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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Whereas we observed previously that concentrations of the lipoxygenase inhibitor nordihydroguaiaretic acid that inhibited leukotriene B4 release from lipopolysaccharide-stimulated human alveolar macrophages in vitro also inhibited subsequent interleukin-8 release, we hypothesized that leukotriene B4 release was required for the release of interleukin-8. Alveolar macrophages from normal nonsmoking volunteers were adhered to plastic and incubated with varying concentrations (25-250nM) of the 5-lipoxygenase activating protein inhibitor MK-886 prior to stimulation with lipopolysaccharide. MK-886 inhibited leukotriene B4 release in a concentration-dependent manner. The concentration of MK-886 that inhibited release by 50% was 53.3 +/- 23.1nM (mean +/- SD), n = 4. Interleukin-8 concentrations in 24hr supernatants were not inhibited by incubation of the cells with any concentration of MK-886, including those that inhibited leukotriene B4 release by > 95%. Thus, MK-886 is an effective inhibitor of human alveolar macrophage release of leukotriene B4, and the release of leukotriene B4 is not a prerequisite for alveolar macrophage release of interleukin-8.
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PMID:The effect of inhibition of leukotriene B4 release on lipopolysaccharide-induced production of neutrophil attractant/activation protein-1 (interleukin-8) by human alveolar macrophages. 838 Sep 37

During the last decade intensive work on the relationships between the liver and the arachidonic acid cascade has greatly expanded our knowledge of this area of research. The liver has emerged as the major organ participating in the degradation and elimination of arachidonate products of systemic origin. The synthesis in the liver of arachidonate products derived from the cyclooxygenase, lipoxygenase and cytochrome P450 system pathways has been demonstrated. The participation of leukotriene B4 and cysteinyl-leukotrienes as mediators of liver damage and the possible therapeutic usefulness of prostaglandins (PGs) in acute liver injury has attracted the interest of clinicians. This article reviews the essential features regarding the role of arachidonate metabolites in liver disease and specially focuses on the cytoprotective effects on the liver displayed by PGE2, PGE1, PGI2 and synthetic PG analogs in experimental models of liver damage induced by ischemia-reperfusion injury, carbon tetrachloride, bacterial lipopolysaccharide and viral hepatitis and on the possible mechanisms underlying liver cytoprotection in these experimental models. The therapeutic usefulness of PGs in clinical practice is critically analyzed on the basis of available evidence in patients with fulminant hepatic failure and primary graft nonfunction following liver transplantation.
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PMID:Liver cytoprotection by prostaglandins. 841 74

The effects of several inhibitors of lipoxygenases were investigated in murine spleen cell cultures activated with endotoxin (lipopolysaccharide). It was found that these inhibitors interfere with the proliferative response of the cultures. Indomethacin, a specific cyclooxygenase inhibitor, had no such effect. Endotoxin induced the synthesis of tumour necrosis factor alpha in spleen cells which was prevented by treatment with a lipoxygenase inhibitor. The inhibition of the mitogenic effect of endotoxin could be reversed by addition of 13-hydroxyoctadecadienoic acid. This was not the case with leukotriene B4 and C4 or 15-hydroxyeicosatetraenoic acid. In contrast, these substances had inhibitory effects on the mitogenicity of spleen cells. It is suggested that 13-hydroxyoctadecadienoic acid is involved in the development of the mitogenic reaction, possibly on the level of tumour necrosis factor alpha production of macrophages present in the cultures.
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PMID:Suppression of endotoxin mitogenicity of spleen cells by lipoxygenase inhibitors and its reversal by 13-hydroxyoctadecadienoic acid. 847 13

Inflammation is characterized by the migration of polymorphonuclear leukocytes from the vasculature into the tissue causing profound injury. Adhesion and migration of neutrophils across the vascular bed are governed by a series of complex events including cytokine/chemokine production which in turn orchestrates the temporal expression of a cohort of adhesion molecules mediating the migration. Many of these adhesion molecules and their inducers are under the control of inflammatory response transcriptional factors such as NF kappa B and AP-1. Recently we showed tepoxalin, previously known as a dual cyclooxygenase/lipoxygenase (CO/LO) inhibitor, to be a potent inhibitor of NF kappa B-induced transcription in vitro. In this study, we demonstrated that when administered in vivo, tepoxalin but not naproxen (a nonsteroidal anti-inflammatory drug, NSAID) or zileuton (an LO inhibitor), effectively inhibits neutrophil migration into inflammatory sites in murine skin stimulated by either lipopolysaccharide (LPS) or tumor necrosis factor-alpha. Immunohistochemical analysis indicates that 10-50 mg/kg of tepoxalin inhibits neutrophil migration. It also effectively blocks the upregulation of Mac-1 (CD11b/CD18) on neutrophils. Quantitative polymerase chain reaction Mac-1 analysis shows that LPS-induced transcription of E-selectin mRNA was dramatically suppressed by both 25 and 50 mg/kg of tepoxalin, whereas the level of ICAM-1 was only affected by 50 mg/kg of tepoxalin. Since it has been documented that the expression of E-selectin and Mac-1 is regulated either directly or indirectly by the transcription factor NF kappa B, our studies provide in vivo evidence that tepoxalin is a potent inhibitor of NF kappa B-mediated events in animal models and this novel molecular mechanism clearly defines it as a new class of anti-inflammatory compounds.
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PMID:Tepoxalin blocks neutrophil migration into cutaneous inflammatory sites by inhibiting Mac-1 and E-selectin expression. 856 54

One hour after lipopolysaccharide (LPS) administration (intravenous) in guinea pigs, alveolar macrophages are primed for an ex vivo increased secretion of arachidonic acid metabolites from the cyclooxygenase and the lipoxygenase pathways, with challenge by a second stimulus. At the same time, maximal levels of tumor necrosis factor-alpha (TNF-alpha) are observed in the circulation and in the bronchoalveolar lavage fluid. An extracellular form of phospholipase A2, corresponding probably to the low-molecular-mass type II enzyme, known to accumulate in inflammatory exudates, appears later in the serum of guinea pigs, to reach maximal levels 6 h after the LPS. Unlike the intracellular enzyme, extracellular phospholipase A2 is not increased by LPS in alveolar macrophages or in bronchoalveolar lavage fluids. After 24 h, at the time when neither TNF-alpha nor extracellular phospholipase A2 is present and priming of macrophages is over, maximal neutrophil infiltration is observed in the alveolar space of LPS-treated guinea pigs. Dexamethasone administered repeatedly during 3 days (subcutaneous) before the LPS challenge prevented both early events such as the macrophage priming and the TNF-alpha appearance and later events such as extracellular phospholipase A2 release and neutrophil recruitment.
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PMID:Modulation by dexamethasone of phospholipase A2 activities in endotoxemic guinea pigs. 856 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

Pulmonary surfactant has a potential role in modulating inflammation in normal and injured lungs. In lung injury, monocytes become activated and participate in lung inflammation. We therefore, investigated the proinflammatory functions of stimulated human blood monocytes after an overnight preincubation period with modified natural porcine surfactant (Curosurf) (500-1000 micrograms/mL). Monocytes were stimulated either with phorbol myristate acetate (PMA), bacterial extract OM-85, lipopolysaccharide (LPS), or Ca2+ ionophore A23187. The present study shows that Curosurf significantly inhibits: 1) the production of superoxide anions stimulated with OM-85 (1 mg/mL, 30 min), but not with PMA (100 ng/mL, 30 min); 2) the release of cyclooxygenase metabolites prostaglandin E2 and thromboxane B2 stimulated with OM-85 (1 mg/mL, overnight); 3) the release of lipoxygenase metabolite leukotriene C4 stimulated with A23187 (10 microM, 10 min); 4) the release of the cytokine TNF-alpha stimulated overnight with either OM-85 (1 mg/mL) or LPS (10 micrograms/mL)) in a dose-dependent fashion. In addition, Curosurf decreases the spontaneous adherence of monocytes to plastic culture wells in a dose-dependent fashion. Experiments performed with staurosporine, an inhibitor of protein kinase C (PKC) indicate that, in contrast with PMA, the production of superoxide anions stimulated by OM-85 is not related to PKC activation. Consequently, we propose that the mechanism involved in the suppressive effects of Curosurf is PKC-independent. In summary, the present study provides experimental evidence that favors the anti-inflammatory role of modified natural porcine surfactant (Curosurf) in human monocytes in vitro.
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PMID:Modified natural porcine surfactant inhibits superoxide anions and proinflammatory mediators released by resting and stimulated human monocytes. 897 99

Astrocytes play an important role in initiating and modulating inflammatory responses within the central nervous system. Extensive studies in rodents have shown that TPA, substance P, calcium ionophore A21387, and lipopolysaccharide (LPS) induce formation and release of arachidonic acid metabolites which have immunoregulatory properties. To better understand the immunopathology of brain injury, we studied the role of inflammatory cytokines such as tumor necrosis factor alpha, interleukin (IL) 6, IL-2, interferon gamma and IL-1 beta in the production of arachidonic acid metabolites in cells from fetal human brain. Among these cytokines, only IL-1 beta significantly stimulated production of prostaglandins E2 and F2 alpha but not PGD2, thromboxane B2 and 6-keto-PGF1 alpha. Under our experimental conditions, these astrocyte cultures did not produce metabolites in the lipoxygenase pathway such as leukotrienes B4 and C4 upon IL-1 beta stimulation. The stimulatory effects of IL-1 beta on the induction of arachidonic acid metabolites have been studied in various human cell types but not in astrocytes. Human astrocyte production of PGF2 alpha and PGE2 but not PGD2, 6-keto-PGF1 alpha and TXB2 when stimulated by IL-1 beta, is thus a novel finding. This observation should initiate investigations into the mechanism of arachidonic acid metabolism and the role of its metabolites in inflammation in the human nervous system.
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PMID:Recombinant human interleukin 1 beta induces production of prostaglandins in primary human fetal astrocytes and immortalized human fetal astrocyte cultures. 898 97

Activated macrophages synthesize a 26-kDa cell surface form and a 17-kDa secreted form of tumor necrosis factor alpha (TNF-alpha). This study was designed to investigate possible differences between the biosynthesis of these two forms by murine peritoneal exudate cells (PEC) and a murine macrophage cell line (RAW 264.7) stimulated with lipopolysaccharide (LPS). Both PEC and RAW 264.7 cells produced surface and secreted TNF-alpha in response to LPS in a dose-dependent manner. However, much lower concentrations of LPS (100 ng/mL) were needed for optimal expression of surface TNF-alpha than for secreted TNF-alpha (1 microgram/mL). Furthermore, concentrations of actinomycin D that inhibit the synthesis of new mRNA and the production of secreted TNF-alpha did not block the expression of surface TNF-alpha on LPS-stimulated cells. Cycloheximide inhibited the production of both forms of TNF-alpha at similar concentrations. The effects, on the expression of the surface form of TNF-alpha, of various pharmacological agents known to inhibit the production of secreted TNF-alpha were studied. It was found that: (1) dexamethasone, a glucocorticoid agonist and (2) ETI and ETYA, inhibitors of lipoxygenase, had no effect on cell surface TNF-alpha at concentrations that inhibited secreted TNF-alpha. The data show that there are differences in the production of surface and secreted TNF-alpha and indicate that the regulation of synthesis of this protein is more complex than that suggested by a mere precursor/product relationship between the two forms.
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PMID:Differential regulation of biosynthesis of cell surface and secreted TNF-alpha in LPS-stimulated murine macrophages. 926 39

In cultured microglial cells pro-inflammatory substances such as lipopolysaccharide and interferon-gamma induce outward-rectifying K+ channels (OR) exhibiting features of the Kv1.3 type. Here we studied the modulation of this channel by arachidonic acid (AA). Micromolar doses of AA (0.3-30 microM; ED50 1.55 microM) depressed OR currents at all the potentials tested. Such effect appeared in less than 30 s, reached the maximum in approximately 2 min, and partially reverted upon removal of AA. We then tested whether AA acted by mechanisms involving enzyme activation. The AA effect on OR remained unchanged in the presence of staurosporine (protein kinase C inhibitor), indomethacin (cyclooxygenase inhibitor), nordihydroguaiaretic acid (lipoxygenase inhibitor), and diphenylene iodonium (NADPH-oxidase inhibitor). The same effect was present in cell-free membrane patches in the outside-out configuration. In whole-cell recording AA induced the following changes in OR current: (a) decrease of OR current peak at all voltages tested; (b) increase of the activation rate and mild shift of the voltage-dependence of the activation; (c) acceleration of the inactivation rate with a concomitant appearance of a second and faster inactivation component; and (d) shift of the voltage-dependence of the inactivation curve. We also observed that upon AA application, the acceleration of activation and inactivation developed earlier than the second component of inactivation. We conclude that AA, by acting on both the channel protein and its lipid environment, causes a quick negative modulation of microglial OR current. We propose that a raised free AA may determine a loss of efficiency of OR in controlling the membrane potential and thus influence the functional reactivity of microglia to inflammatory stimuli.
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PMID:Arachidonic acid-induced inhibition of microglial outward-rectifying K+ current. 943 83


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