UNIPROT:P43026 - FACTA Search

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

The combined effects of hypoxia and interleukin 1, lipopolysaccharide, or tumor necrosis factor alpha on the expression of genes encoding endothelial constitutive and inducible nitric oxide synthases, endothelin 1, interleukin 6, and interleukin 8 were investigated in human primary pulmonary endothelial cells and whole pulmonary artery organoid cultures. Hypoxia decreased the expression of constitutive endothelial nitric oxide synthase (NOS-3) mRNA and NOS-3 protein as compared with normoxic conditions. The inhibition of expression of NOS-3 corresponded with a reduced production of NO. A combination of hypoxia with bacterial lipopolysaccharide, interleukin 1 beta, or tumor necrosis factor alpha augmented both effects. In contrast, the combination of hypoxia and the inflammatory mediators superinduced the expression of endothelin 1, interleukin 6, and interleukin 8. Here, we have shown that inflammatory mediators aggravate the effect of hypoxia on the down-regulation of NOS-3 and increase the expression of proinflammatory cytokines in human pulmonary endothelial cells and whole pulmonary artery organoid cultures.
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PMID:Lipopolysaccharide and interleukin 1 augment the effects of hypoxia and inflammation in human pulmonary arterial tissue. 890 7

The present study examined the temporal pattern and cellular localisation of nitric oxide synthase in Endotoxin-Induced Uveitis (EIU). Lewis rats (n=40) received a single footpad injection of 200 microg of bacterial lipopolysaccharide. Animals were killed at 0, 2, 4, 6, 12, 24, 48 and 72 hr after injection and ocular tissues prepared as iris-ciliary body wholemounts or frozen sections of the anterior segment. The expression of constitutive nitric oxide synthase (cNOS) and inducible nitric oxide synthase (iNOS) was investigated at all time points by immunohistochemistry. A further group of animals (n=6) were killed at the peak of the disease (12 hr) and the cellular co-localisation of iNOS on resident and infiltrating immune cells was investigated by double immunohistochemistry utilising the biotinylated monoclonal antibodies ED1, ED2 and Ox6. Expression of cNOS on iris vessels did not alter during the course of EIU. Quantitative analysis of iris-ciliary body wholemounts revealed the first evidence of iNOS+ at 2 hr which increased dramatically at 4 and 6 hr with a peak at 12 hr. The expression of iNOS in the early phase of the disease (2-6 hr) was associated with small round marginating and newly extravasated cells that on morphological criteria were most likely neutrophils and monocytes. At 12 hr, cells of more mixed morphologies began to express iNOS and double labelling revealed 70% of these cells were also ED1(+) (a lysosomal antigen present in monocytes/macrophages and dendritic cells), 52% were Ox6(+) (MHC class II) (dendritic cells, activated macrophages and some T-cells) and 19% were ED2(+) (pan-specific resident tissue macrophages). Expressed in an alternative manner, 10% of the total ED1(+) cell population, 11% of the ED2(+) cells and 44% of Ox6(+) cells co-expressed iNOS. Expression of iNOS decreased significantly by 24 hr to near baseline levels and was absent by 48 and 72 hr. Within the ciliary processes iNOS+ dendriform cells were noted at 6 hr and accumulations of many small round iNOS+ cells were present at 12 hr. The ciliary epithelium did not at any time express iNOS at the protein level detectable by immunohistochemistry. The results of this study suggest that iNOS expression early in EIU is associated with infiltrating or newly recruited neutrophils and monocytes/macrophages in the iris whereas later in the disease resident tissue macrophages and MHC class II+ cells (activated macrophages and putative dendritic cells) in the iris and ciliary body may synthesise nitric oxide. The role of this late phase of nitric oxide synthesis may include lymphocytostasis and immunosuppression as proposed in other tissue sites. The outcome of the present study may help in planning therapeutic strategies using NOS inhibitors.
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PMID:Cellular localisation and dynamics of nitric oxide synthase expression in the rat anterior segment during endotoxin-induced uveitis. 926 84

To assess the role of nitric oxide (NO) produced by the constitutive (cNOS) and inducible NO synthase (iNOS) in the regulation of vascular functions, we compared the effects of aminoguanidine, a relatively selective inhibitor of iNOS, and NG-nitro-L-arginine methyl ester (L-NAME), a nonselective NOS inhibitor on blood pressure, plasma volume, and albumin escape during the early and delayed phases of endotoxin shock in conscious, chronically catheterized rats. Red blood cell volume and plasma volume were determined by using chromium-51-tagged erythrocytes and iodine-125-labeled albumin, respectively. Injection of lipopolysaccharide (LPS) 10 mg/kg i.v. resulted in a fall in blood pressure, hemoconcentration, and increased total-body albumin escape, which is reflected by a 25% reduction in plasma volume. When LPS was injected into animals pretreated with L-NAME (7.4 mumol/kg i.v. 15 minutes before LPS), losses in plasma volume and albumin escape were significantly greater than in rats that received LPS alone, despite that L-NAME attenuated the hypotensive action of LPS. Aminoguanidine pretreatment (162 mumol/kg) had no effect on the early responses to LPS, whereas it was as potent as L-NAME in reversing hypotension when injected 70 minutes after LPS. Aminoguanidine treatment also prevented further losses in plasma volume and markedly attenuated total-body and organ albumin escape rates elicited by LPS. L-NAME produced only a slight attenuation of LPS-induced losses in plasma volume and albumin escape in most organs studied, whereas it potentiated albumin extravasation in the lung. These results demonstrate that inhibition of cNOS potentiates, whereas inhibition of iNOS markedly attenuates, losses in plasma volume and albumin escape elicited by LPS, and suggest that selective inhibitors of iNOS may be more effective than nonselective inhibitors of all forms of NOS in the therapy of septic shock.
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PMID:Dual role for nitric oxide in the regulation of plasma volume and albumin escape during endotoxin shock in conscious rats. 935 58

1. Microglial cells represent the first line of defence in the brain against infection and damage. However, under conditions of chronic inflammation and neurodegeneration, excessive activation of microglia can contribute to the neurodegenerative process by releasing a cornucopia of potentially cytotoxic substances including the cytotoxic free radical nitric oxide (NO). Although the cell signalling events implicated in NO formation in peripheral macrophages are well defined, events occurring in the phenotypically homologous cerebral microglial cell are not yet fully characterized. 2. In the present study, a cloned murine microglial cell line (N9), stimulated with combined lipopolysaccharide/interferon-gamma (LPS/IFN) incubation, was shown to produce a significant increase in NO formation, as measured by medium nitrite levels, during 8-72 h exposure. 3. LPS/IFN-stimulated NO production was partially inhibited with the nitric oxide synthase (NOS) competitive antagonists; N(omega)-nitro-L-arginine methyl ester and N(omega)-nitro-L-arginine. The ability of the selective inducible (iNOS) inhibitor, aminoguanidine, but not the selective 'neuronal-type' constitutive (cNOS) inhibitor 7-nitroindazole, to inhibit NO production suggested a primary role of iNOS in this response and was confirmed by immunolabelling of activated cells with a specific iNOS antibody. 4. A series of tyrosine kinase inhibitors, herbimycin A, genestein, tyrphostins, AG-126, AG-556 and the tyrosine phosphatase inhibitors, sodium orthovanadate and phenylarsine oxide, significantly attenuated LPS/IFN-mediated NO production. The serine/threonine kinase inhibitors, staursporine (protein kinase C), H-9 (cyclic GMP/cyclic AMP-dependent kinase) or serine/threonine phosphatase inhibitors, cyclosporin A (phosphatase 2B) and okadaic acid (phosphatase 1/2A), reduced NO formation by an apparent cytostatic mechanism, as determined by cellular reduction of 3-(4,5-dimethylthiazol-2-yi)-2,5-diphenyl-tetrazolium bromide (MTT). 5. The present results suggest that the co-ordinated activation of protein tyrosine kinases/phosphatases, and proximal signalling events implicating the interplay between serine-threonine kinases/phosphatases, is intricately linked with inflammatory mediated mechanisms of iNOS activation in microglial cells by regulating the activation of the transcription factor NFkappaB.
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PMID:Suppression of nitric oxide formation by tyrosine kinase inhibitors in murine N9 microglia. 953 16

Considering the structural similarity between gabexate mesylate (FOY), a drug for serine proteinase-mediated diseases, and L-arginine, the effect of gabexate mesylate on the nitric oxide (NO) pathway has been investigated. Gabexate mesylate inhibits competitively constitutive and inducible NO synthase (cNOS and iNOS, respectively), with Ki values of 1.0 x 10(-4) M and 5.0 x 10(-3) M, respectively, at pH 7.4 and 37.0 degrees C. However, gabexate mesylate is not an NO precursor. Moreover, like other NOS inhibitors, gabexate mesylate increases iNOS mRNA expression in rat C6 glioma cells, as induced by E. coli lipopolysaccharide plus interferon-gamma. Finally, gabexate mesylate inhibits dose-dependently nitrite production (i.e. NO release) in rat C6 glioma cells, as induced by E. coli lipopolysaccharide plus interferon-gamma. Thus, this drug should be administered under careful control, since enzyme inhibition may occur also in vivo.
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PMID:Effect of gabexate mesylate (FOY), a drug for serine proteinase-mediated diseases, on the nitric oxide pathway. 961 Mar 82

Nitric oxide (NO) has been implicated in the inhibition of cell proliferation in cytokine and lipopolysaccharide (LPS)-stimulated chondrocytes and is known to be influenced by physical forces in several tissues. In this study, a well-characterized model system utilizing bovine chondrocytes embedded in 3% agarose constructs has been used to investigate the effect of dynamic strain at 0.3, 1, or 3 Hz on NO production. LPS induced a significant increase in nitrite levels, which was reversed by both L-NAME and dexamethasone. Dynamic compressive strain produced a significant reduction in nitrite production. The effect was partially blocked by L-NAME but unaffected by dexamethasone. L-NAME also reversed dynamic compression-induced stimulation of [3H]-thymidine incorporation. NO appears to be a constituent of mechanotransduction pathways which influence proliferation of bovine chondrocytes seeded within agarose constructs. The inhibitor experiments also infer that alterations in cNOS activity primarily determine the response.
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PMID:Dynamic mechanical compression influences nitric oxide production by articular chondrocytes seeded in agarose. 979 16

Early systemic arterial hypotension is a common clinical feature of Pseudomonas septicemia. To determine if Pseudomonas aeruginosa endotoxin induces the release of endothelium-derived nitric oxide (EDNO), an endogenous nitrovasodilator, segments of canine femoral, renal, hepatic, superior mesenteric, and left circumflex coronary arteries were suspended in organ chambers (physiological salt solution, 95% O2/5% CO2, pH 7.4, 37 degrees C) to measure isometric force. In arterial segments contracted with 2 microM prostaglandin F2 alpha, Pseudomonas endotoxin (lipopolysaccharide (LPS) serotype 10(Habs) from Pseudomonas aeruginosa (0.05 to 0.50 mg/ml) induced concentration-dependent relaxation of segments with endothelium (P < 0.05) but no significant change in tension of arteries without endothelium. Endothelium-dependent relaxation in response to Pseudomonas LPS occurred in the presence of 1 microM indomethacin, but could be blocked in the coronary artery with 10 microM NG-monomethyl-L-arginine (L-NMMA), a competitive inhibitor of nitric oxide synthesis from L-arginine. The inhibitory effect of L-NMMA on LPS-mediated vasorelaxation of the coronary artery could be reversed by exogenous 100 microM L-arginine but not by 100 microM D-arginine. These experiments indicate that Pseudomonas endotoxin induces synthesis of nitric oxide from L-arginine by the vascular endothelium. LPS-mediated production of EDNO by the endothelium, possibly through the action of constitutive nitric oxide synthase (NOSc), may decrease systemic vascular resistance and may be the mechanism of early hypotension characteristic of Pseudomonas septicemia.
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PMID:Endothelium-dependent vasodilation in response to Pseudomonas aeruginosa lipopolysaccharide: an in vitro study on canine arteries. 987 5

Nitric oxide from constitutive nitric oxide synthase (NOS) augments gastric mucosal blood flow and is important in mucosal defense. However, the function of the inducible isoform of NOS (iNOS) in the gastric mucosa remains to be fully elucidated. This study was done to examine the role of iNOS in gastric mucosal blood flow and gastric injury following endotoxemia. Conscious rats were given intraperitoneal saline or lipopolysaccharide (LPS, 5 or 20 mg/kg). Five hours later, rats were anesthetized, a laparotomy made, gastric fluid aspirated, and 3 ml of 20% ethanol introduced into the forestomach. Rats were sacrificed 10 min later for assessment of macroscopic injury (mm2) to the gastric mucosa. Other rats did not receive 20% ethanol, but instead, gastric mucosal blood flow was determined with laser Doppler, followed by sacrifice and removal of stomachs for determination of gastric mucosal iNOS immunoreactivity (Western immunoblot). Lipopolysaccharide dose dependently increased gastric injury, decreased gastric mucosal blood flow, and increased gastric mucosal iNOS immunoreactivity compared to rats receiving saline. In additional experiments and using a similar protocol, intraperitoneal administration of aminoguanidine (45 mg/kg), an iNOS inhibitor, reversed lipopolysaccharide-induced gastric injury and restored gastric mucosal blood flow to baseline, whereas the nonselective NOS inhibitor, NG-nitro-l-arginine methyl ester (5 mg/kg) did not. Taken together, these data suggest that upregulation of iNOS is in part responsible for the detrimental effects of LPS on the gastric mucosa, possibly from a reduction in gastric mucosal blood flow.
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PMID:Does upregulation of inducible nitric oxide synthase (iNOS) render the stomach more susceptible to damage? 1035 16

Nitric oxide signalling during the past two decades has been one of the most rapidly growing areas in biology. This simple free radical gas can regulate an ever-growing list of biological processes. Here the regulation of NO synthesis in the liver is reviewed. The biogenesis of nitric oxide (NO) is catalysed by nitric oxide synthases (NOS). These enzymes catalyse the oxidation of one of the guanidino nitrogens of l-arginine by molecular oxygen to form NO and citrulline. Three NOS have been identified: two constitutive (cNOS: type 1 or neuronal and type 3 or endothelial) and one inducible (iNOS: type 2). As to the liver, cNOS activity is normally detectable in Kupffer cells, whereas no cNOS is ever encoded in hepatocytes. However, hepatocytes, Kupffer and stellate cells (the three main types of liver cells) are prompted to express an intense iNOS activity once exposed to effective stimuli such as bacterial lipopolysaccharide and cytokines. This review is focused mainly on two aspects: regulation of NOS activity and expression by endogenous and exogenous compounds. Because NO production has beneficial and detrimental effects, understanding the molecular mechanisms that govern NOS is critical to developing strategies to manipulate NO production in liver diseases.
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PMID:Regulation of nitric oxide synthesis in the liver. 1079 71

The nasal decongestants oxymetazoline and xylometazoline are frequently used in the topical treatment of rhinitis and sinusitis. As nitric oxide (NO) is thought to play a role in inflammation of the upper respiratory tract, the aim of this study was to examine the in vitro effects of these compounds on the activity and the expression of NO producing enzymes, including the inducible form of NO synthase (iNOS) and the constitutive isoform of NO synthase (cNOS). Experiments concerning the effects of both compounds on enzymatic activity and enzyme induction of iNOS were performed in a lipopolysaccharide (LPS) induced rat alveolar macrophage cell line (NR8383) using the Griess assay and the 3H-citrulline assay respectively. The effects on cNOS were examined in fresh rat synaptosomes using the 3H-citrulline assay. The direct scavenging properties of both compounds were investigated using a amperometric NO sensor. Oxymetazoline and xylometazoline were shown to have a dose dependent inhibitory effect on total iNOS activity indicated by nitrite/nitrate formation in the Griess assay. This effect was found to be due to an inhibition of induction of the enzyme rather than inhibition of the enzyme activity, as was investigated in two separate experiments using the 3H-citrulline assay. Inhibition of cNOS was moderate and in the same order of magnitude as the inhibition of enzymatic iNOS activity. Direct scavenging of NO could not be detected. As constitutive nitric oxide synthase activity is thought to serve beneficial physiological functions, and exaggerated inducible nitric oxide synthase activity may cause exacerbation of the inflammatory process, pharmacological treatment influencing the nitric oxide generating system should focus on inhibition of inducible nitric oxide synthase alone. The specific characteristics of these decongestants in vitro suggests suitability for this application and may indicate an additional beneficial effect in the treatment of upper respiratory tract inflammation.
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PMID:Inhibition of nitric oxide synthase by nasal decongestants. 1102 57

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