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)

Nitric oxide (NO) has been implicated in the pathogenesis of the circulatory dysfunction of endotoxin shock. We investigated the effect of aminoguanidine (AG), an inhibitor of nitric oxide synthase (NOS) that is more selective for the inducible NOS, on the circulatory and inflammatory sequelae after administration of a bolus (10 mg/kg iv) of lipopolysaccharide (LPS) (Salmonella enteritidis). Rats receiving LPS + vehicle (LPS + Veh) exhibited a 73% decrease in mean arterial blood pressure (MABP) and a 50% decrease in cardiac index (CI) and SV index (SVI) within 10 min after LPS administration. MABP recovered to 64 +/- 3, 81 +/- 6, and 79 +/- 8 mmHg, at 60, 120, and 180 min post-LPS, respectively. However, CI and SVI remained depressed by 40-50% for the entire experimental period. Systemic vascular resistance (SVRI), heart rate (HR), and hematocrit were significantly elevated at 180 min after LPS administration. There was a 15-fold increase in plasma nitrite/nitrate and significantly elevated tissue nitrite/nitrate in the lung, heart, liver, and intestine after 3 h of acute endotoxemia. Treatment with AG markedly decreased plasma nitrite/nitrate but did not alter the initial hypotension or cardiac depression. However, at 60 min after LPS administration the HR, MABP, and SVRI were higher in the AG-treated rats compared with vehicle, whereas CI and SVI remained depressed. Myeloperoxidase activity was significantly increased in the lung but not in the other tissues after LPS. The AG infusion significantly reduced tissue nitrite/nitrate in the lung and heart compared with LPS + Veh. The data suggest that neither NO nor acute inflammatory cell accumulation is solely responsible for the depressed cardiovascular function after intravenous administration of LPS.
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PMID:Effects of inhibition of nitric oxide synthase by aminoguanidine in acute endotoxemia. 912 47

We investigated the effect of rebamipide, a novel antiinflammatory agent, on liver damage in a rat model of circulatory shock induced by bacterial endotoxin (E. coli lipopolysaccharide, LPS). Endotoxemia for 6 hr resulted in a 5.9-fold rise in the serum levels of nitrite (P < 0.05) with a significant rise in the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactic dehydrogenase (LDH), suggestive of liver dysfunction. The increased activities of serum ALT, AST, and LDH, but not serum nitrite were significantly inhibited by rebamipide (100 mg/kg, orally for five days). Myeloperoxidase activity in the liver was significantly elevated in the rats with endotoxemia by 2.4-fold (P < 0.05), which was also significantly inhibited by rebamipide. Upon LPS injection, serum TNF-alpha levels peaked at 1 hr after LPS (from 167.4 +/- 20.0 to 1570.0 +/- 100.0 pg/ml) and thereafter rapidly declined. The increased TNF-alpha level measured at 1 hr was significantly inhibited by pretreatment with rebamipide (100 mg/kg for five days). It is suggested that rebamipide exerts a strong protective effect on the LPS-induced liver damage through inhibition of activation of neutrophils and TNF-alpha production.
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PMID:Effect of rebamipide on liver damage and increased tumor necrosis factor in a rat model of endotoxin shock. 975 43

Guanine (Gua) modification by nitrating and hydroxylating systems was investigated in DNA. In isolated calf thymus DNA, 8-NO(2)-Gua and 8-oxo-Gua were dose-dependently formed with peroxynitrite, and 8-NO(2)-Gua was released in substantial amounts. Myeloperoxidase (MPO) with H(2)O(2) and NO(2)(-) reacted with calf thymus DNA to form 8-NO(2)-Gua dose dependently without release of 8-NO(2)-Gua. The frequency of strand breaks was higher than the sum of 8-NO(2)-Gua and 8-oxo-Gua, particularly in the MPO-treated DNA, indicating the importance of other types of damage. The activation of human neutrophils and lymphocytes with phorbol ester did not induce 8-NO(2)-Gua and 8-oxo-Gua in their nuclear DNA. However, 8-NO(2)-Gua was found in calf thymus DNA co-incubated with activated neutrophils in the presence of NO(2)(-). No significant formation of 8-NO(2)-Gua was found in liver DNA from mice treated with Escherichia coli lipopolysaccharide. The incubation of peroxynitrite or MPO-H(2)O(2)-NO(2)(-)-treated DNA with formamidopyrimidine glycosylase (Fpg) released 8-oxo-Gua, but not 8-NO(2)-Gua, indicating that 8-NO(2)-Gua is not a substrate for Fpg. Although 8-NO(2)-Gua was generated in isolated DNA by different nitrating systems, other types of damage were formed in abundance, and the lesion could not be found reliably in nuclear DNA, suggesting that the biological importance is limited.
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PMID:Importance of guanine nitration and hydroxylation in DNA in vitro and in vivo. 1098 Apr 3

Hyperbaric oxygen (HBO2) has been shown to inhibit the adhesion function of beta(2)-integrin, which is important in mediating cell-to-cell adhesion and extravasation of inflammatory cells. In the present study, we examined the effects of HBO2 exposure on neutrophil infiltration and tissue injury in a model of acute lung inflammation induced by lipopolysaccharide (LPS) inhalation. Male C57BL/6 mice of 8 weeks old were exposed to 3 atmosphere absolute (ATA) 100% HBO2, 3 ATA hyperbaric air (HBA), or room air for 90 min. After exposure, they were exposed to aerosolized LPS solution (1 mg/ml) or saline in a plexiglass chamber for 10 min. Four hours after inhalation, bronchoalveolar lavage (BAL) was performed to determine protein concentration, LDH activity, total cells, and differential cell counts in the lavage fluid (BALF). Myeloperoxidase (MPO) content, lung histopathology, and plasma nitric oxide (NO) metabolite concentrations were also determined in separate sets of animals. We observed that LPS inhalation increased neutrophil number in the BALF, which was significantly inhibited by HBO2 but not HBA pre-exposure. However, MPO content in the lung was prominently increased by HBO2 pre-exposure, which correlated with increased PMN infiltration in lung tissues. Further, HBO2 plus LPS, but not saline inhalation caused a significant increase in the BALF protein level and LDH activity compared with that of LPS inhalation alone. LPS exposure induced significant increase in plasma NO metabolites, which was not potentiated by HBO2 pre-exposure. The inducible nitric oxide synthase inhibitor, aminoguanidine, significantly attenuated the increases in plasma NO metabolites and tissue MPO content as well as lung injuries. In summary, our data suggest that HBO2 pre-exposure increases the lung's susceptibility to inhaled LPS, which may be related to increased tissue neutrophil infiltration and dependent on interaction(s) between HBO2 exposure with LPS-induced nitric oxide production.
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PMID:Hyperbaric oxygen increases the lung's susceptibility to inhaled lipopolysaccharide in mice. 1217 3

Both cooked red meat intake and chronic inflammation/infection are thought to play a role in the etiology of colon cancer. The heterocyclic amine 2-amino-3-methylimidazo[4,5-f ]quinoline (IQ) is formed during cooking of red meat and may be involved in initiation of colon cancer. Reactive nitrogen oxygen species (RNOS), components of the inflammatory response, contribute to the deleterious effects attributed to inflammation on normal tissues. This study assessed the possible chemical transformation of IQ by RNOS. RNOS were generated by various conditions to react with (14)C-IQ, and samples were evaluated by HPLC. Myeloperoxidase (MPO)-catalyzed reaction was dependent upon both H(2)O(2) and NO(2)(-). This reaction produced an azo-IQ dimer and IQ dimer along with two nitrated IQ products identified by ESI/MS. 2-Nitro-IQ was not detected. Product formation was inhibited by 2 mM cyanide. Reduction in nitrated products observed with 100 mM chloride was not altered with 0.5 mM taurine. Nitrated products were also produced by other conditions, ONOO(-) and NO(2)(-) + HOCl, which generate nitrogen dioxide radical. In contrast, conditions which generate N(2)O(3), such as diethylamine NONOate, produced only small amounts of nitrated products with the major product identified by MS and NMR as N-nitroso-IQ. MPO activation of IQ to bind DNA was dependent upon both H(2)O(2) and NO(2)(-). RNOS generated by ONOO(-) and DEA NONOate also activated IQ DNA binding. The nitrated IQ products were not activated by MPO to bind DNA. In contrast, N-nitroso-IQ was activated to bind DNA by MPO +/- NO(2)(-). HOCl activated N-nitroso-IQ, but not IQ. RAW cells produced N-nitroso-IQ and increased amounts of NO(2)(-)/NO(3)(-), when incubated with 0.1 mM IQ and stimulated with lipopolysaccharide and interferon gamma. Results demonstrate chemical transformation and activation of IQ by RNOS and activation of its N-nitroso product by biological oxidants, events which may contribute to initiation of colon cancer.
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PMID:Nitrosation and nitration of 2-amino-3-methylimidazo[4,5-f]quinoline by reactive nitrogen oxygen species. 1218 90

We recently reported that hypothermia protects against intrapulmonary nitric oxide overproduction and nitric oxide-mediated lung injury in endotoxemic rats. Few studies have been performed to investigate whether hypothermia reduces inflammation by affecting favorable changes in chemokine and pro- and anti-inflammatory cytokine profiles. In this study, we tested the hypothesis that hypothermia decreases concentrations of growth-related oncogene/cytokine-induced neutrophil chemoattractant-1 (GRO/CINC-1), interleukin (IL)-1beta, IL-6, and myeloperoxidase and increases concentration of IL-10 in the lungs endotoxemic rats. Twelve rats were anesthetized and randomized to treatment with either hypothermia (T = 18-24 degrees C; n = 6) or normothermia (T = 36-38 degrees C, n = 6). Endotoxin (15 mg/kg of Escherichia coli lipopolysaccharide) was administered intravascularly and lung tissue was harvested 150 min later. Three additional rats were sham instrumented and maintained as normothermic but not given endotoxin. Hematoxylin & eosin staining was performed for qualitative inspection of tissues. Quantitative analyses of lung homogenates were performed using enzyme-linked immunosorbent assays for IL-1beta, IL-6, IL-10, and GRO/CINC-1. Myeloperoxidase concentrations were determined using a colorimetric assay. Hypothermia attenuated the induction of intrapulmonary IL-1beta (P < 0.05), IL-6 (P < 0.05), GRO/CINC-1 (P < 0.05), and myeloperoxidase (P < 0.05) caused by endotoxin. Inspection of the lungs revealed that hypothermia similarly attenuated histological signs of injury, such as interstitial edema and neutrophil accumulation. Hypothermia increased the intrapulmonary concentration of IL-10 more than 3-fold over that measured in the normothermia (endotoxin-exposed) group (P < 0.05). Hypothermia inhibits neutrophil recruitment in the lungs of endotoxemic rats in part by decreasing proinflammatory cytokine expression. Additionally, hypothermia induces intrapulmonary IL-10 expression. Further studies are needed to investigate whether IL-10 mediates the anti-inflammatory effects of hypothermia.
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PMID:Hypothermia induces interleukin-10 and attenuates injury in the lungs of endotoxemic rats. 1281 67

The formation of reactive nitrogen species in mammalians has both beneficial and undesirable effects. Nitric oxide (NO) production in endothelial cells leads to vascular smooth muscle relaxation, but if reactive nitrogen species are generated in high amounts by cells under inflammatory conditions they are toxic. Flavonoids like (-)-epicatechin show an inverse association of their intake with diseases thought to be associated with overproduction of reactive nitrogen species. We found that the formation of cyclic GMP in cultured porcine aortic endothelial cells was not affected by up to 1 mM (-)-epicatechin. Half maximal inhibition of interferon-gamma/lipopolysaccharide induced nitrite accumulation in murine macrophages required about 0.5 mM of the flavonoid. In contrast, nitration of free tyrosine triggered by 0.1 and 1 mM authentic peroxynitrite was inhibited by (-)-epicatechin with IC(50) values of 6.6 and 28.0 microM, respectively. The presence of 15 mM sodium bicarbonate had no significant effect. Nitration of protein-bound tyrosine in phorbol 12-myristate 13-acetate treated HL-60 cells in the presence of nitrite was inhibited by (-)-epicatechin at a similar concentration range (IC(50)=10-100 microM). Myeloperoxidase activity of phorbol 12-myristate 13-acetate stimulated HL-60 cells was inhibited by (-)-epicatechin with an IC(50) value of 77.4 microM. Epicatechin inhibited dihydrorhodamine oxidation by 50 microM authentic peroxynitrite and 1 mM 3-morpholino-sydnonimine with IC(50) values of 11.8 and 0.63 microM, respectively. Our data suggest that at up to 0.1 mM (-)-epicatechin preferentially inhibits NO-related nitration and oxidation reactions without affecting NO synthesis and cyclic GMP signaling.
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PMID:Interference of the polyphenol epicatechin with the biological chemistry of nitric oxide- and peroxynitrite-mediated reactions. 1501 44

Burn trauma increased blood chemiluminescence, while lipopolysaccharide in a dose of 1 mg/kg potentiated this effect, activated LPO, and decreased plasma antioxidant activity. In erythrocytes, superoxide dismutase activity increased, while activity of peroxide-utilizing enzymes decreased. Myeloperoxidase content increased in the lungs and epidermis. The preparation of alpha-tocopherol, selenium aspartate, and ubiquinone abolished the effect of lipopolysaccharide, but did not modulate the increase in chemiluminescence under the influence of this agent.
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PMID:Protective effect of complex antioxidant preparation containing vitamins and amino acids in rats with burn trauma complicated by endotoxemia. 1736 50

Two transformed murine macrophage cell lines (RAW 264.7 ATCC TIB-71 and CRL-2278) were examined for oxidant production at various times following activation by using a set of fluorescence and ESR-active probes. Stimulation with a soluble agonist or activation with bacterial lipopolysaccharide plus gamma-interferon caused only very small initial increases in O2 consumption above basal rates; however, at 2-4 h post-activation, respiration increased to 2-3-fold and remained at these elevated levels over the subsequent lifetime of the cell (20-30 h). Oxidation reactions were confined primarily within the cell, as was demonstrated by using phagocytosable dichlorodihydrofluorescein-conjugated latex beads and cyclic hydroxylamines with differing membrane permeabilities. From the intrinsic reactivities of these probes and the time course of their oxidations, one infers the induction of apparent peroxidase activity beginning at approximately 2 h post-activation coinciding with the increase in overall respiratory rate; this acquired capability was accompanied by accumulation of a stable horseradish peroxidase-reactive oxidant, presumably H2O2, in the extracellular medium. Nitrite ion rapidly accumulated in the extracellular medium over a period of 5-8 h post-activation in both cell lines, indicating the presence of active nitric oxide synthase (iNOS) during that period. Prostaglandin endoperoxide H synthase (COX-2) activity was detected at 15-20 h post-activation by the use of a sensitive peroxide assay in conjunction with a COX-2 specific inhibitor (DuP-697). Superoxide formation was detected by reaction with hydroethidine within the first hour following activation, but not thereafter. Consistent with the absence of significant respiratory stimulation, the amount of O2*- formed was very small; comparative reactions of cyclic hydroxylamine probes indicated that virtually none of the O2*- was discharged into the external medium. Myeloperoxidase (MPO) activity was probed at various times post-activation by using fluorescein-conjugated polyacrylamide beads, which efficiently trap MPO-generated HOCl in neutrophils to give stable chlorofluorescein products. However, chlorination of the dye was not detected under any conditions in RAW cells, virtually precluding MPO involvement in their intracellular reactions. This same probe was used to determine changes in intraphagosomal pH, which increased slowly from approximately 6.5 to approximately 8.2 over a 20 h post-phagocytosis period. The cumulative data suggest that activation is followed by sequential induction of an endogenous peroxidase, iNOS, and COX-2, with NADPH oxidase-derived O2*- playing a minimal role in the direct generation of intracellular oxidants. To account for reported observations of intracellular tyrosine nitration late in the life cycles of macrophages, we propose a novel mechanism wherein iNOS-generated NO2- is used by COX-2 to produce NO2* as a terminal microbicidal oxidant and nitrating agent.
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PMID:Pathways for intracellular generation of oxidants and tyrosine nitration by a macrophage cell line. 1753 Aug 64

Lesions obtained early in the course of multiple sclerosis (MS) have been studied immunocytochemically, and compared with the early stages of the experimental lesion induced in rats by the intraspinal injection of lipopolysaccharide. Large hemispheric or double hemispheric sections were examined from patients who had died in the course of acute or early relapsing multiple sclerosis. In MS patients exhibiting hypoxia-like lesions [Pattern III; Lucchinetti et al. Ann Neurol (2000) 47: 707-17], focal areas in the white matter showed mild oedema, microglial activation and mild axonal injury in the absence of overt demyelination. In such lesions T-cell infiltration was mild and restricted to the perivascular space. Myeloperoxidase and the inducible form of nitric oxide synthase were expressed primarily by microglia, and the activated form of these cells was associated with extracellular deposition of precipitated fibrin. In addition, these lesions showed up-regulation of proteins involved in tissue preconditioning. When active demyelination started, lesions were associated with massive T-cell infiltration and microglia and macrophages expressed all activation markers studied. Similar tissue alterations were found in rats in the pre-demyelinating stage of lesions induced by the focal injection of bacterial lipopolysaccharide into the spinal white matter. We suggest that the areas of microglial activation represent an early stage of tissue injury, which precedes the formation of hypoxia-like demyelinated plaques. The findings indicate that mechanisms associated with innate immunity may play a role in the formation of hypoxia-like demyelinating lesions in MS.
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PMID:Lesion genesis in a subset of patients with multiple sclerosis: a role for innate immunity? 1795 12


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