Role of Inflammation and Oxidative Stress in the Pathology of Ageing in COPD: Potential Therapeutic Interventions

References

• Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990–2020: Global burden of disease study. Lancet 1997; 349:1498–1504.
   PubMed Web of Science ®Google Scholar
• Chapman KR, Mannino DM, Soriano JB, Vermeire PA, Buist AS, Thune MJ, et al. Epidemiology and costs of chronic obstructive pulmonary disease. Eur Respir J 2006; 27:188–207.
   PubMed Web of Science ®Google Scholar
• MacNee W. Accelerated lung aging: a novel pathogenic mechanism of chronic 603 obstructive pulmonary disease (COPD). Biochem Soc Trans 2009; 37:819–823.
   PubMed Web of Science ®Google Scholar
• Guarente L. Sirtuins, aging, and metabolism. Cold Spring Harb Symp Quant Biol 2011; 76:81–90.
   PubMedGoogle Scholar
• Faner R, Rojas M, MacNee W, Agustí A. Abnormal lung aging in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2012; 186(4):306–313.
   PubMed Web of Science ®Google Scholar
• MacNee W. Pulmonary and systemic oxidant/antioxidant imbalance in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2005; 2:50–60.
   PubMedGoogle Scholar
• MacNee W, Tuder RM. New paradigms in the pathogenesis of chronic obstructive pulmonary disease. I. Proc Am Thorac Soc 2009; 6:527–31.
   PubMedGoogle Scholar
• Rode L, Bojesen SE, Weischer M, Vestbo J, Nordestgaard BG. Short telomere length, lung function and chronic obstructive pulmonary disease in 46 396 individuals. Thorax 2013; 68(5):429–435.
   PubMed Web of Science ®Google Scholar
• Tsuji T, Aoshiba K, Nagai A. Cigarette smoke induces senescence in alveolar epithelial cells. Am J Respir Cell Mol Biol 2004; 31:643–649.
   PubMed Web of Science ®Google Scholar
• Yao H, Chung S, Hwang JW, Rajendrasozhan S, Sundar IK, Dean DA, et al. SIRT1 protects against emphysema via FOXO3mediated reduction of premature senescence in mice. J Clin Invest 2012; 122(6):2032–2045.
   PubMed Web of Science ®Google Scholar
• Szulakowski P, Crowther AJ, Jimenez LA, Donaldson K, Mayer R, Leonard TB, et al. The effect of smoking on the transcriptional regulation of lung inflammation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006; 174:41–50.
   PubMed Web of Science ®Google Scholar
• Barnes PJ, Celli BR. Systemic manifestations and comorbidities of COPD. Eur Respir J 2009; 33:1165–1185.
   PubMed Web of Science ®Google Scholar
• Lambers C, Hacker S, Posch M, Hoetzenecker K, Pollreisz A, Lichtenauer M, et al. T cell senescence and contraction of T cell repertoire diversity in patients with chronic obstructive pulmonary disease. Clin Exp Immunol 2009; 155:466–475.
   PubMed Web of Science ®Google Scholar
• Fairclough L, Urbanowicz RA, Corne J, Lamb JR. Killer cells in chronic obstructive pulmonary disease. Clin Sci(Lond) 2008; 114:533–541.
   PubMed Web of Science ®Google Scholar
• Miniati M, Monti S, Basta G, Cocci F, Fornai E, Bottai M. Soluble receptor for advanced glycation end products in COPD: relationship with emphysema and chronic cor pulmonale: a case–control study. Respir Res 2011; 12:37.
   PubMed Web of Science ®Google Scholar
• Churg A, Wright JL. Proteases and emphysema. Curr Opin Pulmon Med 2005; 11:153–159.
   PubMed Web of Science ®Google Scholar
• Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res 1961; 25:585–621.
   PubMed Web of Science ®Google Scholar
• Serrano M, Blasco MA. Putting the stress on senescence. Curr Opin Cell Biol 2001; 13:748–753.
   PubMed Web of Science ®Google Scholar
• Collado M, Blasco MA, Serrano M. Cellular senescence in cancer and aging. Cell 2007; 130(2):223–233.
   PubMed Web of Science ®Google Scholar
• Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 1995; 92:9363–9367.
   PubMed Web of Science ®Google Scholar
• Marcotte R, Lacelle C, Wang E. Senescent fibroblasts resist apoptosis by downregulating caspase-3. Mech Ageing Dev 2004; 125:777–783.
   PubMed Web of Science ®Google Scholar
• Wang E. Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl2 is involved. Cancer Res 1995; 55:2284–2292.
   PubMed Web of Science ®Google Scholar
• Campisi J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbours. Cell 2005; 120:513–522.
   PubMed Web of Science ®Google Scholar
• Barnes PJ. Targeting histone deacetylase 2 in chronic obstructive pulmonary disease treatment. Expert Opin Ther Targets 2005; 9(6):1111–1121.
   PubMed Web of Science ®Google Scholar
• Kumar M, Seeger W, Voswinckel R. Senescence-associated secretory phenotype and its possible role in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 2014; 51(3):323–333.
   PubMed Web of Science ®Google Scholar
• Amsellem V, Gary-Bobo G, Marcos E, Maitre B, Chaar V, Validire P, et al. Telomere dysfunction causes sustained inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2011; 184(12):1358–1366.
   PubMed Web of Science ®Google Scholar
• Rahman I, Morrison D, Donaldson K, MacNee W. Systemic oxidative stress in asthma, COPD, and smokers. Am J Respir Crit Care Med 1996; 154(4 Pt 1):1055–1060.
   PubMed Web of Science ®Google Scholar
• Yao H, Rahman I. Current concepts on oxidative/carbonyl stress, inflammation and epigenetics in pathogenesis of chronic obstructive pulmonary disease. Toxicol Appl Pharmacol 2011; 254(2):72–85.
   PubMed Web of Science ®Google Scholar
• Igishi T, Hitsuda Y, Kato K, Sako T, Burioka N, Yasuda K, et al. Elevated urinary 8-hydroxydeoxyguanosine, a biomarker of oxidative stress, and lack of association with antioxidant vitamins in chronic obstructive pulmonary disease. Respirology 2003; 8:455–460.
   PubMed Web of Science ®Google Scholar
• Rahman I, van Schadewijk AA, Crowther AJ, Hiemstra PS, Stolk J, MacNee W, et al. 4-Hydroxy-2-nonenal, a specific lipid peroxidation product, is elevated in lungs of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002; 166:490–495.
   PubMed Web of Science ®Google Scholar
• Repine JE, Bast A, Lankhorst I. Oxidative stress in chronic obstructive pulmonary disease. Oxidative Stress Study Group. Am J Respir Crit Care Med 1997; 156:341e57.
   Web of Science ®Google Scholar
• Rahman I, Adcock IM. Oxidative stress and redox regulation of lung inflammation in COPD. Eur Respir J 2006; 28:219–242.
   PubMed Web of Science ®Google Scholar
• Rahman I, MacNee W. Antioxidant pharmacological therapies for COPD. Curr Opin Pharmacol 2012; 12(3):256–265.
   PubMed Web of Science ®Google Scholar
• Laurent P, Janoff A, Kagan HM. Cigarette smoke blocks cross-linking of elastin in vitro. Am Rev Respir Dis 1983; 127:189–192.
   PubMed Web of Science ®Google Scholar
• Kurku H, Kacmaz M, Kisa U, Dogan O, Caglayan O. Acute and chronic impact of smoking on salivary and serum total antioxidant capacity. J Pak Med Assoc 2015; 65(2):164–169.
   PubMed Web of Science ®Google Scholar
• Cantin A, Crystal RG. Oxidants, antioxidants and the pathogenesis of emphysema. Eur J Respir Dis 1985; 66(Suppl 139):7–17.
   Google Scholar
• Lanzetti M, da Costa CA, Nesi RT, Barroso MV, Martins V, Victoni T, et al. Oxidative stress and nitrosative stress are involved in different stages of proteolytic pulmonary emphysema. Free Radic Biol Med 2012; 53(11):1993–2001.
   PubMed Web of Science ®Google Scholar
• Bratic A, Larsson NG. The role of mitochondria in aging. J Clin Invest 2013; 123(3):951–957.
   PubMed Web of Science ®Google Scholar
• Harman D. Free radical theory of aging: an update: increasing the functional life span. Ann N Y Acad Sci 2006; 1067:10–21.
   PubMed Web of Science ®Google Scholar
• Rahman I, Biswas SK, Kode A. Oxidant and antioxidant balance in the airways and airway diseases. Eur J Pharmacol 2006; 533(1–3):222–239.
   PubMed Web of Science ®Google Scholar
• Fischer BM, Pavlisko E, Voynow JA. Pathogenic triad in COPD: oxidative stress, protease-antiprotease imbalance, and inflammation. Int J Chron Obstruct Pulmon Dis 2011; 6:413–421.
   PubMed Web of Science ®Google Scholar
• Comandini A, Marzano V, Curradi G, Federici G, Urbani A, Saltini C. Markers of anti-oxidant response in tobacco smoke exposed subjects: a data-mining review. Pulmon Pharmacol Ther 2010; 23:482–492.
   PubMed Web of Science ®Google Scholar
• Cho HY, Kleeberger SR. Nrf2 protects against airway disorders. Toxicol Appl Pharmacol 2010; 246(3):186–187.
   Web of Science ®Google Scholar
• DeMeo DL, Hersh CP, Hoffman EA, Litonjua AA, Lazarus R, Sparrow D, et al. Genetic determinants of emphysema distribution in the national emphysema treatment trial. Am J Respir Crit Care Med 2007; 176:42–48.
   PubMed Web of Science ®Google Scholar
• Malhotra D, Thimmulappa R, Navas-Acien A, Sandford A, Elliott M, Singh A, et al. Decline in NRF2-regulated Antioxidants in chronic obstructive pulmonary disease lungs due to loss of its positive regulator, DJ-1. Am J Respir Crit Care Med 2008; 178(6):592–604.
   PubMed Web of Science ®Google Scholar
• Kelsen SG, Duan X, Ji R, Perez O, Liu C, Merali S. Cigarette smoke induces an unfolded protein response in the human lung: a proteomic approach. Am J Respir Cell Mol Biol 2008; 38(5):541–550.
   PubMed Web of Science ®Google Scholar
• Jorgensen E, Stinson A, Shan L, Yang J, Gietl D, Albino AP. Cigarette smoke induces endoplasmic reticulum stress and the unfolded protein response in normal and malignant human lung cells. BMC Cancer 2008; 8:229.
   PubMed Web of Science ®Google Scholar
• Garber K. Autophagy. Explaining exercise. Science 2012; 335:281.
   PubMed Web of Science ®Google Scholar
• Kelsen SG. The unfolded protein response in chronic obstructive pulmonary disease. Ann Am Thorac Soc 2016; 13(Suppl 2):S138–S145.
   Google Scholar
• Suzuki M, Betsuyaku T, Ito Y, Nagai K, Nasuhara Y, Kaga K, et al. Down-regulated NF-E2-related factor 2 in pulmonary macrophages of aged smokers and patients with chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 2008; 39:673–682.
   PubMed Web of Science ®Google Scholar
• Wenk MR. The emerging field of lipidomics. Nat Rev Drug Discov 2005; 4:594–610.
   PubMed Web of Science ®Google Scholar
• Telenga ED, Hoffmann RF, Ruben t'Kindt, Hoonhorst SJ, Willemse BW, van Oosterhout AJ, et al. Untargeted lipidomic analysis in chronic obstructive pulmonary disease. Uncovering sphingolipids. Am J Respir Crit Care Med 2014; 190(2):155–164.
   PubMed Web of Science ®Google Scholar
• Takimoto T, Yoshida M, Hirata H, Kashiwa Y, Takeda Y, Goya S, et al. 4-Hydroxy-2-nonenal induces chronic obstructive pulmonary disease-like histopathologic changes in mice. Biochem Biophys Res Commun 2012; 420(1):84–90.
   PubMed Web of Science ®Google Scholar
• Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature 2008; 451:1069–1075.
   PubMed Web of Science ®Google Scholar
• Nakahira K, Haspel JA, Rathinam VA, Lee SJ, Dolinay T, Lam HC, et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol 2011; 12:222–230.
   PubMed Web of Science ®Google Scholar
• Miller KM, Tjeertes JV, Coates J, Legube G, Polo SE, Britton S, et al. Human HDAC1 and HDAC2 function in the DNA-damage response to promote DNA nonhomologous end-joining. Nat Struct Mol Biol 2010; 17:1144–1151.
   PubMed Web of Science ®Google Scholar
• Wagner M, Brosch G, Zwerschke W, Seto E, Loidl P, Jansen-Durr P. Histone deacetylases in replicative senescence: evidence for a senescence-specific form of HDAC-2. FEBS Lett 2001; 499:101–106.
   PubMed Web of Science ®Google Scholar
• Bitterman KJ, Anderson RM, Cohen HY, Latorre-Esteves M, Sinclair DA. Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. J Biol Chem 2002; 277:45099e107.
   Web of Science ®Google Scholar
• Lee IH, Cao L, Mostoslavsky R, Lombard DB, Liu J, Bruns NE, et al. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc Natl Acad Sci USA 2008; 105:3374–3379.
   PubMed Web of Science ®Google Scholar
• Wallace DC. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: A dawn for evolutionary medicine. Annu Rev Genet 2005; 39:359–407.
   PubMed Web of Science ®Google Scholar
• Balaban RS, Nemoto S, Finkel T. Mitochondria, oxidants, and aging. Cell 2005; 120:483–495.
   PubMed Web of Science ®Google Scholar
• Knutson MD, Leeuwenburgh C. Resveratrol and novel potent activators of SIRT1: effects on aging and age-related diseases. Nutr Rev 2008; 66(10):591–596.
   PubMed Web of Science ®Google Scholar
• Ryter SW, Chen ZH, Kim HP, Choi AM. Autophagy in chronic obstructive pulmonary disease: homeostatic or pathogenic mechanism? Autophagy 2009; 5:235–237.
   PubMed Web of Science ®Google Scholar
• Chen ZH, Kim HP, Sciurba FC, Lee SJ, Feghali-Bostwick C, Stolz DB, et al. Egr-1 regulates autophagy in cigarette smoke-induced chronic obstructive pulmonary disease. PLoS One 2008; 3:e3316.
   PubMed Web of Science ®Google Scholar
• Neofytou E, Tzortzaki EG, Chatziantoniou A, Siafakas NM. DNA damage due to oxidative stress in chronic obstructive pulmonary disease (COPD). Int J Mol Sci 2012; 13(12):16853–16864.
   PubMed Web of Science ®Google Scholar
• Krieg AM, Vollmer J. Toll-Like receptors 7, 8, and 9: Linking innate immunity to autoimmunity. Immunol Rev 2007; 220:251–269.
   PubMed Web of Science ®Google Scholar
• Rao T, Richardson B. Environmentally induced autoimmune diseases: potential mechanisms. Environ Health Perspect 1999; 107:737–742.
   PubMed Web of Science ®Google Scholar
• Mukaro VR, Hodge S. Airway clearance of apoptotic cells in COPD. Curr Drug Targets 2011; 12(4):460–468.
   PubMed Web of Science ®Google Scholar
• Yoshida S, Minematsu N, Chubachi S, Nakamura H, Miyazaki M, Tsuduki K, et al. Annexin V decreases PS-mediated macrophage efferocytosis and deteriorates elastase-induced pulmonary emphysema in mice. Am J Physiol Lung Cell Mol Physiol 2012; 303(10):L852–L860.
   Google Scholar
• Eltboli O, Bafadhel M, Hollins F, Wright A, Hargadon B, Kulkarni N, et al. COPD exacerbation severity and frequency is associated with impaired macrophage efferocytosis of eosinophils. BMC Pulmon Med 2014; 14:112.
   PubMed Web of Science ®Google Scholar
• Hamon R, Homan CC, Tran HB, Mukaro VR, Lester SE, Roscioli E, et al. Zinc and zinc transporters in macrophages and their roles in efferocytosis in COPD. PLoS One 2014; 9(10):e110056.
   PubMed Web of Science ®Google Scholar
• Hodge S, Hodge G, Jersmann H, Matthews G, Ahern J, Holmes M, et al. Azithromycin improves macrophage phagocytic function and expression of mannose receptor in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008; 178(2):139–148.
   PubMed Web of Science ®Google Scholar
• Moyzis RK, Buckingham JM, Cram LS, Dani M, Deaven LL, Jones MD, et al. A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes. Proc Natl Acad Sci USA 1988; 85:6622–6626.
   PubMed Web of Science ®Google Scholar
• von Zglinicki T. Oxidative stress shortens telomeres. Trends Biochem Sci 2002; 27:339–344.
   PubMed Web of Science ®Google Scholar
• MacNee W. Aging, inflammation, and emphysema. Am J Respir Crit Care Med 2011; 184(12):1327–1329.
   PubMed Web of Science ®Google Scholar
• Anthonisen NR, Connett JE, Kiley JP, Altose MD, Bailey WC, Buist AS, et al. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The lung health study. JAMA 1994; 272:1497–505.
   Google Scholar
• Lee J, Sandford AJ, Connett JE, Yan J, Mui T, Li Y, et al. The relationship between telomere length and mortality in chronic obstructive pulmonary disease (COPD). PLoS One 2012; 7(4):e35567.
   PubMed Web of Science ®Google Scholar
• Mui TS, Man JM, McElhaney JE, Sandford AJ, Coxson HO, Birmingham CL, et al. Telomere length and chronic obstructive pulmonary disease: evidence of accelerated aging. J Am Geriatr Soc 2009; 57(12):2372–2374.
   PubMed Web of Science ®Google Scholar
• Thériault ME, Paré ME, Maltais F, Debigaré R. Satellite cells senescence in limb muscle of severe patients with COPD. PLoS One 2012; 7(6):e39124.
   Google Scholar
• Alder JK, Guo N, Kembou F, Parry EM, Anderson CJ, Gorgy AI, et al. Telomere length is a determinant of emphysema susceptibility. Am J Respir Crit Care Med 2011; 184:904–912.
   PubMed Web of Science ®Google Scholar
• Faner R, Rojas M, MacNee W, Agustí A. Abnormal lung aging in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2012; 186(4):306–313.
   PubMed Web of Science ®Google Scholar
• Tsuji T, Aoshiba K, Nagai A. Alveolar cell senescence in patients with pulmonary emphysema. Am J Respir Crit Care Med 2006; 174(8):886–893.
   PubMed Web of Science ®Google Scholar
• Barnes PJ, Chowdhury B, Kharitonov SA, Magnussen H, Page CP, Postma D, et al. Pulmonary biomarkers in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006; 174:6–14.
   PubMed Web of Science ®Google Scholar
• Vernooy JH, Kucukaycan M, Jacobs JA, Chavannes NH, Buurman WA, Dentener MA, et al. Local and systemic inflammation in patients with chronic obstructive pulmonary disease: soluble tumor necrosis factor receptors are increased in sputum. Am J Respir Crit Care Med 2002; 166:1218–1224.
   PubMed Web of Science ®Google Scholar
• Agusti A, Edwards LD, Rennard SI, MacNee W, Tal-Singer R, Miller BE, et al. Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype. PLoS One 2012; 7:e37483.
   PubMed Web of Science ®Google Scholar
• De Martinis M, Franceschi C, Monti D, Ginaldi L. Inflamm-ageing and lifelong antigenic load as major determinants of ageing rate and longevity. FEBS Lett 2005; 579(10):2035–2039.
   PubMed Web of Science ®Google Scholar
• Cevenini E, Monti D, Franceschi C. Inflamm-ageing. Curr Opin Clin Nutr Metab Care 2013; 16(1):14–20.
   PubMed Web of Science ®Google Scholar
• Di Stefano A, Caramori G, Ricciardolo FL, Capelli A, Adcock IM, Donner CF. Cellular and molecular mechanisms in chronic obstructive pulmonary disease: an overview. Clin Exp Allergy 2004; 34(8):1156–1167.
   PubMed Web of Science ®Google Scholar
• Samara KD, Tzortzaki EG, Neofytou E, Karatzanis AD, Lambiri I, Tzanakis N, et al. Somatic DNA alterations in lung epithelial barrier cells in COPD patients. Pulmon Pharmacol Ther 2010; 23:208–214.
   PubMed Web of Science ®Google Scholar
• Sancar A, Lindsey-Boltz LA, Unsal-Kacmaz K, Linn S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem 2004; 73:39–85.
   PubMed Web of Science ®Google Scholar
• Nourbakhsh M, Hauser H. Constitutive silencing of IFN-β promoter is mediated by NRF (NF-κB-repressing factor), a nuclear inhibitor of NF-κB. EMBO J 1999; 18:6415–6425.
   PubMed Web of Science ®Google Scholar
• Caramori G, Romagnoli P, Casolari P, Bellaettato, Casoni G, Boschetto P, et al. Nuclear localisation of p65 in sputum macrophages but not in sputum neutrophils during COPD exacerbations. Thorax 2003; 58:348–351.
   PubMed Web of Science ®Google Scholar
• Di Stefano A, Caramori G, Oates T, Capelli A, Lusuardi M, Gnemmi I, et al. Increased expression of nuclear factor-kappaB in bronchial biopsies from smokers and patients with COPD. Eur Respir J 2002; 20:556–563.
   PubMed Web of Science ®Google Scholar
• Tsuji T, Aoshiba K, Nagai A. Alveolar cell senescence exacerbates pulmonary inflammation in patients with chronic obstructive pulmonary disease. Respiration 2010; 80:59–70.
   PubMed Web of Science ®Google Scholar
• Di Stefano A, Capelli A, Lusuardi M, Balbo P, Vecchio C, Maestrelli P, et al. Severity of airflow limitation is associated with severity of airway inflammation in smokers. Am J Respir Crit Care Med 1998; 158:1277–1285.
   PubMed Web of Science ®Google Scholar
• Neeper M, Schmidt AM, Brett J, Yan SD, Wang F, Pan YC, et al. Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. J Biol Chem 1992; 267:14998–15004.
   PubMed Web of Science ®Google Scholar
• Rajendrasozhan S, Yang SR, Kinnula VL, Rahman I. SIRT1, an antiinflammatory and antiaging protein, is decreased in lungs of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008; 177:861–870.
   PubMed Web of Science ®Google Scholar
• Karin M, Lin A. NF-B at the crossroads of life and death. Nature Immunol 2002; 3:221–227.
   PubMed Web of Science ®Google Scholar
• Edwards MR, Bartlett NW, Clarke D, Birrell M, Belvisi M, Johnston SL. Targeting the NF-kappaB pathway in asthma and chronic obstructive pulmonary disease. Pharmacol Ther 2009; 121(1):1–13.
   PubMed Web of Science ®Google Scholar
• Kumar M, Seeger W, Voswinckel R. Senescence-associated secretory phenotype and its possible role in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 2014; 51(3):323–33.
   PubMed Web of Science ®Google Scholar
• Kirstein M, Brett J, Radoff S, Ogawa S, Stern D, Vlassara H. Advanced protein glycosylation induces transendothelial human monocyte chemotaxis and secretion of platelet-derived growth factor: role in vascular disease of diabetes and aging. Proc Natl Acad Sci USA 1990; 87(22):9010–9014.
   PubMed Web of Science ®Google Scholar
• Smith DJ, Yerkovich ST, Towers MA, Carroll ML, Thomas R, Upham JW. Reduced soluble receptor for advanced glycation end-products in COPD. Eur Respir J 2011; 37(3):516–522.
   PubMed Web of Science ®Google Scholar
• Ferhani N, Letuve S, Kozhich A, Thibaudeau O, Grandsaigne M, Maret M, et al. Expression of high-mobility group box 1 and of receptor for advanced glycation end products in COPD. Am J Respir Crit Care Med 2010; 181:917–927.
   PubMed Web of Science ®Google Scholar
• Ohlmeier S, Mazur W, Salmenkivi K, Myllärniemi M, Bergmann U, Kinnula VL. Proteomic studies on receptor for advanced glycation end product variants in idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease. Proteomics Clin Appl 2010; 4(1):97–105.
   PubMed Web of Science ®Google Scholar
• Gopal P, Reynaert NL, Scheijen JL, Schalkwijk CG, Franssen FM, Wouters EF, et al. Association of plasma sRAGE, but not esRAGE with lung function impairment in COPD. Respir Res 2014; 15:24.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Li S, Wang G, Han D, Xie X, Wu Y, et al. Changes of HMGB1 and sRAGE during the recovery of COPD exacerbation. J Thorac Dis 2014; 6(6):734–741.
   PubMed Web of Science ®Google Scholar
• Yue L, Yao H. Mitochondrial dysfunction in inflammatory responses and cellular senescence: pathogenesis and pharmacological targets for chronic lung diseases. Br J Pharmacol 2016; 173(15):2305–2318.
   PubMed Web of Science ®Google Scholar
• Mercado N, Ito K, Barnes PJ. Accelerated ageing of the lung in COPD: new concepts. Thorax 2015; 70(5):482–489.
   PubMed Web of Science ®Google Scholar
• Bratic A, Larsson NG. The role of mitochondria in aging. J Clin Invest 2013; 123:951–957.
   PubMed Web of Science ®Google Scholar
• Gifford JR, Trinity JD, Layec G, Garten RS, Park SY, Rossman MJ, et al. Quadriceps exercise intolerance in patients with chronic obstructive pulmonary disease: the potential role of altered skeletal muscle mitochondrial respiration. J Appl Physiol (1985) 2015; 119(8):882–888.
   PubMed Web of Science ®Google Scholar
• Ito K, Barnes PJ. COPD as a disease of accelerated lung aging. Chest 2009; 135:173–180.
   PubMed Web of Science ®Google Scholar
• Churg A, Wright JL. Proteases and emphysema. Curr Opin Pulmon Med 2005; 11:153–159.
   PubMed Web of Science ®Google Scholar
• Fischer BM, Pavlisko E, Voynow JA. Pathogenic triad in COPD: oxidative stress, protease–antiprotease imbalance, and inflammation. Int J Chron Obstruct Pulmon Dis 2011; 6:413–421.
   PubMed Web of Science ®Google Scholar
• Rahman I, Li XY, Donaldson K, Harrison DJ, MacNee W. Glutathione homeostasis in alveolar epithelial cells in vitro and lung in vivo under oxidative stress. Am J Physiol Lung Cell Mol Physiol 1995; 269:L285–L292.
   PubMed Web of Science ®Google Scholar
• Snider GL, Ciccolella DE, Morris SM, Stone PJ, Lucey EC. Putative role of neutrophil elastase in the pathogenesis of emphysema. Ann NY Acad Sci 1991; 624:45–59.
   PubMed Web of Science ®Google Scholar
• Cavarra E, Lucattelli M, Gambelli F, Bartalesi B, Fineschi S, Szarka A, et al. Human SLPI inactivation after cigarette smoke exposure in a new in vivo model of pulmonary oxidative stress. Am J Physiol Lung Cell Mol Physiol 2001; 281:L412–L417.
   PubMed Web of Science ®Google Scholar
• Shapiro SD. Proteinases in chronic obstructive pulmonary disease. Biochem Soc Trans 2002; 30:98–102.
   PubMed Web of Science ®Google Scholar
• Overbeek SA, Kleinjan M, Henricks PA, Kamp VM, Ricciardolo FL, Georgiou NA, et al. Chemo-attractant N-acetyl proline-glycine-proline induces CD11b/CD18-dependent neutrophil adhesion. Biochim Biophys Acta 2013; 1830(1):2188–2193.
   PubMed Web of Science ®Google Scholar
• Rahman I, MacNee W. Role of oxidants/antioxidants in smoking-induced lung diseases. Free Radic Biol Med 1996; 21:669–681.
   PubMed Web of Science ®Google Scholar
• Li XY, Donaldson K, Rahman I, MacNee W. An investigation of the role of glutathione in increased epithelial permeability induced by cigarette smoke in vivo and in vitro. Am J Respir Crit Care Med 1994; 149(6):1518–1525.
   PubMed Web of Science ®Google Scholar
• Li XY, Rahman I, Donaldson K, MacNee W. Mechanisms of cigarette smoke induced increased airspace permeability. Thorax 1996; 51:465–471.
   PubMed Web of Science ®Google Scholar
• Li XY, Rahman I, Donaldson K, Brown D, MacNee W. The role of tumour necrosis factor in increased airspace epithelial permeability in acute lung inflammation. Am J Respir Cell Mol Biol 1995; 13:185–195.
   PubMed Web of Science ®Google Scholar
• Linden M, Rasmussen JB, Pitulainen E, Tunek A, Larson M, Tegner H, et al. Airway inflammation in smokers and nonobstructive and obstructive chronic bronchitis. Am Rev Respir Dis 1993; 148:1226–1232.
   PubMed Web of Science ®Google Scholar
• Sadowska AM, Manuel-Y-Keenoy B, De Backer WA. Antioxidant and anti-inflammatory efficacy of NAC in the treatment of COPD: discordant in vitro and in vivo dose-effects: a review. Pulmon Pharmacol Ther 2007; 20(1):9–22.
   PubMed Web of Science ®Google Scholar
• Van Schooten FJ, Besaratinia A, De Flora S, D'Agostini F, Izzotti A, Camoirano A, et al. Effects of oral administration of N-acetyl-L-cysteine: a multibiomarker study in smokers. Cancer Epidemiol Biomarkers Prev 2002; 11:167–175.
   PubMed Web of Science ®Google Scholar
• Koechlin C, Couillard A, Cristol JP, Chanez P, Hayot M, Le Gallais D, et al. Does systemic inflammation trigger local exercise-induced oxidative stress in COPD? Eur Respir J 2004; 23:538–544.
   PubMed Web of Science ®Google Scholar
• Zheng JP, Wen FQ, Bai CX, Wan HY, Kang J, Chen P, et al. PANTHEON study group. Twice daily N-acetylcysteine 600 mg for exacerbations of chronic obstructive pulmonary disease (PANTHEON): a randomised, double-blind placebo-controlled trial. Lancet Respir Med 2014; 2(3):187–194.
   PubMed Web of Science ®Google Scholar
• Decramer M, Rutten-van Mölken M, Dekhuijzen PN, Troosters T, van Herwaarden C, Pellegrino R, et al. Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial. Lancet 2005; 365(9470):1552–1560.
   PubMed Web of Science ®Google Scholar
• MacNee W, Rahman I. Oxidants and antioxidants as therapeutic targets in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999; 160(5 Pt 2):S58–s65.
   PubMed Web of Science ®Google Scholar
• Carpagnano GE, Resta O, Foschino-Barbaro MP, Spanevello A, Stefano A, Di Gioia G, et al. Exhaled interleukine-6 and 8-isoprostane in chronic obstructive pulmonary disease: effect of carbocysteine lysine salt monohydrate (SCMC-Lys). Eur J Pharmacol 2004; 505:169–175.
   PubMed Web of Science ®Google Scholar
• Zheng JP, Kang J, Huang SG, Chen P, Yao WZ, Yang L, et al. Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE Study): a randomised placebo-controlled study. Lancet 2008; 371:2013–2018.
   PubMed Web of Science ®Google Scholar
• Ricciardolo FL, Sorbello V, Benedetto S, Paleari D. Effect of Ambroxol and Beclomethasone on Lipopolysaccharide-induced nitrosative stress in bronchial epithelial cells. Respiration 2015; 89(6):572–582.
   PubMed Web of Science ®Google Scholar
• Malerba M, Ponticiello A, Radaeli A, Bensi G, Grassi V. Effect of twelve-months therapy with oral ambroxol in preventing exacerbations in patients with COPD. Double-blind, randomized, multicenter, placebo-controlled study (the AMETHIST Trial). Pulmon Pharmacol Ther 2004; 17(1):27–34.
   PubMed Web of Science ®Google Scholar
• Kensler TW, Wakabayashi N, Biswal S. Cell survival responses to environmental stresses via the Keap1–Nrf2–ARE pathway. Annu Rev Pharmacol Toxicol 2007; 47:89–116.
   PubMed Web of Science ®Google Scholar
• Rangasamy T, Guo J, Mitzner WA, Roman J, Singh A, Fryer AD, et al. Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice. J Exp Med 2005; 202:47–59.
   PubMed Web of Science ®Google Scholar
• Thimmulappa RK, Scollick C, Traore K, Yates M, Trush MA, Liby KT, et al. Nrf2-dependent protection from LPS induced inflammatory response and mortality by CDDO-Imidazolide. Biochem Biophys Res Commun 2006; 351(4):883–889.
   PubMed Web of Science ®Google Scholar
• Ito K, Lim S, Caramori G, Chung KF, Barnes PJ, Adcock IM. Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression, and inhibits glucocorticoid actions in alveolar macrophages. FASEB J 2001; 15:1110–1112.
   PubMedGoogle Scholar
• Rahman I. Antioxidant therapeutic advances in COPD. Ther Adv Respir Dis 2008; 2(6):351–374.
   PubMedGoogle Scholar
• Moodie FM, Marwick JA, Anderson CS, Szulakowski P, Biswas SK, Bauter MR, et al. Oxidative stress and cigarette smoke alter chromatin remodeling but differentially regulate NF-kappaB activation and proinflammatory cytokine release in alveolar epithelial cells. FASEB J 2004; 18:1897–1899.
   PubMed Web of Science ®Google Scholar
• Cosio BG1, Tsaprouni L, Ito K, Jazrawi E, Adcock IM, Barnes PJ. Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J Exp Med 2004; 200:689–695.
   PubMed Web of Science ®Google Scholar
• Meja KK, Rajendrasozhan S, Adenuga D, Biswas SK, Sundar IK, Spooner G, et al. Curcumin restores corticosteroid function in monocytes exposed to oxidants by maintaining HDAC2. Am J Respir Cell Mol Biol 2008; 39(3):312–323.
   PubMed Web of Science ®Google Scholar
• Pandey KB, Rizvi SI. Plant polyphenols as dietary antioxidants in human health and disease. Oxid Med Cell Longev 2009; 2(5):270–278.
   PubMed Web of Science ®Google Scholar
• Tabak C, Arts IC, Smit HA, Heederik D, Kromhout D. Chronic obstructive pulmonary disease and intake of catechins, flavonols, and flavones: the MORGEN Study. Am J Respir Crit Care Med 2001; 164:61–64.
   PubMed Web of Science ®Google Scholar
• Santus P, Sola A, Carlucci P, Fumagalli F, Di Gennaro A, Mondoni M, et al. Lipid peroxidation and 5-lipoxygenase activity in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005; 171(8):838–843.
   PubMed Web of Science ®Google Scholar
• Biswas SK, McClure D, Jimenez LA, Megson IL, Rahman I. Curcumin induces glutathione biosynthesis and inhibits NF-kappaB activation and interleukin-8 release in alveolar epithelial cells: mechanism of free radical scavenging activity. Antioxid Redox Signal 2005; 7(1–2):32–41.
   PubMed Web of Science ®Google Scholar
• Seimetz M, Parajuli N, Pichl A, Veit F, Kwapiszewska G, Weisel FC, et al. Inducible NOS inhibition reverses tobacco-smoke-induced emphysema and pulmonary hypertension in mice. Cell 2011; 147:293–305.
   PubMed Web of Science ®Google Scholar
• Chabrier PE, Auguet M, Spinnewyn B, Auvin S, Cornet S, Demerlé-Pallardy C, et al. BN 80933, a dual inhibitor of neuronal nitric oxide synthase and lipid peroxidation: a promising neuroprotective strategy. Proc Natl Acad Sci USA 1999; 96(19):10824–10829.
   PubMed Web of Science ®Google Scholar
• Filomeni G, Rotilio G, Ciriolo MR. Cell signalling and the glutathione redox system. Biochem Pharmacol 2002; 64(5–6):1057–1064.
   PubMed Web of Science ®Google Scholar
• Souza DG, Vieira AT, Pinho V, Sousa LP, Andrade AA, Bonjardim CA, et al. NF-kappaB plays a major role during the systemic and local acute inflammatory response following intestinal reperfusion injury. Br J Pharmacol 2005; 145:246–254.
   PubMed Web of Science ®Google Scholar
• Aldini G, Vistoli G, Regazzoni L, Benfatto MC, Bettinelli I, Carini M. Edaravone inhibits protein carbonylation by a direct carbonyl-scavenging mechanism: focus reactivity, selectivity, and reaction mechanisms. Antioxid Redox Signal 2010; 12(3):381–392.
   PubMed Web of Science ®Google Scholar
• Braughler JM, Pregenzer JF, Chase RL, Duncan LA, Jacobsen EJ, McCall JM. Novel 21-amino steroids as potent inhibitors of iron-dependent lipid peroxidation. J Biol Chem 1987; 262(22):10438–10440.
   PubMed Web of Science ®Google Scholar
• Smith KR, Uyeminami DL, Kodavanti UP, Crapo JD, Chang LY, Pinkerton KE. Inhibition of tobacco smoke-induced lung inflammation by a catalytic antioxidant. Free Radic Biol Med 2002; 33(8):1106–1114.
   PubMed Web of Science ®Google Scholar
• Sharpe MA, Ollosson R, Stewart VC, Clark JB. Oxidation of nitric oxide by oxomanganese-salen complexes: a new mechanism for cellular protection by superoxide dismutase/catalase mimetics. Biochem J 2002; 366:97–107.
   PubMed Web of Science ®Google Scholar
• Tuder RM, Zhen L, Cho CY, Taraseviciene-Stewart L, Kasahara Y, Salvemini D, et al. Oxidative stress and apoptosis interact and cause emphysema due to vascular endothelial growth factor receptor blockade. Am J Respir Cell Mol Biol 2003; 29:88–97.
   PubMed Web of Science ®Google Scholar
• Nishikawa M, Kakemizu N, Ito T, Kudo M, Kaneko T, Suzuki M, et al. Superoxide mediates cigarette smoke-induced infiltration of neutrophils into the airways through nuclear factor-kappaB activation and IL-8 mRNA expression in guinea pigs in vivo. Am J Respir Cell Mol Biol 1999; 20:189–198.
   PubMed Web of Science ®Google Scholar
• Kinnula VL, Crapo JD. Superoxide dismutases in the lung and human lung diseases. Am J Respir Crit Care Med 2003; 167:1600–1619.
   PubMed Web of Science ®Google Scholar
• Tollefson AK, Oberley-Deegan RE, Butterfield KT, Nicks ME, Weaver MR, Remigio LK, et al. Endogenous enzymes (NOX and ECSOD) regulate smoke-induced oxidative stress. Free Radic Biol Med 2010; 49:1937–1946.
   PubMed Web of Science ®Google Scholar
• Yao H, Arunachalam G, Hwang JW, Chung S, Sundar IK, Kinnula VL, et al. Extracellular superoxide dismutase protects against pulmonary emphysema by attenuating oxidative fragmentation of ECM. Proc Natl Acad Sci USA 2010; 107:15571–15576.
   PubMed Web of Science ®Google Scholar
• Porcu M, Chiarugi A. The emerging therapeutic potential of sirtuin-interacting drugs: from cell death to lifespan extension. Trends Pharmacol Sci 2005; 26:94–103.
   PubMed Web of Science ®Google Scholar
• Frojdo S, Cozzone D, Vidal H, Pirola L. Resveratrol is a class IA phosphoinositide 3-kinase inhibitor. Biochem J 2007; 406(3):511–518.
   PubMed Web of Science ®Google Scholar
• Milne JC, Lambert PD, Schenk S, Carney DP, Smith JJ, Gagne DJ, et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 2007; 450(7170):712–716.
   PubMed Web of Science ®Google Scholar
• Nakamaru Y, Vuppusetty C, Wada H, Milne JC, Ito M, Rossios C, et al. A protein deacetylase SIRT1 is a negative regulator of metalloproteinase-9. FASEB J 2009; 23(9):2810–2819.
   PubMed Web of Science ®Google Scholar
• Hubbard BP, Sinclair DA. Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Trends Pharmacol Sci 2014; 35(3):146–154.
   PubMed Web of Science ®Google Scholar
• Cazzola M, Calzetta L, Rogliani P, Matera MG. The discovery of roflumilast for the treatment of chronic obstructive pulmonary disease. Expert Opin Drug Discov 2016; 1–12.
   Web of Science ®Google Scholar
• Chong J, Leung B, Poole P. Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2013; 11:CD002309. doi: 10.1002/14651858.CD002309.pub4
   PubMed Web of Science ®Google Scholar
• Reid DJ, Pham NT. Roflumilast: a novel treatment for chronic obstructive pulmonary disease. Ann Pharmacother 2012; 46(4):521–529.
   PubMed Web of Science ®Google Scholar
• Grundy S, Plumb J, Kaur M, Ray D, Singh D. Additive anti-inflammatory effects of corticosteroids and phosphodiesterase-4 inhibitors in COPD CD8 cells. Respir Res 2016; 17:9.
   PubMed Web of Science ®Google Scholar