbital-anesthetized mice; venular platelet thrombi were induced with a light/dye endothelial injury model. C57BL/6 mice treated with Escherichia coli endotoxin had enhanced rates of venular platelet thrombus formation: the time to microvessel occlusion was reduced by approximately 50% (P < 0.005) compared with saline-treated animals. Enhanced microvascular thrombosis was evident as early as 2 h after LPS administration. LPS had no effect on thrombosis in either of two mouse strains with altered TLR4 signaling (C57BL/10ScNJ or C3H/HeJ), whereas it enhanced thrombosis in the control strains (C57BL/10J and C3H/HeN). LPS also enhanced platelet adhesion to endothelium in the absence of light/dye injury. Platelet adhesion, but not enhanced thrombosis, was inhibited by depletion of circulating neutrophils. LPS failed to enhance platelet aggregation ex vivo and did not influence platelet P-selectin expression, a marker of platelet activation. These findings support the notion that endotoxemia promotes platelet thrombus formation independent of neutrophils and without enhancement of platelet aggregation, via a TLR4-dependent mechanism.
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PMID:Endotoxin enhances microvascular thrombosis in mouse cremaster venules via a TLR4-dependent, neutrophil-independent mechanism. 1628 41

Shiga toxins (Stxs) produced by Shigella dysenteriae type 1 and enterohemorrhagic Escherichia coli are the most common cause of hemolytic-uremic syndrome (HUS). It is well established that vascular endothelial cells, mainly those located in the renal microvasculature, are targets for Stxs. The aim of the present research was to evaluate whether E. coli-derived Shiga toxin 2 (Stx2) incubated with human microvascular endothelial cells (HMEC-1) induces release of chemokines and other factors that might stimulate platelet function. HMEC-1 were exposed for 24 h in vitro to Stx2, lipopolysaccharide (LPS), or the Stx2-LPS combination, and chemokine production was assessed by immunoassay. More interleukin-8 was released than stromal cell-derived factor 1alpha (SDF-1alpha) or SDF-1beta and RANTES. The Stx2-LPS combination potentiated chemokine release, but Stx2 alone caused more release of SDF-1alpha at 24 h than LPS or Stx2-LPS did. In the presence of low ADP levels, HMEC-1 supernatants activated platelet function assessed by classical aggregometry, single-particle counting, granule secretion, P-selectin exposure, and the formation of platelet-monocyte aggregates. Supernatants from HMEC-1 exposed only to Stx2 exhibited enhanced exposure of platelet P-selectin and platelet-THP-1 cell interactions. Blockade of platelet cyclooxygenase by indomethacin prevented functional activation. The chemokine RANTES enhanced platelet aggregation induced by SDF-1alpha, macrophage-derived chemokine, or thymus and activation-regulated chemokine in the presence of very low ADP levels. These data support the hypothesis that microvascular endothelial cells exposed to E. coli O157:H7-derived Stx2 and LPS release chemokines and other factors, which when combined with low levels of primary agonists, such as ADP, cause platelet activation and promote the renal thrombosis associated with HUS.
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PMID:Shiga toxin 2 and lipopolysaccharide induce human microvascular endothelial cells to release chemokines and factors that stimulate platelet function. 1629 28

Platelet and monocyte activation may contribute to hemolytic anemia, thrombocytopenia and renal failure associated with the hemolytic uremic syndrome (HUS) caused by Escherichia coli O157:H7. Since Shiga toxins (Stxs) and lipopolysaccharide (LPS) from this bacterium are implicated in the pathogenesis of HUS, we examined whether stimulation of THP-1 human monocytic cells by Shiga toxin 2 (Stx2) and LPS can lead to the activation of platelet function. We now show that Stx2 causedTHP-1 cells to release the chemokines IL-8, MDC, and RANTES and that the presence of LPS further stimulated this release. IL-8 was produced in greatest amount and was an effective co-agonist for inducing platelet aggregation. Primary human monocytes also released large amounts of IL-8 in response to LPS and Stx2. Factors released byTHP-1 cells exposed to Stx2 and LPS activated platelet function as evidenced by increased aggregation, serotonin secretion, P-selectin exposure and by the formation of stable platelet-monocyte aggregates. Our data therefore show that monocytes exposed to E.coli-derived Stx2 and LPS release factors which activate platelet function.
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PMID:Shiga toxin 2 and lipopolysaccharide cause monocytic THP-1 cells to release factors which activate platelet function. 1636 2

The purpose of this study was to determine if P-selectin, an adhesion molecule involved in the transendothelial movement of leukocytes, might also have a direct influence on the function of cells that come into contact with it. Human peripheral blood mononuclear cells were incubated on immobilized P-selectin or a control substrate (bovine serum albumin, BSA) and stimulated with bacterial lipopolysaccharide (LPS). After 24 h, the concentrations of proinflammatory cytokines in the supernatants of LPS-stimulated cells incubated on P-selectin were <50% of those produced by cells incubated on BSA (interleukin-1beta: P=0.001, tumor necrosis factor-alpha: P=0.004, and interferon-gamma : P=0.026). In contrast, cells incubated on P-selectin produced 74% more of the anti-inflammatory cytokine interleukin-10 than cells incubated on BSA (P=0.013). Neither P-selectin nor BSA stimulated cytokine production in the absence of LPS. Thus, P-selectin modulated the cytokine secretion of peripheral blood mononuclear cells in a coordinated manner that reduced the inflammatory potential of the cells.
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PMID:Anti-inflammatory influence of P-selectin on human mononuclear cells. 1640 80

Heterotypic platelet-eosinophil/neutrophil aggregation and subsequent release of eosinophil/neutrophil oxidant products contribute to pathogenesis of conditions such as asthma and inflammatory bowel diseases. This study investigates whether warmup exercise (WUE) affects platelet-eosinophil/neutrophil interaction mediated by high-intensity exercise (HIE). Twenty-three healthy sedentary men performed on three occasions light-intensity exercise (LIE, 40%VO(2 max) for 40 min) and HIE (80%VO(2 max) for 40 min) with and without WUE (40%VO(2 max) for 20 min). Before and immediately after exercise, platelet-eosinophil and platelet-neutrophil aggregation (PEA and PNA), reactive oxygen species production of eosinophils and neutrophils (EROS and NROS) enhanced by platelets, and adhesion molecule expression on platelets, eosinophils, and neutrophils were measured. The results of this study demonstrated that HIE enhanced PEA, PNA, and platelet-induced EROS and NROS, was accompanied by increased expressions of Mac-1 on eosinophils and neutrophils and P-selectin on platelets at 5 dyne/cm(2) of shear stress, 100 microg/ml lipopolysaccharide, and 1 microM N-formylmethionyl- leucyl-phenylalanine treatments, whereas the enhancement of HIE on platelet-eosinophil/neutrophil interaction was suppressed by WUE. Conversely, LIE significantly reduced PEA and PNA, suppressed platelet-induced EROS and NROS, and down-regulated eosinophil/neutrophil Mac-1 and platelet P-selectin expressions under various stimuli and shear flow conditions. Moreover, these effects were more pronounced in platelet interaction with eosinophils than with neutrophils. It is concluded that HIE enhances hetero-aggregation, adhesion molecules expressions, and subsequent oxidative bursts mediated by platelets and eosinophils/neutrophils, this effect diminishes after WUE. However, LIE minimizes the risk of thromboinflammation.
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PMID:Warm-up exercise suppresses platelet-eosinophil/neutrophil aggregation and platelet-promoted release of eosinophil/neutrophil oxidant products enhanced by severe exercise in men. 1652 78

We have developed a cell-based model of thrombin generation using activated monocytes as a source of tissue factor (TF) and platelets serving as a surface for thrombin generation. Monocytes are activated by lipopolysaccharide and express cell-bound TF. To these are added physiologic (plasma) concentrations of all the plasma procoagulants as well as TF pathway inhibitor, antithrombin, and C1-esterase inhibitor. Coagulation takes place in microtiter wells and is initiated by factor VIIa (FVIIa) and calcium. At time intervals, aliquots are removed, platelet activation is measured by the expression of P-selectin, and thrombin generation is measured by chromogenic assay. In addition, one can measure the activation of FIX, FX, FVIII, FV, and FXI. Initial results reveal that the FVIIa-TF interaction results in the activation of FX to FXa and FIX to FIXa. FXa stays in the vicinity of the TF-bearing cell and, in the presence of FVa, converts a small amount of prothrombin to thrombin on the surface of the TF cell. This small amount of thrombin is not sufficient to clot fibrinogen, but is sufficient to activate platelets and FVIII, FV, and FXI. Following platelet activation, FVIIIa, FVa, and FXa occupy sites on the activated platelet surface. FIXa, activated by TF-FVIIa, does not remain on the TF cell, but converts FX to FXa on the platelet surface. FXIa acts to boost FIXa generation on the activated platelet, increasing FXa and subsequent thrombin generation. We have also shown that activated protein C does not inactivate Va on the platelet surface but rather on endothelial cell surfaces.
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PMID:A cell-based model of thrombin generation. 1667 64

Acute lung injury in the rat caused by intravenous (i.v.) infusion of cobra venom factor (CVF) or lipopolysaccharide (LPS) is mediated by P-selectin-dependent neutrophil infiltration into the lung. In these lung injury models, P-selectin expression is induced on lung vascular endothelial cells after the CVF or LPS infusion, suggesting soluble P-selectin derived from inflamed sites might also be elevated. Here we established a sensitive enzyme-linked immunosorbent assay (ELISA) to measure soluble P-selectin in plasma, a potential marker of lung injury. Nine anti-rat P-selectin monoclonal antibodies that we established previously were first classified into 5 groups based on real-time biospecific interaction analyses, and used to develop a sandwich ELISA for accurately measuring the amount of soluble P-selectin in plasma. We then used this ELISA to measure the plasma P-selectin levels in Long Evans, Wistar, and Sprague-Dawley rats after the i.v. infusion of CVF or LPS. The elevation in P-selectin levels was significantly different among the strains, but it consistently correlated with the extent of lung inflammation, measured by myeloperoxidase levels in the lung tissues. Thus, our results indicate that the soluble P-selectin in plasma could serve as a sensitive biomarker reflecting lung inflammation, which is of clinical importance for detecting and preventing severe lung injury.
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PMID:Elevation of rat plasma P-selectin in acute lung injury. 1722 17

The endothelial cell-specific granule Weibel-Palade body releases vasoactive substances capable of modulating vascular inflammation. Although innate recognition of pathogens by Toll-like receptors (TLRs) is thought to play a crucial role in promotion of inflammatory responses, the molecular basis for early-phase responses of endothelial cells to bacterial pathogens has not fully been understood. We here report that human aortic endothelial cells respond to bacterial lipoteichoic acid (LTA) and synthetic bacterial lipopeptides, but not lipopolysaccharide or peptidoglycan, to induce Weibel-Palade body exocytosis, accompanied by release or externalization of the storage components von Willebrand factor and P-selectin. LTA could activate rapid Weibel-Palade body exocytosis through a TLR2- and MyD88-dependent mechanism without de novo protein synthesis. This process was at least mediated through MyD88-dependent phosphorylation and activation of phospholipase Cgamma. Moreover, LTA activated interleukin-1 receptor-associated kinase-1-dependent delayed exocytosis with de novo protein synthesis and phospholipase Cgamma-dependent activation of the NF-kappaB pathway. Increased TLR2 expression by transfection or interferon-gamma treatment increased TLR2-mediated Weibel-Palade body exocytosis, whereas reduced TLR2 expression under laminar flow decreased the response. Thus, we propose a novel role for TLR2 in induction of a primary proinflammatory event in aortic endothelial cells through Weibel-Palade body exocytosis, which may be an important step for linking innate recognition of bacterial pathogens to vascular inflammation.
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PMID:Pathogen recognition by Toll-like receptor 2 activates Weibel-Palade body exocytosis in human aortic endothelial cells. 1722 63

LDL-apheresis (LA) was originally used for familial hyperlipidemia, and then in Japan extended to use for the treatment of patients with peripheral arterial disease (PAD) and nephrotic syndrome due to steroid-resistant focal glomerular sclerosis (FGS). The reason why this treatment is applicable for these disorders is due to the fact that LA exerts its favorable effects beyond the lipid-lowering effect. The main underlying mechanisms, for example, in the case of LA application in patients with PAD are: (1) improvement of hemorheology, (2) improvement of endothelial dysfunction, (3) elevations of serum levels of NO and bradykinin, (4) increase in serum levels of vascular endothelial growth factor, and (5) reduction of adhesion molecules on monocytes. Furthermore, we have reported that LA could have anti-inflammatory effects because LA reduces serum levels of P-selectin, which is known to play an important role in the development of atherosclerosis as well as a reduction of serum C-reactive protein levels as standard biomarker of atherosclerosis. Massive proteinuria is also an important challenge in nephrology. The possible mechanisms besides removal of toxic lipids are the reduction of the vasoconstrictive prostanoid and thromboxane A2 (TXA2) and an improvement in macrophage function evidenced by a significant amelioration of interleukin-8 production by lipopolysaccharide-stimulated peripheral blood mononuclear cells. It is intriguing to note that in terms of pharmacodynamics, LA improves steroid and cyclosporine uptake into lymphocytes. Although there are no randomized controlled trials, it is clear that LA has various effects beyond lowering lipids. Making the device more concise and changing it into a whole blood adsorption type, we need to collect more clinical cases and to study the underlying mechanisms further.
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PMID:Applications of LDL-apheresis in nephrology. 1817 56

P-selectin glycoprotein ligand-1 (PSGL-1) is constitutively expressed on leukocytes and was thought to be down-regulated with cell activation. However, this work shows the surprising finding of functional PSGL-1 up-regulation during acute inflammation. PSGL-1 function was studied in our autoperfusion assay, in which blood from a mouse carotid flows through a microchamber coated with a fixed density of P-selectin. Under the inflammatory conditions--uveitis induced by systemic lipopolysaccharide injection--we recorded significantly reduced leukocyte rolling velocity, which suggests PSGL-1 up-regulation; however, flow cytometry showed reduced PSGL-1. When bound leukocytes were released from the vasculature by PSGL-1 blockade, a large peripheral blood leukocyte (PBL) population showed elevated PSGL-1, which could account for the reduced PSGL-1 in the remaining unbound population. In the eye, systemic blockade of PSGL-1 with a monoclonal antibody or recombinant soluble PSGL-1 drastically reduced the severe manifestations of uveitis. Furthermore, PSGL-1 blockade was significantly more effective in reducing retinal leukostasis than was P-selectin blockade. Our results provide surprising evidence for functional PSGL-1 up-regulation in PBLs during acute inflammation. The temporal overlap between PSGL-1 and P-selectin up-regulation reveals an as yet unrecognized collaboration between this receptor-ligand pair, increasing efficiency of the first steps of the leukocyte recruitment cascade.
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PMID:Surprising up-regulation of P-selectin glycoprotein ligand-1 (PSGL-1) in endotoxin-induced uveitis. 1905 46


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