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)

Respiratory tract infections are major causes of excessive morbidity and mortality in hospitalized patients. Persons with systemic sepsis have an especially high risk of acquiring these infections, which indicates that their lung antibacterial defenses are compromised. To evaluate the effects of sepsis on pulmonary antibacterial defenses, we injected either saline or 5 mg/kg of Escherichia coli lipopolysaccharide intravenously into Sprague-Dawley rats. Two hours later, the animals were challenged by aerosol inhalation with either Staphylococcus aureus or Pseudomonas aeruginosa. It is known that phagocytic defenses against aerosolized S. aureus challenges are provided solely by the alveolar macrophage; in normal animals challenged with P. aeruginosa, however, an intrapulmonary inflammatory response is elicited. Animals pretreated with endotoxin showed a significant decrease in pulmonary bactericidal activity against S. aureus with 31 +/- 3% bacteria remaining viable at 4 hr compared with 20 +/- 2% in the controls, which indicates a defect in alveolar macrophage antimicrobial activity. After P. aeruginosa challenge, saline-injected control animals developed a marked intrapulmonary inflammatory response and killed greater than 85% of their initial inoculum by 4 hr. By contrast, endotoxin-treated animals failed to recruit neutrophils into the alveoli in response to P. aeruginosa, resulting in a proliferation of this pathogen within the lung (212 +/- 6% bacteria remaining viable at 4 hr). Endotoxin is known to be a potent stimulus for the production of tumor necrosis factor (TNF) by the host. TNF is a potent inflammatory mediator and promotes neutrophil adhesion to the vascular endothelium. In these experiments, serum TNF peaked at 28,390 +/- 7,766 Units/ml. 90 min after intravenous endotoxin. Histopathology of the lungs in these animals showed considerable sequestration of the neutrophils within the pulmonary vasculature. These data show that systemic endotoxin significantly impairs lung host defenses against intrapulmonary bacterial challenges and suggest that TNF-mediated events may play a central role.
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PMID:Endotoxin-induced suppression of lung host defenses. 212 Mar 77

Chemotactic peptides in the circulation stimulate neutrophils to become sequestered in the pulmonary vasculature, and low concentrations of bacterial lipopolysaccharide (LPS) enhance and prolong this effect. This interaction of neutrophils with the vascular endothelium is thought to involve, in part, the increase in adhesiveness induced in neutrophils by such stimuli. In this study, the binding of albumin-coated latex beads to neutrophils was used to determine whether the enhancement seen with LPS results from an increase in the number of adhesive cells, from the enhancement of the adhesiveness of individual neutrophils, or both. Chemotactic peptides alone and LPS alone induced an increase both in the adhesive population and in the number of beads bound per individual neutrophil. The number of beads bound per cell increased over a very wide range of stimulus concentrations, showing that the degree of adhesiveness of an individual cell in the population varies over a considerable range. Trace concentrations of LPS (10 ng/ml or less), i.e., levels close to those measurable in vivo, had little effect on the proportion of neutrophils that were stimulated by chemotactic factor to become adhesive but did significantly enhance the number of beads bound to each individual neutrophil. The enhancement may require the presence of the CD11/18 glycoprotein complex, but was not further upregulated by LPS. No evidence could be obtained to suggest that the effect of LPS involved release of tumor necrosis factor (TNF) from the numbers of monocytes in the preparation, and the observations are consistent with a direct effect of LPS on the neutrophils. It is suggested that this increase in adhesive sites on the cell could explain the persistence of the sequestration of neutrophils in the microvasculature seen in the presence of both chemoattractants and LPS by enhancing the "strength" of the adhesion to endothelial cells. The increased adhesion may also set the stage for enhanced endothelial injury.
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PMID:Interaction between chemoattractants and bacterial lipopolysaccharide in the induction and enhancement of neutrophil adhesion. 218 56

Human vascular endothelium plays a major role in hemostatic processes. Human venous endothelial cells (HEC) may promote coagulation by generation of thromboplastin. This tissue factor production is enhanced by bacterial lipopolysaccharide (LPS). However, the mechanisms of this enhancement remain unclear. In order to quantify by image analysis the nuclear modifications induced by LPS on HEC, umbilical cord vein HEC were cultured in vitro with or without E. coli LPS (10 micrograms/ml) for 0 to 6 h. At the end of culture, tissue factor expression was evaluated by the ability of a cellular extract to shorten the coagulation time of human citrated plasma. Simultaneously, the morphology of LPS treated and control HEC was analysed using a SAMBA 200 cell image processor after Feulgen staining. This analysis indicates that LPS treatment induces nuclear modifications as early as 1 h after culture onset, before any tissue factor expression. This activity appears only between 2 and 4 h of culture with LPS. Our data show that image analysis permits the detection of very early nuclear events in HEC and that these events precede the expression of functional properties which may be implicated in thrombotic processes.
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PMID:Nuclear textural changes preceding endotoxin mediated enhancement of thromboplastin synthesis in human endothelial cells in vitro. 227 59

Glucocorticoids exert their actions through a time-dependent, receptor-mediated, protein synthesis- and RNA synthesis-dependent mechanism. We have assessed the effects of 24-h culture of human neutrophils with dexamethasone on degranulation, chemotaxis, binding to vascular endothelium and formation of leukotriene B4. Purified neutrophils contained an average of 2896 [3H]dexamethasone binding sites per cell with a Kd of 4.1 X 10(-9) M for [3H]dexamethasone binding. Cells exposed to dexamethasone (10(-6) M) released equal or greater quantities of the lysosomal enzymes, lysozyme and beta-glucuronidase in response to formylmethionyl-leucyl-phenylalanine, serum activated zymosan, and the tumor promoting phorbol diester 12-O-tetradecanoylphorbol-13-acetate compared to controls. Culture with dexamethasone also did not inhibit neutrophil chemotaxis in response to a range of concentrations of formylmethionyl-leucyl-phenylalanine, or did it inhibit binding of neutrophils to cultured endothelial cells stimulated by either leukocyte activators (formylmethionyl-leucyl-phenylalanine and platelet-activating factor) or endothelial activators (interleukin-1, lipopolysaccharide or 12-O-tetradecanoylphorbol-13-acetate). Spontaneous adherence of neutrophils to endothelial cells was inhibited (82.9 +/- 6.8% of control, P less than .025, n = 18). Neither in vitro or in vivo glucocorticoids inhibited neutrophil leukotriene B4 formation induced by either the calcium ionophore A23187 or serum activated zymosan. We conclude that human neutrophils are not functionally inactivated by glucocorticoids and suggest that the mechanism by which glucocorticoids inhibit neutrophil accumulation at inflammatory sites may be by inhibition of the production of chemoattractants and endothelial activators rather than inhibition of their actions.
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PMID:An assessment of the effects of glucocorticoids on degranulation, chemotaxis, binding to vascular endothelium and formation of leukotriene B4 by purified human neutrophils. 254 40

Interleukin-6 (IL-6) is a cytokine which is not only produced by a wide variety of different cells but one which also affects the function of diverse tissues. We have studied the expression of the IL-6 gene in freshly explanted human umbilical vein endothelial cells (HUVEC) and have also evaluated the effect of IL-6 on HUVEC proliferation. Cytokines like interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor (TNF) as well as bacterial products such as the lipopolysaccharide (LPS) rapidly enhance production of biologically active IL-6 by HUVEC (IL-6 bioassay: increase in alpha 1-antichymotrypsin secretion by Hep3B2 cells and its neutralization by antiserum to E. coli-derived human IL-6). The two inducible RNA start sites in the IL-6 gene that are used in cytokine-induced fibroblasts (at +1 and -21) are also used in the same relative proportion (+1 greater than -21) in cytokine or LPS-induced HUVEC as determined by S1-nuclease protection assays for IL-6 transcripts. Immunoaffinity chromatography followed by Western blotting shows that IL-6 species secreted by IL-1 alpha-induced HUVEC are of molecular mass 23-25, 27-30 and 45 kDa as judged by SDS-PAGE under reducing conditions. Finally, rIL-6 inhibits [3H]-thymidine incorporation by HUVEC in a dose-dependent manner. Thus IL-6 is not only produced by HUVEC but may also affect its proliferation. The ability of the vascular endothelium to rapidly secrete IL-6 in response to inflammation-associated cytokines is of strategic value since it generates a circulatory signal which helps mobilize the acute phase plasma protein response and enlists the immune system in host defence.
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PMID:Interleukin-6 gene expression in human endothelial cells: RNA start sites, multiple IL-6 proteins and inhibition of proliferation. 264 5

The pathogenesis of acute lung injury in humans is obscure, but lipopolysaccharide (LPS), complement activation, and neutrophils have been implicated. We investigated in rabbits the interaction of small amounts of intravascularly administered LPS (100 ng) with neutrophil chemotactic factors, the synthetic chemotactic peptide formyl-norleucyl-leucyl-phenylalanine (FNLP), and the biologically relevant chemotactic fragments of C5 (C5f). These neutrophil stimuli produce neutropenia when injected intravascularly in rabbits, reflecting neutrophil adherence to vascular endothelium. When LPS was injected with FNLP, the duration of neutropenia was enhanced. Studies with radiolabeled neutrophils infused in vivo demonstrated prolonged neutrophil sequestration within the lung in rabbits that were given FNLP plus LPS, an effect that was visible for 4 h after injection. Morphometric analysis of tissue sections 4 h after infusion confirmed the presence of greater numbers of neutrophils in the lungs of animals receiving LPS and FNLP. When a combination of LPS and chemotactic factors was infused at both zero and 6 h, we found a marked enhancement of lung vascular permeability at 24 h (as assessed by radiolabeled albumin accumulation), an effect not seen with either LPS or chemotactic factor alone. Ultrastructural studies revealed neutrophil sequestration and alteration in endothelial cells in the animals that received the combination of LPS and chemotactic factors. Neutrophil depletion with nitrogen mustard completely abolished the increased vascular permeability seen in animals that received LPS and chemotactic factors. This study suggests that small amounts of intravascularly administered LPS enhance the sequestration of neutrophils within the lung and increase lung vascular permeability and endothelial injury caused by neutrophils stimulated by intravascularly administered chemotactic factors. This mechanism may be relevant to the production of acute lung injury in human beings.
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PMID:Neutrophil-mediated pulmonary vascular injury. Synergistic effect of trace amounts of lipopolysaccharide and neutrophil stimuli on vascular permeability and neutrophil sequestration in the lung. 330 Apr 42

Glucocorticoids block the localized accumulation of leukocytes as sites of inflammation by preventing their adherence to vascular endothelium. This implies that glucocorticoids are acting either on the leukocytes, endothelium, or cells which produce adherence-promoting factors (such as interleukin 1 (IL-1)). Previous studies have shown that dexamethasone (DEX) treatment of either polymorphonuclear leukocytes (PMN) or human umbilical vein vascular endothelial cells (VEC) or both in vitro does not prevent adherence induced by thrombin or formylmethionyl-leucyl-phenylalanine (f-met peptide). We now show that pretreatment of PMN and/or VEC for 24 hr with 0.1 microM DEX had no effect on adherence of PMN to VEC activated with IL-1 (2 U/ml), lipopolysaccharide (1 microgram/ml), or 12-O-tetradecanoylphorbol-13-acetate (30 ng/ml) suggesting that glucocorticoids may inhibit adherence in vivo by blocking formation of IL-1 and other adherence-inducing stimuli. We have recently established that cultured human lung fragments produce IL-1 in vitro. To investigate whether glucocorticoids could inhibit the production of adherence-inducing factors, we examined the effect of glucocorticoids on IL-1 production from human lung tissue. Treatment of human lung fragments in vitro for 18 hr with glucocorticoids such as DEX and hydrocortisone resulted in dose dependent inhibition of IL-1 production; these and other glucocorticoids, at concentrations ranging between 0.1 and 1 microM, produced greater than 50% inhibition of IL-1 release. Nonglucocorticoid steroids including testosterone and beta-estradiol (1 microM) had no effect. Inhibition of IL-1 production occurred after a lag period 5 of 16 hr, and the relative glucocorticoid potencies agreed with their known anti-inflammatory potencies in vivo (beta-methasone approximately triamcinolone acetonide greater than DEX greater than fludrocortisone greater than prednisolone greater than hydrocortisone). Inhibition of IL-1 production in vivo may, in part, explain the remarkable ability of glucocorticoids to prevent the adherence of leukocytes to endothelium and their accumulation at an inflammatory site.
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PMID:Interleukin 1 production by human lung tissue. II. Inhibition by anti-inflammatory steroids. 349 58

Cultured human endothelial cells exposed to interleukin-1 (IL-1) exhibited increased adhesiveness for human polymorphonuclear leukocytes (PMNs). This phenomenon was dose-dependent, maximal increased adhesion being observed at 0.25 U/ml IL-1. ECs required a minimum exposure time of 30 min. with IL-1 followed by at least 1-2 hours incubation for expression of increased adhesiveness. Incubation for shorter periods of time did not induce significant changes in EC-PMN adhesion compared with cultures having received no IL-1. No change in adhesion was observed when IL-1 was co-incubated with ECs and PMNs. Similar results were observed using lipopolysaccharide (LPS) as stimulus. It is concluded that increased adhesion of PMNs to vascular endothelium is mediated by the direct interaction of endogenous (IL-1) and exogenous (LPS) substances with ECs, the expression of which requires a latent period of 1-2 hours and is protein synthesis-dependent. The implications of these novel findings in pathological disease states are discussed.
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PMID:Increased adhesion of polymorphonuclear leukocytes to vascular endothelium by specific interaction of endogenous (interleukin-1) and exogenous (lipopolysaccharide) substances with endothelial cells 'in vitro'. 633 94

Severe infections and particularly infectious shock are frequently accompanied by a varying degrees of disseminated intra-vascular coagulation (DIC). The mechanism at work is complex, involving endotoxin or bacterial lipopolysaccharide constituents that damage vascular endothelium and activate intrinsic coagulation, platelet function and the release of leucocyte coagulation-promoting compounds. The activation of coagulation in turn activates prekallikrein and complement and plays a part in shock. The laboratory plays an essential role in diagnosing DIC, determining its repercussions on the parameters of haemostasis and in monitoring its course under antibiotics, which in some cases may be combined with carefully controlled heparin treatment. Sensitive and specific tests are the assays for fibrinogen-fibrin degradation products (FDP) and soluble complexes (SC) using the haemagglutination test or the ethanol test. The platelet count should be combined with measurement of the bleeding time. A varying degree of thrombopenia is frequent but non specific. In cases of septicemia, it is an early warning sign. A selective fall in proaccelerin is an indirect early sign. A fall in antithrombin III (AT III) is considered a good sign of DIC but it does not occur in every case, and is most liable to be present in liver failure. From the FDP and fibrinogen results, it should be clear whether one is dealing with compensated, decompensated or even over-compensated DIC. Diagnosis should be complemented by a careful search for the clinical signs of coagulation and haemorrhage. It is indispensable for investigations to be repeated every 6-12 hours, for the sake both of treatment strategy, which can be extremely difficult, and DIC monitoring.
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PMID:[Diagnosis of defibrination syndromes in infectious pathology]. 673 53

Cultured mouse peritoneal macrophages secrete a growth-promoting activity that stimulates 3 types of nonlymphoid mesenchymal cells in vitro: fibroblasts, vascular smooth muscle, and vascular endothelium. Production of this macrophage-derived growth factor (MDGF) is directly related to the number of viable macrophages and their time in culture, and is independent of platelet- or plasma-derived serum growth factors. Treatment of cultured macrophages with latex, bacterial lipopolysaccharide, or phorbol myristate acetate results in increased growth factor activity. Preliminary biochemical characterization of MDGF indicates that it is a heat labile (100 degrees C, 2 min), non-dialyzable protein, which contains at least 1 essential disulfide bond. Growth-promoting activity is not adsorbed by CM-Sephadex chromatography, under conditions that effectively remove platelet-derived growth factor(s). Serine protease activity is not required for the action of MDGF. Secretion of macrophage-derived growth factor may be relevant to the function of mononuclear phagocytes in several pathologic processes, including the neovascularization and fibroplasia of wound healing, smooth muscle hyperplasia in atherosclerosis, and proliferative glomerulonephritis.
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PMID:Stimulation of nonlymphoid mesenchymal cell proliferation by a macrophage-derived growth factor. 720 74


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