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      Decreased Serum Sirtuin-1 in COPD

      research-article
      , MD, PhD a , , MD, PhD b , , MD, PhD c , , PhD a , , MSc a , , MD, PhD d , , DM, DSc a , , DVM, PhD a ,
      Chest
      American College of Chest Physicians
      biomarker, COPD, emphysema, serum, sirtuin-1, 6MWD, 6-min walking distance, Aado2, alveolar-arterial oxygen difference, BODE, BMI, airflow obstruction, dyspnea, and exercise capacity, Dlco, diffusing capacity for carbon monoxide, DMEM, Dulbecco's Modified Eagle Medium, ELISA, enzyme-linked immunosorbent assay, FBS, fetal bovine serum, GOLD, Global Initiative for Chronic Obstructive Lung Disease, HRCT, high-resolution CT, IC, inspiratory capacity, KCO%, diffusing capacity of the lung per unit volume, MRC, Medical Research Council, NAD, nicotinamide adenine dinucleotide, RPMI, Roswell Park Memorial Institute medium, RV, residual volume, s120S, serum SIRT1, SIRT1, silent information regulator 2 homolog 1, TLC, total lung capacity

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          Abstract

          Background

          The protein deacetylase sirtuin-1 (SIRT1) is an antiaging molecule that is decreased in the lung in patients with COPD. Recently, SIRT1 was reported to be detectable in serum, but serum SIRT1 (s120S) levels have not yet been reported in patients with COPD.

          Methods

          Serum SIRT1 protein of all samples was measured by Western blot, and the SIRT1 protein band densities were calculated and compared with clinical parameters.

          Results

          Several molecular sizes of SIRT1, including 120 kDa (actual size) and fragments (102 and 75 kDa) were quantified by Western blot. Among them, only the 120-kDa s120S was significantly decreased in patients with COPD compared with the control subjects without COPD (s120S ratio in healthy subjects = 0.90 ± 0.34 vs those with COPD = 0.68 ± 0.24; P = .014) and was positively correlated with airway obstruction (FEV 1/FVC, r = 0.31 ; P = .020); its severity measured by FEV 1 % predicted ( r = 0.29 ; P = .029). s120S also showed a positive correlation with BMI ( r = 0.36 ; P = .0077) and diffusing capacity of the lung per unit volume (the carbon monoxide transfer coefficient: K CO%) ( r = 0.32 ; P = .025). It was also significantly decreased with increasing severity of lung emphysema ( r = –0.40 ; P = .027) and with a clinical history of frequent COPD exacerbations (infrequent vs frequent, 0.76 ± 0.20 vs 0.56 ± 0.26 ; P = .027). SIRT1 was not detected in supernatant of A549 and primary epithelial cells in normal culture conditions.

          Conclusions

          s120S was decreased in the patients with COPD, potentially as reflected by the reduced SIRT1 within cells as a result of oxidative stress, and might be a potential biomarker for certain disease characteristics of COPD.

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          Most cited references39

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          Susceptibility to exacerbation in chronic obstructive pulmonary disease.

          Although we know that exacerbations are key events in chronic obstructive pulmonary disease (COPD), our understanding of their frequency, determinants, and effects is incomplete. In a large observational cohort, we tested the hypothesis that there is a frequent-exacerbation phenotype of COPD that is independent of disease severity. We analyzed the frequency and associations of exacerbation in 2138 patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. Exacerbations were defined as events that led a care provider to prescribe antibiotics or corticosteroids (or both) or that led to hospitalization (severe exacerbations). Exacerbation frequency was observed over a period of 3 years. Exacerbations became more frequent (and more severe) as the severity of COPD increased; exacerbation rates in the first year of follow-up were 0.85 per person for patients with stage 2 COPD (with stage defined in accordance with Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages), 1.34 for patients with stage 3, and 2.00 for patients with stage 4. Overall, 22% of patients with stage 2 disease, 33% with stage 3, and 47% with stage 4 had frequent exacerbations (two or more in the first year of follow-up). The single best predictor of exacerbations, across all GOLD stages, was a history of exacerbations. The frequent-exacerbation phenotype appeared to be relatively stable over a period of 3 years and could be predicted on the basis of the patient's recall of previous treated events. In addition to its association with more severe disease and prior exacerbations, the phenotype was independently associated with a history of gastroesophageal reflux or heartburn, poorer quality of life, and elevated white-cell count. Although exacerbations become more frequent and more severe as COPD progresses, the rate at which they occur appears to reflect an independent susceptibility phenotype. This has implications for the targeting of exacerbation-prevention strategies across the spectrum of disease severity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT00292552.)
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            Sirtuin 1 and sirtuin 3: physiological modulators of metabolism.

            The sirtuins are a family of highly conserved NAD(+)-dependent deacetylases that act as cellular sensors to detect energy availability and modulate metabolic processes. Two sirtuins that are central to the control of metabolic processes are mammalian sirtuin 1 (SIRT1) and sirtuin 3 (SIRT3), which are localized to the nucleus and mitochondria, respectively. Both are activated by high NAD(+) levels, a condition caused by low cellular energy status. By deacetylating a variety of proteins that induce catabolic processes while inhibiting anabolic processes, SIRT1 and SIRT3 coordinately increase cellular energy stores and ultimately maintain cellular energy homeostasis. Defects in the pathways controlled by SIRT1 and SIRT3 are known to result in various metabolic disorders. Consequently, activation of sirtuins by genetic or pharmacological means can elicit multiple metabolic benefits that protect mice from diet-induced obesity, type 2 diabetes, and nonalcoholic fatty liver disease.
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              Decreased histone deacetylase activity in chronic obstructive pulmonary disease.

              Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation that is greater in patients with advanced disease. We asked whether there is a link between the severity of disease and the reduction in histone deacetylase (HDAC) activity in the peripheral lung tissue of patients with COPD of varying severity. HDAC is a key molecule in the repression of production of proinflammatory cytokines in alveolar macrophages. HDAC activity and histone acetyltransferase (HAT) activity were determined in nuclear extracts of specimens of surgically resected lung tissue from nonsmokers without COPD, patients with COPD of varying severity, and patients with pneumonia or cystic fibrosis. Alveolar macrophages from nonsmokers, smokers, and patients with COPD and bronchial-biopsy specimens from nonsmokers, healthy smokers, patients with COPD, and those with mild asthma were also examined. Total RNA extracted from lung tissue and macrophages was used for quantitative reverse-transcriptase-polymerase-chain-reaction assay of HDAC1 through HDAC8 and interleukin-8. Expression of HDAC2 protein was quantified with the use of Western blotting. Histone-4 acetylation at the interleukin-8 promoter was evaluated with the use of a chromatin immunoprecipitation assay. Specimens of lung tissue obtained from patients with increasing clinical stages of COPD had graded reductions in HDAC activity and increases in interleukin-8 messenger RNA (mRNA) and histone-4 acetylation at the interleukin-8 promoter. The mRNA expression of HDAC2, HDAC5, and HDAC8 and expression of the HDAC2 protein were also lower in patients with increasing severity of disease. HDAC activity was decreased in patients with COPD, as compared with normal subjects, in both the macrophages and biopsy specimens, with no changes in HAT activity, whereas HAT activity was increased in biopsy specimens obtained from patients with asthma. Neither HAT activity nor HDAC activity was changed in lung tissue from patients with cystic fibrosis or pneumonia. Patients with COPD have a progressive reduction in total HDAC activity that reflects the severity of the disease. Copyright 2005 Massachusetts Medical Society.
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                Author and article information

                Contributors
                Journal
                Chest
                Chest
                Chest
                American College of Chest Physicians
                0012-3692
                1931-3543
                1 August 2017
                August 2017
                : 152
                : 2
                : 343-352
                Affiliations
                [a ]Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, England
                [b ]Third Respiratory Medicine Department, Sismanogleion General Hospital, Athens, Greece
                [c ]First Respiratory Medicine Department, University of Athens, Sotiria Hospital, Athens, Greece
                [d ]Division of Respiratory Diseases I, National and Kapodistrian University of Athens, Athens, Greece
                Author notes
                [] CORRESPONDENCE TO: Kazuhiro Ito, PhD, Airway Disease Section, National Heart and Lung Institute, Imperial College School of Medicine, Dovehouse St, London SW3 6LY, UKAirway Disease SectionNational Heart and Lung InstituteImperial College School of MedicineDovehouse StLondon SW3 6LYUK k.ito@ 123456imperial.ac.uk
                Article
                S0012-3692(17)30921-2
                10.1016/j.chest.2017.05.004
                5540026
                28506610
                1ac309da-c8da-4ebe-a59b-ab601222af15
                © 2017 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                Categories
                Original Research: COPD

                Respiratory medicine
                biomarker,copd,emphysema,serum,sirtuin-1,6mwd, 6-min walking distance,aado2, alveolar-arterial oxygen difference,bode, bmi, airflow obstruction, dyspnea, and exercise capacity,dlco, diffusing capacity for carbon monoxide,dmem, dulbecco's modified eagle medium,elisa, enzyme-linked immunosorbent assay,fbs, fetal bovine serum,gold, global initiative for chronic obstructive lung disease,hrct, high-resolution ct,ic, inspiratory capacity,kco%, diffusing capacity of the lung per unit volume,mrc, medical research council,nad, nicotinamide adenine dinucleotide,rpmi, roswell park memorial institute medium,rv, residual volume,s120s, serum sirt1,sirt1, silent information regulator 2 homolog 1,tlc, total lung capacity

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