Effects of Aminoguanidine, an Inhibitor of Inducible Nitric Oxide Synthase, on Nitric Oxide Production and Its Metabolites in Healthy Control Subjects, Healthy Smokers, and COPD Patients

Brindicci, Caterina; Ito, Kazuhiro; Torre, Olga; Barnes, Peter J.; Kharitonov, Sergei A.

doi:10.1378/chest.08-0964

Cited by 46 publications

(37 citation statements)

References 56 publications

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“…Also, proinflammatory cytokine-induced iNOS expression was decreased by oxidative stress, such as hydrogen peroxide (H 2 O 2 ), cigarette smoke-conditioned medium (CSM), and the peroxynitrite generator SIN1 (data not shown), consistent with findings in severe COPD, in which there is a high level of oxidative stress and peroxynitrite formation (13,26,27).…”

Section: Choosesupporting

confidence: 70%

“…Furthermore, nebulized aminoguanidine, a weakly selective iNOS inhibitor, markedly reduces (∼90%) NO produced in the central airways (J NO ) in asthma (12), whereas in COPD the increased exhaled NO from peripheral lung (C alv ) is decreased by less than 50% (13). The increase in C alv and exhaled ONOO − levels was not completely suppressed by nebulized aminoguanidine in patients with COPD (13), suggesting that an isoform(s) different from iNOS may also be involved in peripheral NO production in patients with COPD.…”

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confidence: 99%

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Nitric Oxide Synthase Isoenzyme Expression and Activity in Peripheral Lung Tissue of Patients with Chronic Obstructive Pulmonary Disease

Brindicci

Kharitonov²,

Ito³

et al. 2010

Am J Respir Crit Care Med

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Rationale: Nitric oxide (NO) is increased in the lung periphery of patients with chronic obstructive pulmonary disease (COPD). However, expression of the NO synthase(s) responsible for elevated NO has not been identified in the peripheral lung tissue of patients with COPD of varying severity. Objectives:Methods: Protein and mRNA expression of nitric oxide synthase type I (neuronal NOS [nNOS]), type II (inducible NOS [iNOS]), and type III (endothelial NOS [eNOS]) were quantified by Western blotting and reverse transcription-polymerase chain reaction, respectively, in specimens of surgically resected lung tissue from nonsmoker control subjects, patients with COPD of varying severity, and smokers without COPD, and in a lung epithelial cell line (A549). The effects of nitrative/oxidative stress on NOS expression and activity were also evaluated in vitro in A549 cells. nNOS nitration was quantified by immunoprecipitation and dimerization of nNOS was detected by low-temperature SDS-PAGE/Western blot in the presence of the peroxynitrite generator, 3-morpholinosydnonimine-N-ethylcarbamide (SIN1), in vitro and in vivo. Measurements and Main Results:Lung tissue from patients with severe and very severe COPD had graded increases in nNOS (mRNA and protein) compared with nonsmokers and normal smokers. Hydrogen peroxide (H 2 O 2 ) and SIN1 as well as the cytokine mixture (IFN-γ, IL-1β, and tumor necrosis factor-α) increased mRNA expression and activity of nNOS in A549 cells in a concentration-dependent manner compared with nontreated cells. Tyrosine nitration resulted in an increase in nNOS activity in vitro, but did not affect its dimerization. Conclusions:Patients with COPD have a significant increase in nNOS expression and activity that reflects the severity of the disease and may be secondary to oxidative stress.

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Section: Choosesupporting

confidence: 70%

mentioning

confidence: 99%

Nitric Oxide Synthase Isoenzyme Expression and Activity in Peripheral Lung Tissue of Patients with Chronic Obstructive Pulmonary Disease

Brindicci

Kharitonov²,

Ito³

et al. 2010

Am J Respir Crit Care Med

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“…7,26 Our observation that eNOS was also induced in the lung after elastase instillation was in line with the expression in COPD of constitutive NOS isoforms, as evidenced by the partial inhibition of alveolar NO production by inhaled aminoguanidine, a specific iNOS inhibitor, in these patients. 10 Strengthening the relevancy of our model, the NOS expression profile induced by elastase instillation in our experiments was identical to that induced by cigarette smoke exposure in rats. 27 Activity of all NOS isoforms can be regulated post-translationally, 10,28 and it might be hypothesized that the lack of effect of eNOS or iNOS inactivation be related to already low levels of eNOS or iNOS activity.…”

Section: Discussionsupporting

confidence: 55%

“…10 Strengthening the relevancy of our model, the NOS expression profile induced by elastase instillation in our experiments was identical to that induced by cigarette smoke exposure in rats. 27 Activity of all NOS isoforms can be regulated post-translationally, 10,28 and it might be hypothesized that the lack of effect of eNOS or iNOS inactivation be related to already low levels of eNOS or iNOS activity. This question is of particular concern in the case of eNOS because we did not observe any morphological or biochemical effect of eNOS deletion.…”

Section: Discussionsupporting

confidence: 55%

“…6 In line with these results, the expression of iNOS is exaggerated and is correlated with the extent of protein nitration in the alveolar walls of patients with pulmonary emphysema. 7 However, although markers of nitrosative stress are present in the lung of patients with emphysema, leading some authors to suggest a role for this phenomenon in the process of disease 6,[8][9][10] ; the relationship between nitrosative stress and the development of emphysema is unknown.…”

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Role of nitric oxide synthases in elastase-induced emphysema

Boyer

Plantier

Dagouassat

et al. 2011

Laboratory Investigation

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Nitric oxide (NO) in combination with superoxide produces peroxynitrites and induces protein nitration, which participates in a number of chronic degenerative diseases. NO is produced at high levels in the human emphysematous lung, but its role in this disease is unknown. The aim of this study was to determine whether the NO synthases contribute to the development of elastase-induced emphysema in mice. nNOS, iNOS, and eNOS were quantified and immunolocalized in the lung after a tracheal instillation of elastase in mice. To determine whether eNOS or iNOS had a role in the development of emphysema, mice bearing a germline deletion of the eNOS and iNOS genes and mice treated with a pharmacological iNOS inhibitor were exposed to elastase. Protein nitration was determined by immunofluorescence, protein oxidation was determined by ELISA. Inflammation and MMP activity were quantified by cell counts, RT-PCR and zymography in bronchoalveolar lavage fluid. Cell proliferation was determined by Ki67 immunostaining. Emphysema was quantified morphometrically. iNOS and eNOS were diffusely upregulated in the lung of elastase-treated mice and a 12-fold increase in the number of 3-nitrotyrosine-expressing cells was observed. Over 80% of these cells were alveolar type 2 cells. In elastaseinstilled mice, iNOS inactivation reduced protein nitration and increased protein oxidation but had no effect on inflammation, MMP activity, cell proliferation or the subsequent development of emphysema. eNOS inactivation had no effect. In conclusion, in the elastase-injured lung, iNOS mediates protein nitration in alveolar type 2 cells and alleviates oxidative injury. Neither eNOS nor iNOS are required for the development of elastase-induced emphysema.

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Exhaled Breath Condensate Biomarkers of Airway Inflammation and Oxidative Stress in COPD

Montuschi

2011

Studies on Experimental Models

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Effects of Aminoguanidine, an Inhibitor of Inducible Nitric Oxide Synthase, on Nitric Oxide Production and Its Metabolites in Healthy Control Subjects, Healthy Smokers, and COPD Patients

Cited by 46 publications

References 56 publications

Nitric Oxide Synthase Isoenzyme Expression and Activity in Peripheral Lung Tissue of Patients with Chronic Obstructive Pulmonary Disease

Nitric Oxide Synthase Isoenzyme Expression and Activity in Peripheral Lung Tissue of Patients with Chronic Obstructive Pulmonary Disease

Role of nitric oxide synthases in elastase-induced emphysema

Exhaled Breath Condensate Biomarkers of Airway Inflammation and Oxidative Stress in COPD

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