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)

Peripheral arterial disease (PAD) is a common manifestation of atherosclerosis that is associated with systemic inflammation. The aim of our study was to assess whether plasma markers of inflammation increased after exercise in patients with PAD. The study was conducted on two groups of 20 subjects each: one group (mean age 68.4 +/- 5.09 years) was affected by PAD with claudication, while the other group consisted of healthy controls (66.9 +/- 6.1 years). Concentrations of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFalpha) were determined in plasma, in supernatants and in cells stimulated with 1 mg lipopolysaccharide in all patients. E-selectin (ES), L-selectin (LS) and P-selectin (PS) concentrations and plasma concentrations of VCAM-1 and ICAM-1 were also determined. All determinations were performed in patients at rest and after the treadmill exercise. Resting values of soluble mediators were greater in PAD patients than in controls. They increased in both groups after the treadmill test, even if post-treadmill concentrations were significantly higher in PAD patients (PAD p < 0.001 or 0.0001, controls p < 0.05 or 0.001). These results confirm that white blood cell activation is characteristic of systemic atherosclerosis and that these inflammation markers increase in conditions of hemodynamic stress.
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PMID:High circulating levels of cytokines (IL-6 and TNFalpha), adhesion molecules (VCAM-1 and ICAM-1) and selectins in patients with peripheral arterial disease at rest and after a treadmill test. 1286 7

Epinephrine is known to enhance lipopolysaccharide (LPS)-induced interleukin (IL)-8 secretion in a platelet dependent manner. To determine whether thromboxane A2 (TxA2; a product from activated platelets) is involved in this process, blood samples drawn either before or 2 h after oral administration of 440 mg acetylsalicylic acid (ASA) were stimulated with LPS (5 ng mL(-1)) and different concentrations of epinephrine were added (0.1-100.0 micromol L(-1)). ASA ingestion significantly (global P < 0.05) reduced the enhancing effect of epinephrine on LPS-induced IL-8 release by 15-28%. To further explore whether TxA2 may be involved in this process, a TxA2 agonist (U46619) was added to whole blood together with LPS instead of epinephrine. U46619 mimicked the epinephrine effect: 20 ng mL(-1) U46619 enhanced LPS-induced IL-8 release by 39% (P < 0.05). Furthermore, preincubation of whole blood with 75 micro mol L-1 or 150 micromol L(-1) SQ29548, a TxA2 receptor antagonist, completely blocked epinephrine's promoting effect on LPS-induced IL-8 release. Since thrombin-activated platelets have been reported to be important in the production of IL-8 in monocytes through the activation of monocytes by exposed RANTES in a P-selectin-dependent reaction, we suggest that the epinephrine effect is mediated by enhanced TxA2 production and subsequent rise in the exposure of RANTES and P-selectin on the platelets of whole blood.
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PMID:The promoting effect of epinephrine on lipopolysaccharide-induced interleukin-8 production in whole blood may be mediated by thromboxane A2. 1287 75

The salutary effects of high-density lipoproteins (HDLs) in animal and human models of endotoxic shock have in the past been attributed to the ability of this lipoprotein to bind to lipopolysaccharide. However, the precise mechanisms for the protective effect of HDL are unclear. The first objective of this study was to determine the effects of HDLs on the organ injury and dysfunction associated with acute severe endotoxemia. Second, to gain insight into the mechanism of action of HDL, we also investigated the effect of HDLs on 1) the expression of P-selectin and intercellular adhesion molecule-1 in the kidneys of rats treated with endotoxin and 2) the rise in the plasma levels of tumor necrosis factor-alpha (TNF-alpha). Rats were given Escherichia coli lipopolysaccharide (6 mg/kg i.v.), pretreated with either vehicle (n = 9) or reconstituted HDL (rHDL; apolipoprotein A-I/phosphatidylcholine proteoliposomes, n = 10), and were monitored for 6 h. Here we report that rHDL attenuates the renal injury and dysfunction caused by endotoxin in the rat. In addition, rHDL reduced the degree of histological tissue injury in the lung, liver and intestine and attenuated the expression of P-selectin and intercellular adhesion molecule-1 in the renal glomerulus. Interestingly, pretreatment of rats with rHDL did not prevent the hypotension nor the rise in plasma levels of TNF-alpha (at 90 min) caused by endotoxin. Thus, rHDL reduces the organ injury/dysfunction, but does not affect the circulatory failure, nor the rise in plasma levels of TNF-alpha caused by endotoxin in the rat. We propose that the mechanisms of these beneficial effects of HDL may be related to direct inhibition of adhesion molecule expression.
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PMID:Reconstituted high-density lipoprotein attenuates organ injury and adhesion molecule expression in a rodent model of endotoxic shock. 1462 80

To investigate the status of soluble adhesion molecules (sAMs) during aging, the present study determined protein levels of several major sAMs in serum samples obtained from rats at different ages. These sAMs include E-selectin, P-selectin, vascular cell adhesion molecule 1 (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1). Fischer 344 rats, ages 6, 12, 18, and 24 months, fed ad libitum (AL) and calorie restricted (CR) diets were used in this study. Analysis by Western blotting showed that the levels of all sAMs studied increased during aging in AL rats, but were effectively blunted in the CR rats. Total reactive oxygen species/reactive nitrogen species (ROS/RNS) levels were measured by fluorescent probe 2',7'-dichlorofluorescin diacetate. Increased ROS/RNS levels were found to coincide with increased levels of superoxide-generating xanthine oxidase in serum during aging, but were found suppressed by CR. Increases in sAMs levels were duplicated in another experiment in which young (13-month-old) and old (31-month-old) rats were injected with proinflammatory lipopolysaccharide. These findings suggest that the altered expressions of sAMs may be due to increased oxidative stress with advanced age and that these increases were prevented by CR through its antioxidative action.
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PMID:Alteration of soluble adhesion molecules during aging and their modulation by calorie restriction. 1468 95

Leukocyte recruitment in the liver includes a two-step procedure in which selectin-dependent leukocyte rolling is a prerequisite for subsequent CD18-dependent leukocyte firm adhesion in postsinusoidal venules. However, the roles of the individual selectins in leukocyte rolling and adhesion, hepatocellular injury, and apoptosis remain elusive. Therefore, we examined the pathophysiological role of P-, E-, and L-selectin in male C57BL/6 mice challenged with lipopolysaccharide (LPS) and D-galactosamine (Gal) by use of intravital microscopy of the liver microcirculation. In control animals, administration of LPS-Gal provoked reproducible hepatic damage, including marked increases of leukocyte recruitment, liver enzymes, and hepatocyte apoptosis and reduced sinusoidal perfusion. Interestingly, pretreatment with an anti-P-selectin antibody (RB40.34) markedly reduced leukocyte rolling and firm adhesion by 65 and 71%, respectively. Moreover, interference with P-selectin function significantly improved sinusoidal perfusion and reduced the increase in liver enzymes by 49 to 84% in endotoxemic mice. Moreover, the activity of caspase-3 and the number of apoptotic hepatocytes were significantly reduced by 55 and 54%, respectively, in RB40.34-treated animals. In contrast, administration of an anti-E-selectin antibody (10E9.6) and an anti-L-selectin antibody (Mel-14) did not protect against endotoxin-induced leukocyte responses or hepatic injury. In conclusion, our novel findings document a principal role of P-selectin in mediating leukocyte rolling, a precondition to the subsequent firm adhesion of leukocytes in liver injury. Furthermore, our novel data demonstrate that inhibition of P-selectin function reduces hepatocellular injury and apoptosis, suggesting a causal relationship between leukocyte recruitment on one hand and hepatocellular injury and apoptosis on the other hand. Based on these findings, it is suggested that P-selectin may be an important therapeutic target in endotoxin-induced liver injury.
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PMID:Important role of P-selectin for leukocyte recruitment, hepatocellular injury, and apoptosis in endotoxemic mice. 1471 45

Although monocyte-endothelial cell interactions represent an initial step in controlling the recruitment of monocytes in inflamed tissues, their dynamic processes in microvessels of lymphoid (Peyer's patches) and non-lymphoid (villus) regions in gut-associated lymphoid tissue remain poorly understood. We monitored the migration of fluorescence-labelled monocytes derived from the spleen in intestinal microvessels with or without lipopolysaccharide (LPS) treatment and investigated the role of adhesion molecules, P-selectin, vascular cell adhesion molecule (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). In control mice, there were few interactions between infused monocytes and the endothelium of intestinal microvessels. The monocyte-endothelial interactions (both rolling and adhesion) were significantly increased in intestinal microvessels of LPS-treated mice compared with those in controls. Anti-P-selectin monoclonal antibody (MoAb) significantly suppressed the LPS-induced increase in monocyte rolling in postcapillary venules of Peyer's patches and submucosal venules. Anti-VCAM-1 MoAbs significantly suppressed the LPS-induced increase in monocyte adhesion to postcapillary venules (PCVs) of Peyer's patches, submucosal venules, and villus capillaries. In contrast, anti-ICAM-1 MoAb significantly suppressed the number of adherent monocytes in PCV of Peyer's patches but not in submucosal venules or villus capillaries. These observations demonstrated that LPS treatment resulted in a significant increase in recruitment of monocytes both in microvessels of lymphoid and non-lymphoid regions and that P-selectin, VCAM-1 and ICAM-1 appeared to play important roles in LPS-induced interactions.
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PMID:Endotoxin stimulates monocyte-endothelial cell interactions in mouse intestinal Peyer's patches and villus mucosa. 1473 49

We have generated transgenic mice expressing the leech anticoagulant hirudin and human tissue factor pathway inhibitor tethered to the cell surface by fusion with fragments of human CD4 and P-selectin. Expression of the transgenes is under the control of the CD31 (platelet endothelial cell adhesion molecule [PECAM]) promoter, limiting expression to endothelial cells, monocytes, and platelets. In addition, the P-selectin sequence directs expression to secretory granules. Functional cell surface expression only occurs when the cells are activated. In a mouse model of systemic lipopolysaccharide (LPS)-induced endotoxemia, we show that expression of either anticoagulant on activated endothelium inhibits the widespread intravascular thrombosis, thrombocytopenia, and consumptive coagulopathy associated with endotoxemia. Importantly, non- LPS-treated transgenic mice had normal baseline bleeding times. We speculate that targeted delivery of anticoagulants to the endothelium may be a strategy worth pursuing in clinical sepsis to improve efficacy of systemic anticoagulation while minimizing potential hemorrhagic side effects.
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PMID:Inhibition of intravascular thrombosis in murine endotoxemia by targeted expression of hirudin and tissue factor pathway inhibitor analogs to activated endothelium. 1512 22

1. Macrolides have long been used as anti-bacterial agents; however, there is some evidence that may exert anti-inflammatory activity. Therefore, erythromycin was used to characterize the mechanisms involved in their in vivo anti-inflammatory activity. 2. Erythromycin pretreatment (30 mg kg(-1) day(-1) for 1 week) reduced the lipopolysaccharide (LPS; intratracheal, 0.4 mg kg(-1))-induced increase in neutrophil count and elastase activity in the bronchoalveolar lavage fluid (BALF) and lung tissue myeloperoxidase activity, but failed to decrease tumor necrosis factor-alpha and macrophage-inflammatory protein-2 augmented levels in BALF. Erythromycin pretreatment also prevented lung P-selectin, E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) mRNA upregulation in response to airway challenge with LPS. 3. Mesentery superfusion with LPS (1 mug ml(-1)) induced a significant increase in leukocyte-endothelial cell interactions at 60 min. Erythromycin pretreatment abolished the increases in these parameters. 4. LPS exposure of the mesentery for 4 h caused a significant increase in leukocyte rolling flux, adhesion and emigration, which were inhibited by erythromycin by 100, 93 and 95%, respectively. 5. Immunohistochemical analysis showed that LPS exposure of the mesentery for 4 h caused a significant enhancement in P-selectin, E-selectin, ICAM-1 and VCAM-1 expression that was downregulated by erythromycin pretreatment. 6. Flow cytometry analysis indicated that erythromycin pretreatment inhibited LPS-induced CD11b augmented expression in rat neutrophils. 7. In conclusion, erythromycin inhibits leukocyte recruitment in the lung and this effect appears mediated through downregulation of CAM expression. Therefore, macrolides may be useful in the control of neutrophilic pulmonary diseases.
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PMID:Erythromycin exerts in vivo anti-inflammatory activity downregulating cell adhesion molecule expression. 1566 59

Profound thrombocytopenia occurs in humans with sepsis and in mice administered lipopolysaccharide (LPS). Growing evidence indicates that platelets may contribute to these abnormalities, but whether that is a direct result of LPS activation of platelets or an indirect result of other inflammatory mechanisms remains unclear. Here we demonstrate that although platelets do not increase P-selectin expression in response to LPS, platelets bind more avidly to fibrinogen under flow conditions in a Toll-like receptor-4 (TLR4)-dependent manner. In addition, we find that CD41+ megakaryocytes grown from fetal livers and adult circulating platelets express significant amounts of TLR4. LPS induced thrombocytopenia in wild-type mice but not in TLR4-deficient (TLR4def) mice. Wild-type platelets accumulated in the lungs of wild-type mice in response to LPS; TLR4def platelets did not. However, wild-type platelets did not accumulate in the lungs of LPS-treated TLR4def mice. Neutrophils also accumulated in the lungs, and this preceded platelet accumulation. Neutrophil depletion completely abolished LPS-induced platelet sequestration into the lungs, but platelet depletion did not affect neutrophil accumulation. Thus, our data show for the first time that platelets do express functional levels of TLR4, which contribute to thrombocytopenia through neutrophil-dependent pulmonary sequestration in response to LPS.
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PMID:Platelets express functional Toll-like receptor-4. 1596 12

The aim of this study was to investigate the role of blood cells in the expression of tissue factor (TF) and P-selectin in platelets and microparticles from blood stimulated with lipopolysaccharide (LPS), with or without the further addition of phorbol myristyl acetate (PMA). TF activity was found to be associated with platelets after 2 h incubation of whole blood with LPS or LPS + PMA, while no TF activity was detected in microparticles from blood subjected to such stimulation. In blood stimulated for 6 and 24 h, addition of PMA to the samples led to a substantial increase in TF activity associated with microparticles, compared with stimulation with LPS alone. Addition of PMA to blood samples also led to a three-fold increase in the amount of P-selectin found in the isolated microparticle fraction, and a 50% reduction in P-selectin measured in platelets, compared with LPS alone used for stimulation. In a different experiment, TF-rich microparticles were shown to be absorbed very efficiently by neutrophils in a calcium-independent reaction. Our results imply that LPS stimulation of whole blood is associated with a direct transfer of TF from monocytes to platelets in the absence of free TF-rich microparticles, which probably is accounted for by the fusion of TF-rich microparticles with activated platelets exposing P-selectin. Further addition of PMA to samples generates both free TF-rich microparticles as well as enhanced transfer of TF from monocytes to platelets.
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PMID:Generation of tissue factor-rich microparticles in an ex vivo whole blood model. 1609 30


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