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      Oxidative stress and Nrf2 expression in peripheral blood mononuclear cells derived from COPD patients: an observational longitudinal study

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          Abstract

          Background

          A persistent low inflammatory-oxidative status and the inadequacy of the antioxidant nuclear factor-E2-related factor 2 (Nrf2) have been implicated in chronic obstructive pulmonary disease (COPD) progression. Therefore this study was aimed to assess the association between lung function decline and oxidative-inflammatory markers and Nrf2 signaling pathway expression in peripheral blood mononuclear cells (PBMCs) over time.

          Methods

          33 mild-moderate COPD outpatients (mean age 66.9 ± 6.9 years) were age-sex matched with 37 no-COPD subjects. A clinical evaluation, blood sampling tests and a spirometry were performed at baseline and after a mean follow-up of 49.7 ± 6.9 months.

          Results

          In COPD, compared to no-COPD, we found a faster lung function decline at follow-up. Although similar prevalence of smoking, hypertension, diabetes and dyslipidemia, systemic markers of inflammation (hs-CRP and white blood cells, WBCs) and oxidative stress (8-isoprostane) were significantly increased in COPD at follow-up, while the antioxidant glutathione (GSH) was significantly reduced. Moreover the expression of Nrf2 and of Nrf2-related genes heme oxygenase (HO)-1 and glutamate-cysteine ligase catalytic (GCLC) subunit in PBMCS were significantly down-regulated in COPD at follow-up, whereas no changes were observed in no-COPD. The percent variation (Δ) of FEV 1 detected after the follow-up in COPD patients was directly correlated with ΔNrf2 (r = 0.826 p < 0.001), ΔHO-1 (r = 0.820, p < 0.001) and ΔGCLC (r = 0.840, p < 0.001). Moreover ΔFEV 1 was also directly correlated with ΔGSH (r = 0.595, p < 0.01) and inversely correlated with Δ8-iso (r = − 0.587, p < 0.01) and with baseline smoking history (r = − 0.39, p < 0.03). No correlation was found between ΔFEV 1, ΔCRP and ΔWBCs. By means of hierarchical stepwise multiple linear regression, taking into account other baseline key factors related to FEV 1, ΔNrf2, ΔHO-1and ΔGCLC were found to be significant predictors of ΔFEV 1, explaining 89.5% of its variance.

          Conclusions

          Although our results must be confirmed in larger trial they suggest that the down-regulation of Nrf2/ARE gene expression in PBMCs may be one of the determinants of FEV 1 decline and of COPD progression. Therefore the future possibility to counteract Nrf2 decline in COPD patients may help in reducing the negative effects of the oxidative stress-induced progression of the disease.

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          Most cited references32

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          Oxidative stress in COPD.

          Oxidative stress is now recognized as a major predisposing factor in the pathogenesis of COPD. Existing therapies for COPD are ineffective at halting disease progression, with bronchodilators being the mainstay of pharmacotherapy, providing symptomatic relief only. It is, therefore, important for a better understanding of the underlying mechanisms by which oxidative stress drives disease pathogenesis to develop novel and more effective therapies. Antioxidant capacity in COPD is substantially reduced as a result of cigarette smoking and exacerbations, with oxidative stress persisting long after the cessation of cigarette smoking or exacerbation, due to the continued production of reactive oxygen species from endogenous sources. We discuss (1) how oxidative stress arises in the lung, (2) how it is neutralized, (3) what genetic factors may predispose to the development of COPD, and (4) how this impacts inflammation and autoimmunity in the development of emphysema and small airways disease. Finally, various strategies have been considered to neutralize the increased oxidative burden present in COPD. This review highlights why current antioxidant strategies have so far failed and what promising alternatives are on the horizon. Moreover, a number of studies have shown that there is no single "magic bullet" to combat oxidative stress, but instead a combination therapy, targeting oxidative stress in the various subcellular compartments, may prove to be more effective in COPD.
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            Smoking cessation and lung function in mild-to-moderate chronic obstructive pulmonary disease. The Lung Health Study.

            Previous studies of lung function in relation to smoking cessation have not adequately quantified the long-term benefit of smoking cessation, nor established the predictive value of characteristics such as airway hyperresponsiveness. In a prospective randomized clinical trial at 10 North American medical centers, we studied 3, 926 smokers with mild-to-moderate airway obstruction (3,818 with analyzable results; mean age at entry, 48.5 yr; 36% women) randomized to one of two smoking cessation groups or to a nonintervention group. We measured lung function annually for 5 yr. Participants who stopped smoking experienced an improvement in FEV(1) in the year after quitting (an average of 47 ml or 2%). The subsequent rate of decline in FEV(1) among sustained quitters was half the rate among continuing smokers, 31 +/- 48 versus 62 +/- 55 ml (mean +/- SD), comparable to that of never-smokers. Predictors of change in lung function included responsiveness to beta-agonist, baseline FEV(1), methacholine reactivity, age, sex, race, and baseline smoking rate. Respiratory symptoms were not predictive of changes in lung function. Smokers with airflow obstruction benefit from quitting despite previous heavy smoking, advanced age, poor baseline lung function, or airway hyperresponsiveness.
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              Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke–induced emphysema in mice

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                Author and article information

                Contributors
                annamaria.frattapasini@univr.it
                Journal
                Respir Res
                Respir. Res
                Respiratory Research
                BioMed Central (London )
                1465-9921
                1465-993X
                30 January 2020
                30 January 2020
                2020
                : 21
                : 37
                Affiliations
                [1 ]ISNI 0000 0004 1763 1124, GRID grid.5611.3, Department of Medicine, Section of General Medicine and Atherothrombotic and Degenerative Diseases, , University of Verona, ; Verona, Italy
                [2 ]Department of Medicine, Unit of Respiratory Diseases, Verona, Italy
                [3 ]ISNI 0000 0004 1763 1124, GRID grid.5611.3, Department of Diagnostics and Public Health, Unit of Epidemiology & Medical Statistics, , University of Verona, ; Verona, Italy
                Article
                1292
                10.1186/s12931-020-1292-7
                6993453
                32000766
                cb49def5-1649-4ad5-bf50-a14622f364b3
                © The Author(s). 2020

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 21 August 2019
                : 14 January 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100006747, Fondazione Cassa di Risparmio di Verona Vicenza Belluno e Ancona;
                Categories
                Research
                Custom metadata
                © The Author(s) 2020

                Respiratory medicine
                copd progression,oxidative stress,nrf2/are gene expression,pbmcs
                Respiratory medicine
                copd progression, oxidative stress, nrf2/are gene expression, pbmcs

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