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)

Previous studies have shown that: (a) platelet activating factor induces shock and intestinal injury, (b) exogenous platelet activating factor stimulates synthesis of endogenous platelet activating factor, and (c) tumour necrosis factor alpha and endotoxin synergise to induce shock and bowel injury in animals. These last two effects are largely mediated by platelet activating factor forming phospholipase A2 A2, a key enzyme for platelet activating factor synthesis, was examined in mouse intestine. It was found that tumour necrosis factor alpha and endotoxin synergise to stimulate platelet activating factor forming phospholipase A2 activity in the intestine, as well as platelet activating factor production, and these effects were blocked by pretreatment with platelet activating factor antagonists, SRI-63-441 and WEB 2086. In addition, exogenous platelet activating factor stimulates intestinal phospholipase A2 activity. These results show that tumour necrosis factor alpha and lipopolysaccharide synergistically activate the phospholipase A2 that participates in platelet activating factor formation, and this activation is largely mediated by endogenous platelet activating factor. Furthermore, platelet activating factor itself increases phospholipase A2 activity, suggesting that platelet activating factor induces its own synthesis, probably by phospholipase A2 activation.
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PMID:Tumour necrosis factor and endotoxin synergistically activate intestinal phospholipase A2 in mice. Role of endogenous platelet activating factor and effect of exogenous platelet activating factor. 830 72

A novel fluorescence assay for phospholipase A2 [Wilton (1990) Biochem. J. 266, 435-439] has been used to study the Group-II rat liver mitochondrial enzyme, and a number of novel properties of this enzyme were identified. (1) The enzyme activity was located in the liver macrophages (Kupffer cells) while negligible activity was associated with hepatocytes. (2) Although subcellular fractionation of whole liver confirmed the predominantly mitochondrial location of this enzyme activity, the analysis of the hepatocyte-free Kupffer-cell-enriched fraction revealed a different enzyme distribution, with the majority of activity being associated with the microsomal membrane fraction. (3) Bacterial endotoxin has been previously shown to be scavenged by Kupffer cells in rats. Treatment of rats with bacterial lipopolysaccharide (endotoxin) resulted in a dramatic time- and dose-dependent increase in liver phospholipase A2 activity. (4) It is known that injection of endotoxin into rodents results in elevated serum phospholipase A2 activity, while a similar phenomenon is seen in the condition of septic shock in man. The source of this serum enzyme was unknown. In this study perfusion of livers from rats pretreated with lipopolysaccharide with physiological saline demonstrated a 6-fold increase in phospholipase A2 activity in the perfusate compared with sham-treated controls, with only minor release of hepatic lipase. (5) Western-blot analysis confirmed an increased release of this Group-II phospholipase A2 into the perfusate of lipopolysaccharide-treated rats compared with sham-treated controls. These results suggest that liver Kupffer cells are a major source of the endotoxin-induced serum Group-II phospholipase A2 activity associated with bacterial infection and trauma.
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PMID:Rat liver mitochondrial phospholipase A2 is an endotoxin-stimulated membrane-associated enzyme of Kupffer cells which is released during liver perfusion. 832 56

Macrophage-like P388D1 cells release [3H]arachidonic acid and produce prostaglandin E2 (PGE2) upon stimulation with bacterial lipopolysaccharide (LPS) and platelet-activating factor (PAF). To determine whether group II phospholipase A2 (PLA2) is involved in this release, we treated P388D1 cells with antisense inhibitors specific for group II PLA2 RNA. Treatment with oligonucleotide ASGII decreased PLA2 activity in P388D1 cell homogenates by approximately 60% and reduced the release of [3H]arachidonic acid and PGE2 from activated cells to nearly resting cell levels. The inhibition by antisense oligonucleotide ASGII was blocked when its sense complement, SGII, was included in the incubation mixture. Stably transfected P388D1 cells expressing an antisense construct for group II PLA2 also produced reduced quantities of PGE2 in response to LPS and PAF. These data suggest that prostaglandin production by activated P388D1 cells involves phospholipid hydrolysis by group II PLA2. Oligonucleotide ASGII also blocked the appearance of a heparin-releasable group II PLA2 in the culture supernatants of P388D1 cells. The disappearance of this protein correlated with reduced PGE2 production by activated cells, indicating that an extracellular heparin-associated pool of group II PLA2 is involved in prostaglandin production by P388D1 cells.
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PMID:Antisense inhibition of group II phospholipase A2 expression blocks the production of prostaglandin E2 by P388D1 cells. 840 42

The protein tyrosine kinase (PTK) inhibitor genistein has been demonstrated to inhibit platelet-activating factor-stimulated prostaglandin E2 (PGE2) production in lipopolysaccharide (LPS)-primed P388D1 macrophage-like cells (Glaser et al., J Biol Chem 265: 8658-8664, 1990). Therefore, the role of PTK in eicosanoid biosynthesis was investigated in murine resident peritoneal macrophages using genistein and tyrphostin-25, selective PTK inhibitors. Genistein, a competitive inhibitor of ATP binding on PTK, inhibited PGE2 production (IC50 = 20 microM) in response to zymosan, calcium ionophore A23187, and phorbol myristate acetate stimulation. Genistein also inhibited leukotriene C4 (LTC4) production in response to zymosan and calcium ionophore A23187 (IC50 = 10 and 15 microM, respectively) stimulation. Tyrphostin-25, a competitive inhibitor of substrate binding on PTK, inhibited zymosan-stimulated PGE2 and LTC4 production, IC50 = 20 and 7 microM, respectively. Neither genistein nor tyrophostin-25 had any effect on human synovial fluid phospholipase A2 (PLA2) activity in vitro or on cyclooxygenase activity in the intact macrophage; however, tyrphostin-25 did affect 5-lipoxygenase activity (determined from the metabolism of exogenously applied arachidonic acid). These results suggest PTK-mediated phosphorylation as a common event in the signal transduction mechanisms of different stimuli which activate PLA2 for arachidonic acid release and subsequent eicosanoid biosynthesis. Immunoblot analyses of zymosan-stimulated peritoneal exudate cells with the phosphotyrosine monoclonal antibody clone 4G10 demonstrated an increase in protein phosphotyrosine levels in eight major protein bands on sodium dodecyl sulfate-polyacrylamide gel electrophoresis: p59, 71, 76, 90, 100, 112, 125 and 150. Maximal phosphorylation of these protein substrates occurred after 1-2 min stimulation. Zymosan and LPS stimulation of peritoneal exudate cells produced similar patterns of protein tyrosine phosphorylation. Zymosan-stimulated tyrosine phosphorylation was inhibited by tyrphostin-25 in a concentration-dependent manner between 10 and 60 microM, demonstrating a similar concentration response between effects on tyrosine phosphorylation and eicosanoid biosynthesis in the murine peritoneal macrophage. The use of selective PTK inhibitors suggests a common role for PTK and tyrosine phosphorylation in eicosanoid biosynthesis in the murine peritoneal macrophage.
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PMID:Regulation of eicosanoid biosynthesis in the macrophage. Involvement of protein tyrosine phosphorylation and modulation by selective protein tyrosine kinase inhibitors. 844 70

Murine peritoneal exudate macrophages (PEM) co-express granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage CSF (M-CSF) receptors, among others. Treatment of PEM with lipopolysaccharide (LPS) or tumor-promoting phorbol ester (12-O-tetradecanoylphorbol-13-acetate [TPA]) induces a rapid but transient loss of M-CSF receptors in PEM. GM-CSF receptors are not affected by this treatment. The loss of M-CSF receptors induced by LPS can be inhibited by neomycin and compound 48/80, two potent phospholipase C (PLC) inhibitors, but not by phospholipase A2, calpain, protein kinase C (PKC) or protease inhibitors. On the other hand, the loss of M-CSF receptors induced by TPA has been prevented by PKC inhibitors but not by PLC inhibitors. PLC inhibitors also prevent LPS-suppressed receptor-mediated internalization of radiolabeled recombinant human (rh) M-CSF by macrophages. Similar prevention of LPS-induced M-CSF receptor downregulation was observed in human monocytes that had been pretreated with PLC inhibitors. Our results show that 1) TPA-induced M-CSF receptor loss is strictly dependent on PKC activation; 2) PLC activation alone also leads to downregulation of M-CSF receptors; and 3) LPS-induced M-CSF receptor downregulation in PEM is mediated primarily through a PLC-dependent pathway. Our data also imply that the expression of M-CSF but not GM-CSF receptors is linked to an important, yet unknown, PLC-sensitive component(s) whose hydrolysis may lead to downregulation of M-CSF receptors.
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PMID:Downregulation of M-CSF receptors by lipopolysaccharide in murine peritoneal exudate macrophages is mediated through a phospholipase C dependent pathway. 851 62

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

The effect of lipopolysaccharide (LPS) upon the cellular content of mRNA for several enzymes associated with the arachidonic acid cascade was determined in human microvessel-derived endothelial cells. Cells were treated with either vehicle or 10 ng/mL LPS for up to 24 h. Reverse transcription followed by DNA amplification and Southern blotting were used to quantify mRNA for prostaglandin H synthase-1, prostaglandin H synthase-2, cytoplasmic PLA2, and a group II secretory PLA2. LPS treatment resulted in an increase in prostaglandin H synthase-2 mRNA after 4 h with a second peak occurring at 12 h of incubation. The expression of prostaglandin H synthase-1 mRNA was not altered by LPS treatment. An increase in cytoplasmic PLA2 mRNA but not group II PLA2 mRNA was seen after 12 h. These data demonstrate that LPS can increase mRNA production for the inducible form of prostaglandin H synthase and for cytoplasmic PLA2 in a time-dependent manner in human microvessel-derived endothelial cells. These multiple, specific increases in the prostaglandin H synthase-2 and phospholipase A2 mRNA values suggest a complex interaction between bacterial LPS and the endothelial cell eicosanoid system.
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PMID:Lipopolysaccharide induces time-dependent increases in prostaglandin H synthase-2 and cytosolic phospholipase A2 mRNA in cultured human microvessel-derived endothelial cells. 860 1

Using a model of endotoxemia triggered by the intravenous injection of bacterial lipopolysaccharide (0.1 and 1 mg/kg) to guinea-pigs, we investigated the interference of fenspiride, an anti-inflammatory drug recommended for the treatment of inflammatory diseases of the upper respiratory tract. Administered orally at 60 mg/kg, fenspiride reduced the lipopolysaccharide-induced early rise of tumor necrosis factor concentrations in serum (4.2 +/- 0.9 vs. 2.3 +/- 0.5 ng/ml, P < 0.05) and in the bronchoalveolar lavage fluid (55.7 +/- 20 vs. 19.7 +/- 7.5 ng/ml, P < 0.05). The lipopolysaccharide-induced primed stimulation of alveolar macrophages, defined as their enhanced release of arachidonic acid metabolites as compared to cells from untreated controls upon stimulation with N-formyl-methionyl-phenylalanine was also reduced by fenspiride (1551.5 +/- 183.7 vs. 771.5 +/- 237.5 pg/mu g protein, P < 0.05 for thromboxane B2 and 12.6 +/- 4.9 vs. 3.6 +/- 0.9 pg/ mu g protein, P < 0.05 for leukotriene C4). Finally, fenspiride reduced the increased serum concentrations of extracellular type II phospholipase A2 (3.9 +/- 1.2 vs. 1.2 +/- 0.1 nmol/ml per min, P < 0.01), the intensity of the neutrophilic alveolar invasion and the lethality due to the lipopolysaccharide. The protective effect of fenspiride may result from the inhibition of the formation of tumor necrosis factor, a major mediator of the effects of lipopolysaccharide.
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PMID:Fenspiride: an anti-inflammatory drug with potential benefits in the treatment of endotoxemia. 875 Jul 32

We examined the secretion of antimicrobial proteins and peptides into surgically isolated and continuously perfused segments of rat small intestine. Up to nine discrete antimicrobial molecules appeared in the intestinal perfusates following intravenous administration of bethanechol, a cholinergic agonist, or intralumenal instillation of lipopolysaccharide (LPS). Among them were three markers of Paneth cell secretion: lysozyme; type II (secretory) phospholipase A2; and at least one intestinal defensin, RIP-3, that appeared to be an alternatively processed variant of the rat neutrophil defensin RatNP-3. Both bethanechol- and LPS-stimulated intestinal lumenal perfusates (washings) contained molecules that killed Escherichia coli, Salmonella typhimurium, and Listeria monocytogenes in vitro. These molecules were more active against the avirulent S. typhimurium strain 7953S (phoP) than against its virulent parent, S. typhimurium 14028S. These data demonstrate that small intestinal Paneth cells secrete antimicrobial peptides in vivo, that this secretion is regulated by the autonomic (parasympathetic) cholinergic nervous system, and that the release of antimicrobial molecules can be triggered by the presence of bacterial LPS in the intestinal lumen.
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PMID:Secretion of type II phospholipase A2 and cryptdin by rat small intestinal Paneth cells. 894 60

In previous work, we reported that chlorpromazine inhibits tumor necrosis factor (TNF) production in endotoxin lipopolysaccharide-treated mice, and protects against lipopolysaccharide toxicity. Chlorpromazine is used as an antipsychotic and has several effects on the central nervous system. It acts on different neurotransmitter receptors and has other biochemical activities some of which, like inhibition of phospholipase A2, might be responsible for the inhibitory effect on TNF production. To investigate the role of these actions in the inhibition of TNF production by chlorpromazine, we have synthesized some chlorpromazine derivatives that do not have central activities. Some of these analogs have lost their affinity for various receptors and their phospholipase A2 inhibitory activity, but still inhibit TNF production. No correlation was found between TNF inhibition and the ability to inhibit nitric oxide (NO) synthase, whereas a good correlation was evident between TNF inhibition and antioxidant activity.
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PMID:Mechanism of inhibition of tumor necrosis factor production by chlorpromazine and its derivatives in mice. 899 23


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