UMLS:C0406810 - FACTA Search

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Query: UMLS:C0406810 (NAME)
13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Respiratory syncytial virus (RSV) is an important respiratory pathogen that preferentially infects epithelial cells in the airway, and causes a local inflammatory response. Although it has been previously demonstrated that RSV-infected airway epithelial produce cytokines, including interleukin-8 (IL-8), which contributes to the inflammatory response, the regulation of this effect of RSV is unknown. To further characterize the mechanisms by which RSV infection triggers release of IL-8, we first exposed cultured A549 cells to RSV, and measured IL-8 release via enzyme-linked immunosorbent assays (ELISA), and IL-8 messenger RNA (mRNA) induction via Northern blot analysis. We observed a dose- and time-dependent release of IL-8 in response to RSV. The optimal dose of RSV was 10(4) TCID50/ml, and maximal release of IL-8 was measured at 72 to 96 h after infection. RSV induced a biphasic (early and late) increase in IL-8 mRNA. The early phase was independent of viral infection, whereas the more pronounced late phase required the presence of live virus and infection of the epithelium. Partial (< 50%) cytopathic effects were noted at 48 h and progressed to 75% at 96 h. The monolayer was still intact at 96 h. Inhibitors of nitric oxide, including NG-monomethyl-L-arginine (L-NMMA), NG-nitro-L-arginine methyl ester (L-NAME), and aminoguanidine had no effect on IL-8 release or IL-8 mRNA induction. We did, however, demonstrate a dose-dependent decrease in IL-8 release and IL-8 mRNA induction in RSV-infected epithelial treated with the antioxidants dimethyl sulfoxide (DMSO) or 5,5-dimethyl-1-pyrroline-N-oxide (DMPO). Peak effects were noted at a concentration of 2% DMSO and 50 microM DMPO. The antioxidants did not inhibit viral replication or infection. This data suggest that RSV-induced IL-8 production in airway epithelium is mediated via changes in oxidant tone. The data also suggest a potential therapeutic role for antioxidants in RSV infections.
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PMID:Oxidant tone regulates IL-8 production in epithelium infected with respiratory syncytial virus. 762 91

While the regulation of nitric oxide (NO) by inflammatory cytokines or lipopolysaccharide (LPS) has received considerable attention, NO modulation of cytokine expression has yet to be fully explored. The NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), inhibited interleukin (IL)-8 and IL-6 production in LPS-stimulated human whole blood in a dose-dependent manner. In the presence of 1 microgram/mL LPS, L-NAME blocked IL-8 release (72 +/- 4% inhibition at 20 mM (mean +/- SEM, p < .05)) 24 h post-LPS without affecting cellular viability. IL-6 production was significantly inhibited only with the highest dose of L-NAME used. L-NAME inhibition of IL-8 production was also observed at the mRNA level. Conversely, direct exposure of whole blood to NO with the spontaneous NO liberator DETA NONOate caused a dose-dependent stimulation of IL-8, but had no effect on IL-6 release. IL-8 concentrations rose from 8.3 +/- 1.9 ng/mL at 24 h to 31.7 +/- 7.6 ng/mL at 72 h with a single stimulation of 10 mM DETA NONOate. The hydroxyl radical scavenger dimethyl sulfoxide (DMSO) prevented the DETA NONOate induction of IL-8, suggesting the participation of the hydroxyl radical in the NO-induced IL-8 production. These results provide important evidence substantiating a role for NO as a regulator of cytokine expression.
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PMID:Nitric oxide regulation of interleukin-8 gene expression. 898 33

1. We have investigated the role of phosphatases in modulating contractile responses to electrical field stimulation (EFS), methacholine, substance P and capsaicin in guinea-pig isolated main bronchus by use of the phosphatase 1 and 2A inhibitor okadaic acid. 2. Non-adrenergic non-cholinergic (eNANC) contractile responses were elicited by EFS (3 Hz, 20 s, 0.5 ms max. voltage) in the guinea-pig isolated main bronchus in the presence of the non-selective muscarinic antagonist, atropine (1 microM), the non-selective beta-adrenoceptor antagonist; propranolol (1 microM), the neutral endopeptidase inhibitor thiorphan (10 microM) and the cyclo-oxygenase inhibitor, indomethacin (5 microM). Okadaic acid significantly attenuated eNANC contractile responses (% inhibition) elicited by EFS (0.01 microM, 15.2 +/- 26.9%; 0.03 microM, 30.4 +/- 13.9%; 0.01 microM, 39.8 +/- 5.1%; 0.3 microM, 59.5 +/- 8.7%; 1 microM 77.8 +/- 7.8%; P < 0.05, n = 4). In contrast, the inactive analogue 1-Nor okadaone (0.3 microM) failed to attenuate significantly eNANC contractile responses (% inhibition elicited by 1-Nor okadaone, -1.25 +/- 8.5% vs dimethylsulphoxide (DMSO), -13.5 +/- 21.5%; P > 0.05, n = 4). 3. Cholinergic contractile responses were elicited by EFS (1-30 Hz, 10 s, 0.5 ms max. voltage) in guinea-pig isolated bronchus in the presence of the nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME, 30 microM). Okadaic acid failed to attenuate significantly the contractile (% methacholine Emax) response elicited by EFS at all frequencies tested compared with the control (1 Hz, control, 22 +/- 7.9% vs okadaic acid, 18 +/- 7.7%; 3 Hz, control, 26 +/- 6.9% vs okadaic acid, 27 +/- 9.1%; 10 Hz, control, 36 +/- 7.6% vs okadaic acid, 33 +/- 8.9%; 30 Hz, control, 50 +/- 7.6% vs okadaic acid, 42 +/- 14%; P > 0.05, n = 4). 4. Okadaic acid (0.3 microM) failed to alter significantly the contractile potency (pD2) to capsaicin (okadaic acid, 9.0 +/- 0.5, vs DMSO, 9.2 +/- 0.4; P > 0.05 n = 6), substance P (okadaic acid, 7.6 +/- 0.3 vs DMSO, 8.2 +/- 0.2; P > 0.05 n = 7) or methacholine (okadaic acid, 6.4 +/- 0.2 vs DMSO, 6.4 +/- 0.3; P > 0.05 n = 4). 5. Okadaic acid (0.01-1 microM) did not appear to reverse substance P-induced tone. The maximal relaxant response (% reversal of substance P-induced tone) mediated by okadaic acid (1 microM) was 33 +/- 11.7% (n = 4), this was not significantly different from the DMSO (0.8%) or a time-dependent fall in tone of 34.3 +/- 23.1% (n = 4) and 33 +/- 15.8% (n = 4), respectively. Okadaic acid (0.3 microM) failed to augment isoprenaline-induced relaxation responses in substance P contracted bronchus (okadaic acid, 6.5 +/- 0.4 vs DMSO, 5.9 +/- 0.3; P > 0.05, n = 9). 6. These results indicate that protein phosphatases appear to regulate the release of sensory neuropeptides from airway sensory nerves in response to electrical field stimulation.
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PMID:The effect of okadaic acid on non-adrenergic non-cholinergic contraction in guinea-pig isolated bronchus. 915 25

Nitric oxide (NO) synthase inhibitors, such as NG-nitro-L-arginine methyl ester (L-NAME), have been shown to attenuate endotoxin-induced uveitis (EIU) but they could increase leukocyte adhesion to the vascular endothelium. We hypothesize that a concomitant treatment with the 5-lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) in 50% dimethylsulfoxide (DMSO, a hydroxyl radical scavenger) could improve the anti-inflammatory activity of L-NAME. EIU was induced in albino rabbits by intravitreal injection of 100 ng lipopolysaccharide. Animals were treated with multiple intraperitoneal injections of 50% DMSO in phosphate-buffered saline (PBS), NDGA (10 mg/kg) in 50% DMSO, L-NAME (50 mg/ kg) in PBS, or the combination NDGA+L-NAME. Uveitis was assessed by slit lamp examination, protein levels in aqueous humor, and myeloperoxidase (MPO) activity in the iris/ciliary body 6 h after induction. Nitrite, leukotriene B4 (LTB4), prostaglandin E2 (PGE2), platelet-activating factor (PAF) and interleukin-1 beta (IL-1 beta) levels in aqueous humor were also determined. NDGA or L-NAME alone did not show a significant reduction of uveitis intensity, although a significant decrease in MPO or in proteins was found, respectively. The combination NDGA+L-NAME significantly reduced the uveitis intensity, MPO in the iris/ciliary body, and the levels of nitrites, LTB4, PGE2, and PAF in aqueous humor. IL-1 beta levels were lower than the detection limit of the radioimmunoassay in all treatment groups. We conclude that concomitant treatment with NDGA in DMSO improves the anti-inflammatory activity of L-NAME during the early phase of EIU, suggesting that the inhibition of NO synthesis could enhance leukocyte infiltration and the release of oxygen free radicals.
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PMID:Concomitant treatment with a 5-lipoxygenase inhibitor improves the anti-inflammatory effect of the inhibition of nitric oxide synthase during the early phase of endotoxin-induced uveitis in the rabbit. 926 46

1. Tumour necrosis factor-alpha (TNF-alpha) is implicated in the pathogenesis of many pulmonary and airway diseases. TNF-alpha stimulation may release interleukin-8 (IL-8) in airways mediated via an increase in intracellular oxidant stress. In the present study, we have assessed leukosequestration and IL-8 release in the airways in response to intratracheal administration of human recombinant TNF-alpha, and examined the modulatory role of endogenous NO by pretreatment with a NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME). 2. TNF-alpha (10(2)-10(-4) u) was administered intratracheally in male guinea-pigs which were anaesthetized with urethane and were ventilated artificially. TNF-alpha induced a time- and dose-related increase in neutrophil numbers and a concomitant increase in human IL-8 equivalent level retrieved from bronchoalveolar lavage (BAL) with the peak effect at 10(3) u at 6 h of TNF-alpha injection (late phase). Intratracheal administration of recombinant human (rh)IL-8 (0.025, 0.25, 2.5 ng) producing a similar range of human IL-8 equivalent levels in BAL as measured in our results induced neutrophil recovery in BAL fluid to a similar extent. Administration of anti-IL-8 antibody prevented the late phase of neutrophil recruitment induced by TNF-alpha or rhIL-8. 3. Pretreatment with L-NAME significantly enhanced the TNF-alpha (10(3) u)-induced neutrophil recruitment and human IL-8 equivalents production at 6 h, but not at 1 h of TNF-alpha administration (early phase). L-Arginine reversed the responses to L-NAME. Pretreatment with 0.2% DMSO (i.v.) significantly inhibited TNF-alpha-induced neutrophil recruitment and human IL-8 equivalents release both in the early and late phase of the responses. Pretreatment with DMSO also inhibited the enhancement effect of L-NAME on the late phase of TNF-alpha-induced responses. DMSO failed to modify exogenous rhIL-8-induced neutrophil recruitment. Neither L-NAME nor DMSO alone induced any significant change in neutrophil numbers or human IL-8 equivalent level in BAL fluid. 4. Neutrophil depletion by cyclophosphamide pretreatment failed to modify TNF-alpha-induced human IL-8 equivalent release. 5. The expression of beta 2-integrin, CD11b/CD18 on neutrophils was increased only in the late but not early phase of TNF-alpha stimulation. L-NAME failed to modify these responses. 6. In conclusion, we demonstrated that NO may be an important endogenous inhibitor of TNF-alpha-induced leukocyte chemotaxis via inhibition of IL-8 production. Thus, the production of NO in airway inflammatory diseases may play a negative feedback role in self-limiting the magnitude of inflammatory responses.
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PMID:Effect of endogenous nitric oxide on tumour necrosis factor-alpha-induced leukosequestration and IL-8 release in guinea-pigs airways in vivo. 929 35

1. To determine the acute effects of irradiation on the functionality of vessel, rat aortic rings were mounted in an organ bath for isometric tension measurements and irradiated (60Co, 1 Gy min(-1), 15 min). 2. Irradiation, which is without effect on non-contracted or endothelium-denuded vessels, led to an immediate and reversible increase in vascular tone on (-)-phenylephrine (1 microM)-precontracted aortic rings. The tension reached a plateau about 5 min after the beginning of irradiation. 3. The maximal radiation-induced contraction occurred on aortic rings relaxed by acetylcholine (ACh) (1 microM). In this condition, the addition of catalase (1000 u ml(-1)), which reduces hydrogen peroxide, and DMSO (0.1% v/v), which scavenges hydroxyl radical, had no influence on tension level while superoxide dismutase (SOD) (100 u ml(-1)), a superoxide anion scavenger, reduced the observed contraction. A similar result was obtained in the presence of indomethacin (10 microM), a cyclo-oxygenase blocker. 4. Pretreatment of rings with the nitric oxide synthase inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME) (10-100 microM) inhibited the radiation-induced contraction. 5. This effect was dose rate-dependent and even occurred for a very low dose rate (0.06 Gy min(-1)). 6. The present results indicate that gamma-radiation induces an instantaneous vascular tone increase that is endothelium and dose rate-dependent. This effect is (i) maximal when nitric oxide (NO) is produced, (ii) greatly reduced by SOD and (iii) inhibited by L-NAME, suggesting a major involvement of complexes between NO and superoxide anion.
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PMID:Early effects of acute gamma-radiation on vascular arterial tone. 955 1

In the present investigation involvement of endothelial-derived reactive oxygen species (ROS) and their interaction with nitric oxide (NO), during norepinephrine (NE)-induced contraction of rat aortic rings was studied. NE (1x10(-10) M to 1x10(-5) M) caused concentration-dependent contractio n of the endothelium intact aortic rings. In the presence of hydroxyl radical scavengers, histidine (1x10(-3) M), mannitol (3x10(-3) M), dimethyl sulfoxide (50x10(-3) M) or thiourea (1x10(-3) m), superoxide dismutase (superoxide radical scavenger, SOD 10 or 100 U ml-1) or catalase (hydrogen peroxide inactivator 3, 10, or 100 U ml-1) the concentration-response curve of NE was shifted towards the right. Interestingly, in NG-nitro-l-arginine methyl ester (L-NAME) (1x10(-5) M, a NO synthase inhibitor) pretreated rings, NE-induced contractions were not inhibited by SOD or extracellular hydroxyl radical scavengers (mannitol and histidine). However, in these rings NE-induced contractions were found to be attenuated by endogenous hydroxyl radical scavengers (thiourea and DMSO) or catalase. In the endothelium denuded rings no significant effect of these scavengers on NE-induced contractions was observed. These results thus indicate the involvement of endothelium-derived hydrogen peroxide, superoxide and hydroxyl radicals in the NE-induced contractions. In addition, endothelial NO interacts with the ROS generated during rat aortic ring contractions.
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PMID:Role of endothelial-derived reactive oxygen species and nitric oxide in norepinephrine-induced rat aortic ring contractions. 977 89

The present study analyses the influence of hypertension and endothelium on the effect induced by hydrogen peroxide (H2O2) on basal tone in aortic segments from normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) of 6-month-old, as well as the possible mechanisms involved. Single (1 mM) or cumulative (100 nM-10 mM) concentrations of H2O2 produced a transient contraction or a concentration-dependent increase of basal tone, respectively, in segments from WKY and SHR. In both cases, the contractions were higher in intact segments from hypertensive than from normotensive rats, and increased by endothelium removal in both strains. Catalase (1000 u ml(-1), a H2O2 scavenger) abolished the contraction elicited by 1 mM H2O2 in both strains. Superoxide dismutase (SOD, 150 u ml(-1)) and dimethylsulphoxide (DMSO, 7 mM), scavengers of superoxide anions and hydroxyl radicals, respectively, did not alter H2O2-induced contractions in intact segments from both strains. However, L-NG-nitroarginine methyl ester (L-NAME, 100 microM, a nitric oxide synthase inhibitor) increased the response to H2O2 in normotensive rats, although the increase was less than that produced by endothelium removal. Incubation of segments with 1 mM H2O2 for 15 min and subsequent washout reduced the contractile responses induced by 75 mM KCl in intact segments from SHR and in endothelium-denuded segments from both strains; this effect being prevented by catalase (1000 u ml(-1)). Indomethacin (10 microM, a cyclo-oxygenase inhibitor) and SQ 29,548 (10 microM, a prostaglandin H2/thromboxane A2 receptor antagonist) practically abolished the contractions elicited by H2O2 in normotensive and hypertensive rats. We conclude that: (1) the oxidant stress induced by H2O2 produces contractions mediated by generation of a product of the cyclo-oxygenase pathway, prostaglandin H2 or more probably thromboxane A2, in normotensive and hypertensive rats; (2) oxygen-derived free radicals are not involved in the effect of H2O2; (3) in normotensive rats, endothelium protects against H2O2-mediated injury to contractile machinery, determined by the impairment of KCl-induced contractions; and (4) endothelial nitric oxide has a protective role on the contractile effect induced by H2O2, that is lost in hypertension.
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PMID:Contractile responses elicited by hydrogen peroxide in aorta from normotensive and hypertensive rats. Endothelial modulation and mechanism involved. 986 64

In prostglandin F2alpha(PGF2alpha)-precontracted isolated canine basilar arterial rings, hydrogen peroxide (H2O2) produced endothelium-dependent relaxations at concentrations of from 4.4 x 10(-7) - approximately 4.4 x 10(-5) M. Removal of extracellular Ca2+ ([Ca2+]0) attenuated the relaxant effects of H2O2. Complete inhibition of H2O2 relaxant action was obtained after buffering intracellular Ca2+ ([Ca2+]i), in the endothelial cells, with 10 microM 1,2-bis (2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid (BAPTA-AM). The H2O2-induced relaxations could be abolished completely by 1200 u/ml catalase and was suppressed significantly by 0.5 microM atropine, 150 microM NG-monomethyl-arginine (L-NMMA), 50 microM NG-nitro-L-arginine methyl ester (L-NAME), 1 microM Fe2+, or 5 microM methylene blue. These inhibitory effects of L-NMMA, L-NAME, or atropine could be reversed partly by 50 microM L-arginine. The Fe2+ inhibition of H2O2-stimulated relaxation was reduced significantly by either 1 mM deferoxamine (a Fe2+ chelator) or 100 microM dimethyl sulfoxide (DMSO, a *OH scavenger). Such relaxant effects of H2O2 were enhanced, significantly, by an acetylcholinesterase antagonist, neostigmine. A variety of pharmacological antagonists (of diverse vasodilator agents) could not inhibit the relaxant action of H2O2. Our observations suggest that at suitable pathophysiological concentrations, H2O2 could induce release of an endothelium-derived relaxing factor (EDRF), probably nitric oxide (NO), from endothelial cells of the canine cerebral artery. The H2O2 relaxant effects are clearly Ca2+-dependent, require formation of cyclic guanosine monophosphate (cGMP), and may be associated with release of endogenous acetylcholine (ACh).
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PMID:Endothelium-dependent relaxation to hydrogen peroxide in canine basilar artery: a potential new cerebral dilator mechanism. 986 58

In phenylephrine-precontracted rings, H2O2 produced an endothelium-dependent relaxation at concentrations of 4.4 x 10(-7) to approximately 4.4 x 10(-5) M. Removal of extracellular Ca2+ ([Ca2+]0) markedly attenuated the relaxant effects of H2O2. Complete inhibition of the H2O2 relaxant action was obtained after buffering intracellular Ca2+ ([Ca2+]i) in endothelial cells, with 10 microM acetyl methyl ester of bis (o-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid (BAPTA-AM). These relaxant effects of H2O2 were nearly abolished by 15 x 10(-5)M N(G)-monomethyl-arginine (L-NMMA) or 5 x 10(-5) M N(G)-nitro-L-arginine (L-NAME) and were attenuated markedly by the presence of either 10(-6) M Fe2+, 10(-6) M Fe3+, or 5 x 10(-6) M methylene blue. These inhibitory effects of L-NMMA or L-NAME could be reversed partly by 5 x 10(-5) M L-arginine. These Fe(2+)- and Fe(3+)-induced inhibitions of H2O2-stimulated relaxation were reduced significantly by either 1.0 mM deferoxamine (a Fe2+ chelator) or 100 microM dimethyl sulfoxide (DMSO). In addition, 17-octadecynoic acid (2.5 microM) or proadifen (10 microM) (both antagonists of cytochrome P450 metabolism of fatty acids) markedly decreased the H2O2 relaxant effects. Proadifen (10 microM) produced concentration-dependent impairment of vasorelaxation to acetylcholine. A variety of amine antagonists and a cyclo-oxygenase inhibitor all fail to interfere with or attenuate the H2O2-induced relaxations. Our observations suggest that, at suitable pathophysiologic concentrations, H2O2 could induce release of an endothelium-derived relaxing factor, probably nitric oxide, from endothelial cells. The H2O2 relaxant effects are clearly Ca(2+)-dependent and require formation of cyclic guanosine monophosphate (cGMP). These vasorelaxing effects of H2O2 appear to be induced by H2O2 itself. Hydrogen peroxide may stimulate production of some unknown metabolites metabolized by cytochrome P450-dependent enzymes.
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PMID:Hydrogen peroxide-induced endothelium-dependent relaxation of rat aorta involvement of Ca2+ and other cellular metabolites. 1052 71

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