Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many types of cells in the immune system have been found to produce nitric oxide (NO), which performs multiplex functions. However, in myelin basic protein peptide 68-86 (MBP 68-86)-induced experimental autoimmune encephalomyelitis (EAE) in Lewis rats, we found that elevated NO production was generated from spleen cells (SC), not from lymph node cells (LNC). LNC expressed lower NO synthase 2 (NOS2) and produced lower levels of NO than SC upon MBP 68-86 stimulation. Expression of B7-1(CD80) and B7-2(CD86) molecules was much lower on LNC than on SC. Blocking of B7-1 or B7-2 ligation resulted in reduced NO production by SC. Unlike SC, LNC were resistant to interferon-gamma- or lipopolysaccharide-induced NO production. NO derived from SC suppressed cell proliferation and induced apoptosis in vitro. Addition of N(omega)-nitrol-L-arginine methylester (L-NAME) into cell cultures promoted cell expansion and reduced apoptosis. These results indicate that NO production originates from SC, but not from LNC. Low expression of co-stimulatory molecules and NOS2 of LNC limits NO induction. The high levels of NO derived from SC are involved in the self-limiting mechanisms of autoimmune responses by inhibiting cell expansion and promoting cell apoptosis.
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PMID:Limitation of nitric oxide production: cells from lymph node and spleen exhibit distinct difference in nitric oxide production. 1072 70

1. Laminitis, an important cause of lameness in domestic ungulates, occurs as a result of altered digital perfusion. Endotoxin and cytokines may mediate the vascular derangements observed through alterations in nitric oxide production. In this study, the vascular responses of the isolated ovine digital artery were examined and the influence of endotoxin and cytokines investigated. 2. Neither removal of the endothelium nor incubation with N(G)-nitro-L-arginine methyl ester (L-NAME, 300 microM) altered the response to phenylephrine (PE, 1 nM to 300 microM). Indomethacin (10 microM) decreased PE log EC(50) from -6.22+/-0.08 to -6.55+/-0.07. Acetylcholine (1 nM to 1 mM) and bradykinin (BK, 100 pM to 3 microM) induced endothelium-dependent relaxation. Bradykinin-induced relaxation was reduced by L-NAME, E(max) falling from -61.7+/-7.4 to -34.0+/-2.1%. Addition of indomethacin further reduced BK E(max) to -9.6+/-2.8%. Sodium nitroprusside (1 nM to 300 microM) produced endothelium-independent relaxation that was unaffected by L-NAME or indomethacin. 3. Following a 6 h incubation with endotoxin (3 microml(-1)), arterial responses to PE and BK did not differ from polymyxin B-treated controls (10 microg ml(-1)). Arteries incubated for 6 h with interferon-gamma (IFN-gamma, 10 ng ml(-1)) and tumour necrosis factor-alpha (TNF-alpha, 5 ng ml(-1)) exhibited greater relaxation to BK (E(max)-50.0+/-5.1%) than polymyxin B-treated controls (E(max)-33.1+/-4.0%), but did not differ in their response to PE. 4. Prolonged incubation (16 h) with endotoxin (3 microg ml(-1)) did not alter the response to PE, however incubation with IFN-gamma (10 ng ml(-1)), TNF-alpha (5 ng ml(-1)) and interleukin-1beta (20 ng ml(-1)) for 16 h increased PE log EC(50) from -6.44+/-0.09 to -6. 10+/-0.11. 5. Nitric oxide is an important mediator of endothelium-dependent relaxation in ovine digital arteries but does not modulate PE-induced vasoconstriction. Incubation with cytokines decreased the sensitivity of digital arteries to PE.
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PMID:The role of nitric oxide in the responses of the ovine digital artery to vasoactive agents and modification of these responses by endotoxin and cytokines. 1078 Oct 5

The kinin B1 receptor is an inducible receptor expressed in response to inflammatory mediators. We sought to determine whether kinin B1 receptor can be expressed on human brain endothelial cells (HBECs) in vitro and whether signaling via this receptor can regulate permeability and chemokine production properties of these cells. Multiplex RT-PCR amplification and western blot techniques were used to evaluate B1 receptor expression by HBECs. Although B1 receptor mRNA and protein could not be detected on resting HBECs, interferon-gamma induced a dose- and time-dependent up-regulation of B1 receptor mRNA and protein on HBECs. Stimulation of interferon-gamma-treated HBECs with the selective B1 agonist R-838 (Sar [D-Phe8] des Arg9-BK) induced a dose- and time-dependent increase in the production of inositol 3,4,5 tri-phosphate and nitric oxide. Permeability of the HBECs monolayer, as measured by BSA diffusion, was significantly increased by application of the B1 agonist. This biological effect of R-838 could be prevented by R-715, a B1 receptor antagonist and by L-NAME, a nitric oxide synthase blocker. R-838 also inhibited interleukin-8 release from HBECs. We demonstrate that B1 receptors can be up regulated on the surface of HBECs by molecules released during inflammatory response and that signaling via this receptor can regulate BBB permeability and chemokine production in vitro.
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PMID:Kinin B1 receptor expression and function on human brain endothelial cells. 1107 80

The present study investigated the effect of nitric oxide (NO) on megakaryocyte (Mk) proliferation induced by thrombopoietin (TPO). Low-density mononuclear cells (MNCs) and CD34+ cells from human bone marrow (BM) were cultured in liquid medium in the presence of sodium nitroprusside (SNP) or (Z)-1-[2-(aminoethyl)-N-(2-ammonioethyl) amino] diazen-1-ium-1, 2-diolate (DETA/NO) and then stimulated with TPO. Mk number decreased in both NO donors, as identified by flow cytometry 11 to 13 days after TPO stimulation. Nitrite, cyanide, or the carrier molecule DETA failed to reproduce the inhibition caused by NO donors. When CD34+ cells were treated with DETA/NO, the inhibition of Mk growth was even more pronounced than that in MNCs. Failure of the guanosine 3',5'-cyclic monophosphate (cGMP) analog 8-bromoguanosine 3',5'-cyclic monophosphate (8-Br-cGMP) to inhibit Mk proliferation suggests that cGMP is not involved in Mk suppression mediated by NO. On the other hand, DNA analysis by flow cytometry showed that apoptosis of CD34+ cells and Mks seemed to be at least one of the mechanisms associated with the cytotoxic DETA/NO effect. Stimulation of MNCs or CD34+ cells with tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) increased endogenous NO levels and suppressed Mk growth. Treatment with NO synthesis inhibitors such as L -N(G)-monomethyl arginine (L -NMMA) or L -N(G)-nitroarginine methyl ester hydrochloride (L -NAME) partially reversed Mk growth inhibition induced by TNF-alpha and IFN-gamma, although increased NO levels returned to normal values. The results presented here strongly indicate that NO regulates the growth of Mks induced by TPO by a direct effect on both progenitors and mature Mks.
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PMID:Effect of nitric oxide on megakaryocyte growth induced by thrombopoietin. 1128 20

Neuronal damage in glutaryl-CoA dehydrogenase deficiency (GDD) has previously been addressed to N-methyl-D-aspartate (NMDA) receptor-mediated neurotoxicity of the accumulating neurotoxic metabolite 3-hydroxyglutarate. However, acute encephalopathic crises in GDD patients are typically precipitated by febrile illness or even routine vaccinations, suggesting a potentiating role of inflammatory cytokines. In the present study we investigated the effect of interleukin-1beta and interferon-gamma on 3-hydroxyglutarate toxicity in rat cortical astrocyte cultures and neonatal rat hippocampal cultures. A cotreatment of both culture systems with interleukin-1beta and interferon-gamma induced the protein expression of astrocytic inducible nitric oxide synthase (iNOS), resulting in increased nitric oxide (NO) production. Cytokine pretreatment alone had no effect on cell viability but potentiated 3-hydroxyglutarate neurotoxicity. NOS inhibition by aminoguanidine and L-NAME prevented an iNOS-mediated potentiation of 3-hydroxyglutarate neurotoxicity but failed to protect neurons against 3-hydroxyglutarate alone. In contrast, superoxide dismutase/catalase as well as MK-801 prevented toxicity of 3-hydroxyglutarate alone as well as its potentiation by iNOS, supporting a central role of NMDA receptor stimulation with subsequently increased superoxide anion production. It is concluded that the potentiation of 3-hydroxyglutarate neurotoxicity is most probably due to an induction of astrocytic iNOS and concomitantly increased NO production, enabling enhanced peroxynitrite formation. Thus, we provide evidence for a neuroimmunological approach to the precipitation of acute encephalopathic crises in GDD by inflammatory cytokines.
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PMID:Potentiation of 3-hydroxyglutarate neurotoxicity following induction of astrocytic iNOS in neonatal rat hippocampal cultures. 1142 52

Leukocyte accumulation has been shown to be increased in sepsis. Moreover, in inducible nitric oxide synthase (iNOS) knockout mice, a further increase in leukocyte accumulation has been observed during sepsis, suggesting that nitric oxide (NO) may affect leukocyte/endothelial interaction. Accelerated peroxynitrite formation also occurs during sepsis. In the present study, the effect of peroxynitrite or NO on leukocyte adhesion to nitric oxide synthase (NOS)-inhibited or endotoxin-treated endothelium was examined. Bovine aortic endothelial cells were treated with either L-NAME or lipopolysaccharide (LPS) and interferon-gamma for 4 hr and subsequent leukocyte adhesion was measured. Both L-NAME and LPS treatment resulted in increased leukocyte adhesion compared with control. Neither a peroxynitrite donor, SIN-1, nor a direct NO donor, DETA-NO, had any effect on leukocyte adhesion to untreated endothelium. However, when the L-NAME or LPS-treated endothelial cells were treated simultaneously with either SIN-1 or DETA-NO, there was a significant reduction in leukocyte adhesion. Moreover, at the concentrations used in the present study, neither peroxynitrite nor NO showed harmful effects on normal cultured endothelial cells. These data demonstrating inhibition of leukocyte adhesion to endotoxin-treated endothelium suggest that peroxynitrite or NO may exert a beneficial effect during sepsis.
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PMID:Effects of nitric oxide and peroxynitrite on endotoxin-induced leukocyte adhesion to endothelium. 1147 60

Communication of agonist-induced membrane potential changes along blood vessels has been proposed to contribute to the coordination of microvascular function. Factors mediating septic shock may compromise this coordination. Using electrophysiology in a simplified in vitro model of endothelial cells grown as capillary-like structures, we aimed to determine (i) the effect of lipopolysaccharide (LPS) on endothelial cell membrane potential responses to ATP and KCl and (ii) the effect of LPS and nitric oxide (NO) on cell-to-cell communication. Treatment of 'capillaries' with LPS (10 microg/ml for 1 h) did not affect local responsiveness to ATP or KCl, but reduced cell communication by a tyrosine-kinase-dependent mechanism. Treatment of 'capillaries' with the NO donor DETA (100 microM) or the NO synthase inhibitor L-NAME (100 microM) had no effect on cell communication or the response to LPS. Endogenous NO production, stimulated by LPS + interferon-gamma (100 U/ml) treatment, also had no effect on cell communication beyond that of LPS alone. We conclude that LPS, but not NO, can modulate conduction of agonist-induced electrical responses along endothelial capillary-like structures in vitro.
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PMID:Communication of agonist-induced electrical responses along 'capillaries' in vitro can be modulated by lipopolysaccharide, but not nitric oxide. 1229 3

The role of nitric oxide (NO) in acute lung injury remains controversial. Although inhaled NO increases oxygenation in clinical trials, inhibiting NO-synthase (NOS) can be protective. To examine the latter, nickel-exposed mice were treated with saline or NOS inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME). Initial microarray analysis of nickel-induced gene expression of saline-treated mice revealed increased inflammatory mediator, matrix injury-repair, and hypoxia-induced factor-mediated sequences and decreased lung-specific (e.g., surfactant-associated protein B and C) sequences. Compared with saline control, L-NAME-treated mice had enhanced survival with attenuated serum nitrate/nitrite, endothelial NOS activity, and lavage neutrophils and protein. Although initial cytokine (i.e., interferon-gamma, interleukins-1beta and -6, macrophage inflammatory protein-2, monocyte chemotactic protein-1, and tumor necrosis factor-alpha) gene expression was similar between groups, subsequent larger cytokine increases only occurred in saline-treated mice. Similarly, surfactant protein gene expression decreased initially in both groups yet was restored subsequently with L-NAME treatment. Interestingly, the role of inducible NOS (iNOS) in these responses seems minimal. iNOS gene expression was unaltered, iNOS activity and nitrotyrosine residues were undetectable, and an iNOS antagonist, aminoguanidine, failed to increase survival. Rather, systemic L-NAME treatment appears to attenuate pulmonary endothelial NOS activity, subsequent cytokine expression, inflammation, and protein permeability, and thereby restores surfactant gene expression and increases survival.
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PMID:Inhibition of nitric oxide restores surfactant gene expression following nickel-induced acute lung injury. 1254 Apr 86

To investigate the effects of intrinsic nitric oxide (NO) on the expression of interleukin-4 (IL-4) mRNA and interferon-gamma (IFN-gamma) mRNA in the airway inflammation of asthma, the rat models of asthmatic inflammation were established by sensitizing and then challenging the animals with ovalbumin. The 24 animals were randomly divided into control group, sensitized group, sensitized and L-Arg-treated group as well as L-NAME-treated group equally. By using in situ hybridization combined with compute physiological quantitative imaging analysis techniques, the influence of intrinsic NO on the expression of IL-4 mRNA and IFN-gamma mRNA in the airway inflammatory cells was observed. In situ hybridization study demonstrated that IL-4 mRNA expression was obviously increased as compared with that in the control group, mainly distributed in the inflammatory cells in the submucous of airways in the sensitized group. The increase of intensity of IL-4 mRNA expression was positively correlated with the numbers of eosinophil (Eos) and lymphocyte (both with P < 0.05) in the sensitized group. There was no statistically difference in IFN-gamma expression between the control group and the sensitized group. Imaging analysis showed that L-NAME could inhibit the expression of IL-4 mRNA (P < 0.05) and increase the expression of IFN-gamma mRNA (P < 0.05), while L-Arg could increase the expression of IL-4 mRNA in inflammatory cells (P < 0.05). It was indicated that a suitable levels of intrinsic NO can influence the expression of IL-4 mRNA of Th2 lymphocytes and the expression of IFN-gamma mRNA of Th1 lymphocytes and in turn, promote the development of asthmatic airway inflammation.
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PMID:Effects of intrinsic nitric oxide on the expression of interleukin-4 and IFN-gamma mRNA in the bronchial and lung tissues of sensitized rats. 1284 50

Interactions and possible cross talk between inducible nitricoxide synthase (iNOS), cyclooxygenase-2 (COX-2) and matrix metalloproteinase-9 (MMP-9), were studied in rat aortic vascular smooth muscle cells stimulated with bacterial lipopolysaccharide (LPS), interferon-gamma (IFN-gamma), and phorbol 12-myristate13-acetate (PMA). The expression and activity of iNOS, COX-2, and MMP-9 were characterized at the transcriptional, protein, and enzyme activity levels. The NOS inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME) was used to investigate the effects of NO on COX-2 and MMP-9 at the transcriptional level. The measurements of mRNAs for these enzymes using real-time polymerase chain reaction (PCR) showed that COX-2 mRNA was up-regulated 2.3-fold, whereas MMP-9 mRNA up-regulation was 11.7-fold in the presence of LPS, IFN-gamma, and PMA. Real-time PCR results indicated that L-NAME exerted an inhibitory effect on COX-2 and MMP-9 mRNA synthesis. Both superoxide dismutase (SOD) and the SOD mimetic Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (MnTMPyP) did not modify significantly the up-regulation of these enzymes, indicating that neither superoxide nor peroxynitrite are involved in this mechanism. Furthermore, NO-mediated up-regulation of MMP-9 was cGMP-dependent since 1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an inhibitor of soluble guanylate cyclase, blocked, in a concentration-dependent manner, the increased expression of MMP-9, an effect reversed by 8-bromo-cGMP, a soluble analog of cGMP. Our findings suggest that NO and cGMP are necessary to up-regulate the expression of MMP-9.
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PMID:Nitric oxide and cyclic GMP increase the expression of matrix metalloproteinase-9 in vascular smooth muscle. 1295 9


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