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)

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

The activity of inducible nitric oxide synthase (iNOS) enzyme was quantified in chicken macrophages. Macrophages from Cornell K-strain (B15B15), GB1 (B13B13), and GB2 (B6B6) chickens and a transformed cell line (MQ-NCSU) were incubated with or without varying concentrations of bacterial lipopolysaccharide (LPS). The culture supernatants were tested for the presence of nitrite. Macrophages from either source produced minimal nitrite (< 4.4 microM/1 x 10(6) cells) levels without LPS stimulation. However, nitrite levels produced by K-strain (42 microM) and MQ-NCSU (41 microM) macrophages were higher (P < 0.05) than those produced by the GB1 (14 microM) and GB2 (14 microM) per 1 x 10(6) macrophages with optimum LPS concentration range of 50 ng to 1 microgram/mL. The addition of an L-arginine analog, NGMMLA, at a concentration of 200 microM completely abolished nitrite production. The addition of 10% vol/vol lymphokines exhibited an additive effect on nitrite production in conjunction with LPS. The increased nitrite production by the K-strain and MQ-NCSU macrophages corresponded to an increased expression of iNOS mRNA as compared to the mRNA produced by GB1 and GB2 macrophages. The iNOS mRNA kinetics study revealed that mRNA levels peaked between 6 to 12 h. The cells from avian lymphoid lineage failed to produce any detectable iNOS activity. These studies showed that macrophages from varying sources differ in NOS activity and implied that genetic background may dictate the extent of arginine-mediated contribution in various biological and immunological functions.
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PMID:Nitric oxide synthase activity and mRNA expression in chicken macrophages. 935 46

The localization of nitric oxide (NO) synthase (NOS) isoforms was examined in the endolymphatic sac (ES) of the pigmented guinea pig by indirect immunohistochemistry. The cytoplasm of the epithelial cells in the ES showed both NOS-I and -III immunoreactivity, whereas their nuclei appeared negative. NOS-III staining was also observed in the endothelial lining of the blood vessels. These findings support the hypothesis that NO in the epithelial cells may play an important role for the active intracellular transport of the endolymph and ion. NO may also be crucially involved in the regulation of ES blood flow. Immunostaining for NOS II revealed no reactivity in general, while in lipopolysaccharide-inoculated animals, intense reactivity was found in the cytoplasm of the ES epithelial cells as well as macrophages in the lumen. Thus it has been indicated that NO also may play an important role in the immunodefensive mechanisms in the ES.
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PMID:Localization of nitric oxide synthase isoforms (I, II and III) in the endolymphatic sac of the guinea pig. 936 46

We studied the effect of PPM-18, a chemically synthesized naphthoquinone derivative and also an anti-inflammatory agent, on the lipopolysaccharide (LPS)-activated inducible NO synthase (iNOS) expression in rat alveolar macrophages. Pretreatment of macrophages with PPM-18 (0.1-10 microM) significantly inhibited nitrite production, iNOS protein expression and iNOS mRNA accumulation. PPM-18 did not directly affect the enzymic activities of iNOS and other constitutive NOS forms. The LPS-induced increase in nuclear transcription factor kappaB (NF-kappaB) p65 and p50 in nucleus was suppressed by PPM-18 (10 microM). Moreover electrophoretic mobility-shift assays demonstrated that PPM-18 inhibited DNA binding to NF-kappaB induced by LPS in whole cells but not when added in the nuclear extract, suggesting that PPM-18 did not interfere directly with the binding of NF-kappaB to DNA and that some events had to be processed before NF-kappaB could bind DNA. Examination of NF-kappaB showed that PPM-18 stabilized the NF-kappaB inhibitor, IkappaBalpha, by preventing its degradation from NF-kappaB. Therefore the stabilization of IkappaBalpha might have contributed to the inhibition of NF-kappaB activation. These results also indicate strongly that NF-kappaB is involved in the production of NO on stimulation by LPS. PPM-18 significantly decreased the production of tumour necrosis factor alpha in response to LPS. PPM-18 protects mice against LPS-induced lethal toxicity. These results also indicate that PPM-18 is a potent inhibitor of iNOS expression by blocking the binding of NF-kappaB to promoter and exerts a beneficial effect in the mouse model of sepsis.
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PMID:Inhibition of nitric oxide synthase expression by PPM-18, a novel anti-inflammatory agent, in vitro and in vivo. 937 89

Bovine retinal pigmented epithelial (RPE) cells express an inducible nitric oxide synthase (NOS-2) after activation with interferon (IFN)-gamma and lipopolysaccharide (LPS). Experiments were performed to investigate the effects of IFN-alpha and IFN-beta on NOS-2 activity. These types of interferons did not aid LPS in the production of nitrite, but markedly inhibited in a concentration-dependent manner the nitrite release due to LPS/IFN-gamma. Analysis by Western and Northern blots showed that RPE cells co-stimulated with IFN-alpha or IFN-beta with LPS/IFN-gamma accumulated lower levels of NOS-2 protein and mRNA than in the presence of LPS/IFN-gamma alone. The presence of IFN-alpha or IFN-beta did not accelerate mRNA degradation, implying that these interferons did not affect NOS-2 mRNA stability, but more probably NOS-2 gene expression. Furthermore, IFN-gamma binding studies demonstrated that the inhibitory effect of IFN-alpha and IFN-beta is not caused by a blocking of IFN-gamma receptors. Analysis of NF-kappaB activation by electrophoretic mobility shift assay demonstrated that LPS/IFN-gamma-induced NF-kappaB binding was not changed by the presence of IFN-alpha. However, similar experiments revealed that the activation of interferon regulatory factor-1 (IRF-1) by LPS/IFN-gamma was decreased by IFN-alpha. This phenomenon could be due to the decline of IRF-1 mRNA and the up-regulation of IRF-2 mRNA, an IRF-1 repressor, by IFN-alpha. These results suggest that the inhibitory effect of IFN-alpha and -beta on NOS-2 induction could be partially explained by their effect on the induction of the IRFs, which were involved in NOS-2 gene transcription.
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PMID:Inhibition of inducible nitric oxide synthase expression by interferons alpha and beta in bovine retinal pigmented epithelial cells. 940 17

Hepatic injury and chronic wounding are characterized by increased synthesis of extracellular matrix proteins including hyaluronan (HA). Recently, it has been recognized that low-molecular-weight fragments of HA, but not native HA (e.g., high-molecular-weight HA), induce inflammatory gene expression, and activate the transcriptional regulator, nuclear factor kappaB (NF-kappaB). The inducible isoform of nitric oxide synthase (iNOS) is induced by cytokines and/or lipopolysaccharide (LPS) through the NF-kappaB signal transduction pathway. Because of this association, we hypothesized that HA fragments might also stimulate iNOS gene transcription. The aims of this study were therefore to determine whether HA or HA fragments induced iNOS in hepatic cells, and to characterize the signaling pathway. HA fragments (100 microg/mL) markedly stimulated iNOS messenger RNA (mRNA) in endothelial and Kupffer cells, but minimally induced this mRNA in hepatocytes and stellate cells. High-molecular-weight HA (200 microg/mL) had no effect on iNOS mRNA in any cell type. The addition of interferon gamma (IFN-gamma) to HA fragments resulted in stimulation of iNOS mRNA 2-, 3-, 4-, and 10-fold above that for HA fragments alone in hepatocytes, endothelial, Kupffer, and stellate cells, respectively. The combination of HA fragments and LPS did not result in an incremental increase in iNOS mRNA induction. iNOS protein and nitrite levels (used as a measure of NO production and NOS enzymatic activity) paralleled closely iNOS mRNA expression and increased proportionally to HA fragment concentration in a dose-dependent fashion. At 1 hour following stimulation, NF-kappaB DNA binding activity was detected in extracts from Kupffer cells stimulated with HA fragments, but not in those exposed to media alone or to high-molecular-weight HA. Finally, inhibitors of NF-kappaB blocked HA fragment-dependent iNOS mRNA induction in Kupffer and sinusoidal endothelial cells. The data indicate that HA fragments, but not high-molecular-weight HA, induce iNOS in liver, having the greatest effects on endothelial and Kupffer cells. We speculate that HA fragments may be an important stimulus for NO production in various forms of liver disease, particularly as a cofactor with inflammatory cytokines.
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PMID:Stimulation of inducible nitric oxide synthase in rat liver by hyaluronan fragments. 942 22

The regulation of the manganese-dependent superoxide dismutase (Mn-SOD) was studied in immortalized microglial cells (line BV-2). BV-2 cells, activated with lipopolysaccharide (LPS), exhibited an increase in Mn-SOD-like immunoreactivity, that was associated with an accumulation of nitrite in the culture medium and an increase in immunoreactivity for the inducible type of nitric oxide synthase (i-NOS). The i-NOS inhibitor L-N6-(1-iminoethyl)-lysine (NIL, 600 microM) suppressed the nitrite accumulation and the increase in Mn-SOD-like immunoreactivity in activated cells without significant effect on the level of i-NOS-like immunoreactivity. The NO donor sodium nitroprusside dose-dependently increased Mn-SOD-like immunoreactivity in NIL-pretreated BV-2 cells. These results indicate that the induction of Mn-SOD in activated BV-2 cells is mediated in part by NO, or its metabolites.
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PMID:Induction of manganese superoxide dismutase in BV-2 microglial cells. 942 24

The roles of nitric oxide derived from either the constitutive endothelial NO synthase (eNOS or NOS3) or the inducible NOS (iNOS or NOS2) in hepatic injury during endotoxemia remain controversial. To investigate this further, rats received a bolus of lipopolysaccharide (LPS) following implantation of osmotic pumps containing one of two nonselective NOS inhibitors (NMA or NAME), one of two inducible NOS inhibitors (NIL or AG), or saline. The inhibitors were infused continuously into the liver via the portal vein. Treatment of LPS-injected rats with NMA and NAME resulted in 106 and 227% increases, respectively, in circulating hepatic enzyme levels compared to LPS-treated control rats. In contrast, infusion of the iNOS-selective inhibitors had no effect on the LPS-induced hepatic necrosis. In rats receiving NAME, LPS induced greater neutrophil infiltration and ICAM-1 expression than in the LPS + saline group, whereas NIL infusion did not. The increased hepatic necrosis and PMN infiltration in the LPS + NAME group was partially prevented by a simultaneous infusion of a liver-selective NO donor. Inhibition of PMN accumulation using an anti-ICAM-1 antibody or by PMN depletion using vinblastine pretreatment, however, did not reverse the increased necrosis with NAME infusion during endotoxemia. In contrast to the assessment for necrosis, increased apoptosis was observed in the livers of LPS-treated rats receiving infusions of either NAME or NIL, but not with LPS alone. These data indicate that NO produced by eNOS may be adequate to prevent necrosis by a mechanism independent of PMN, while induced NO appears to prevent apoptosis.
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PMID:Differential effects of nonselective nitric oxide synthase (NOS) and selective inducible NOS inhibition on hepatic necrosis, apoptosis, ICAM-1 expression, and neutrophil accumulation during endotoxemia. 944 11

Ischemia-reperfusion (IR) lung injury occurs after various clinical procedures, including cardiopulmonary bypass. It is not clear whether endogenous nitric oxide (NO) is protective or injurious in lungs subjected to IR. Thus, in this study we examined the contribution of endogenous NO to IR injury in isolated, blood-perfused rat lungs. Lungs of male Wistar rats (300 g) were subjected to 30 min ischemia and 180 min reperfusion (I30R180). Lungs were sampled for inducible nitric oxide synthase (i-NOS) mRNA expression (each n = 3) and NOS enzyme activity (each n = 4) at different time points. NOS inhibitors NG-nitro-L-arginine-methyl ester (10[-4] M) and aminoguanidine (10[-4] M) were used to study the contribution of NO to IR injury in lungs subjected to I30R30 and I30R180. The contribution of i-NOS to IR lung injury was studied by inducing i-NOS enzyme with Salmonella lipopolysaccharide, followed by I30R30. We found that ischemia-reperfusion alone can upregulate i-NOS mRNA and i-NOS enzyme activity (p < 0.05, ANOVA), but downregulate constitutive NOS enzyme activity over 180 min reperfusion. Endogenously produced NO is protective against lung injury in I30R180 in normal rats and lung injury in I30R30 in septic rats. NO is also pivotal in maintaining pulmonary vascular homeostasis in septic rat lungs undergoing IR.
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PMID:The role of endogenous nitric oxide in modulating ischemia-reperfusion injury in the isolated, blood-perfused rat lung. 944 9

Interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), and lipopolysaccharide (LPS) were examined for their ability to regulate the activity and protein levels of inducible nitric oxide synthase (NOS II) in cultured rat colonic smooth muscle cells. Treatment with these agents resulted in a time-dependent increase in NOS II activity. After 48 h, NOS II activity, measured as L-[3H]citrulline production, was increased 24.3 +/- 6.9 pmol.min-1.mg protein-1 by 1 nM IL-1 beta and 3.2 +/- 1.1 pmol.min-1.mg protein-1 by 1 nM TNF-alpha, and increased synergistically by a combination of the two (51.8 +/- 7.3 pmol.min-1.mg protein-1). Measurement of NOS II activity as nitrite production yielded similar results: IL-1 beta, 27.2 +/- 1.2; TNF-alpha, 1.6 +/- 0.1; and IL-1 beta + TNF-alpha, 46.8 +/- 3.2 pmol.min-1.mg protein-1 above basal. LPS (10 micrograms/ml) had a small but significant effect at 48 h that was only additive with that of IL-1 beta. The increase in NOS II activity induced by IL-1 beta and TNF-alpha was inhibited 73-86% by transforming growth factor-beta 1 (TFG-beta 1). The NOS isoform induced by IL-1 beta and TNF-alpha was identified as NOS II by Western immunoblot analysis and confirmed by its 66-97% inhibition by 100 microM S-methylisothiourea, a selective NOS II inhibitor, and its Ca(2+)-independent activity. We conclude that the cytokines IL-1 beta and TNF-alpha act independently and synergistically to stimulate NOS II expression and enzymatic activity in rat colonic smooth muscle through a mechanism sensitive to inhibition by TGF-beta 1.
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PMID:Synergistic regulation of NOS II expression by IL-1 beta and TNF-alpha in cultured rat colonic smooth muscle cells. 945 87

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