Role of Oxidative Stress Induced by Cigarette Smoke in the Pathogenicity of Chronic Obstructive Pulmonary Disease

  • Anuradha Ratna
  • Shyamali Mukherjee
  • Salil K. DasEmail author


Cigarette smoke (CS) exposes lungs to oxidative stress and inflammation and is a major risk factor for the development of chronic obstructive pulmonary disease (COPD). COPD is a complex lung disease characterized by chronic inflammation with limited airflow and chronic bronchitis associated with mucus hypersecretion, thickened small airway walls, and emphysema. CS-induced oxidative stress is responsible for altered cellular metabolism, including increased infiltrating immune cells, pro-inflammatory cytokine production, protease–antiprotease imbalance, lipid peroxidation, apoptosis, upregulation of unfolded protein response (UPR), and protein misfolding. This chapter reviews the current knowledge on different mechanisms through which both direct and secondhand CS-induced oxidative stress in lungs plays a significant role in the pathogenesis of COPD. Despite the presence of considerable reports recognizing the harmful effects of CS-generated oxidative stress, effective treatment for COPD is lacking. Extensive research on the immune and pathogenetic mechanisms of COPD will help in developing new treatment strategies. Clinical trials leveraging multiple antioxidants, anti-inflammatory processes, and UPR inhibitors are urgently needed to advance COPD therapies.


Cigarette smoke Oxidative stress Antioxidant COPD Inflammation Protease–antiprotease Mitochondria UPR 



The work is supported by grants from Fuji Oil Company, Osaka, Japan, and NIH (MeTRC5U5AMD007593). The Meharry Office for Scientific Editing and Publications provided language editing support.


  1. 1.
  2. 2.
    Veigi G, Scognamiglio A, Baldacci S, Pistelli F, Carrozzi L (2001) Epidemiology of chronic obstructive pulmonary disease (COPD). Respiration 68(1):4–19CrossRefGoogle Scholar
  3. 3.
    Roth C (2010) Factsheet chronic obstructive pulmonary disease (COPD). National Institutes of Health 10.
  4. 4.
    Cosio MG, Saetta M, Agusti A (2009) Immunologic aspects of chronic obstructive pulmonary disease. N Engl J Med 360(23):2445–2454PubMedCrossRefGoogle Scholar
  5. 5.
    Miravitlles M, Soler-Cataluna JJ, Calle M, Soriano JB (2013) Treatment of COPD by clinical phenotypes: putting old evidence into clinical practice. Eur Respir J 41:1252–1256PubMedCrossRefGoogle Scholar
  6. 6.
    Kenche H, Baty CJ, Vedagiri K, Shapiro SD, Blumental-Perry A (2013) Cigarette smoking affects oxidative protein folding in endoplasmic reticulum by modifying protein disulfide isomerase. FASEB J 27:965–977PubMedCrossRefGoogle Scholar
  7. 7.
    Cavalcante AG, de Bruin PF (2009) The role of oxidative stress in COPD: current concepts and perspectives. J Bras Pneumol 35:1227–1237PubMedCrossRefGoogle Scholar
  8. 8.
    World Health Organization (2015)
  9. 9.
    Das SK (2003) Harmful effects of cigarette smoking. Mol Cell Biochem 253(1):159–165PubMedCrossRefGoogle Scholar
  10. 10.
    El-Zein RA, Young RP, Hopkins RJ, Etzel CJ (2012) Genetic predisposition to chronic obstructive pulmonary disease and/or lung cancer: important considerations when evaluating risk. Cancer Prev Res (Phila) 5:522–527CrossRefGoogle Scholar
  11. 11.
    Mehta AJ, Miedinger D, Keidel D, Bettschart R, Bircher A, Bridevaux PO, Curjuric I, Kromhout H, Rochat T, Rothe T, Russi EW, Schikowski T, Schindler C, Schwartz J, Turk A, Vermeulen R, Probst-Hensch N, Kunzli N, Team S (2012) Occupational exposure to dusts, gases, and fumes and incidence of chronic obstructive pulmonary disease in the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults. Am J Respir Crit Care Med 185:1292–1300PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Schikowski T, Adam M, Marcon A, Cai Y, Vierkotter A, Carsin AE, Jacquemin B, Al Kanani Z, Beelen R, Birk M, Bridevaux PO, Brunekeef B, Burney P, Cirach M, Cyrys J, de Hoogh K, de Marco R, de Nazelle A, Declercq C, Forsberg B, Hardy R, Heinrich J, Hoek G, Jarvis D, Keidel D, Kuh D, Kuhlbusch T, Migliore E, Mosler G, Nieuwenhuijsen MJ, Phuleria H, Rochat T, Schindler C, Villani S, Tsai MY, Zemp E, Hansell A, Kauffmann F, Sunyer J, Probst-Hensch N, Kramer U, Kunzli N (2014) Association of ambient air pollution with the prevalence and incidence of COPD. Eur Respir J 44:614–626PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Stockley RA (2014) Alpha1-antitrypsin review. Clin Chest Med 35:39–50PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    National Center for Chronic Disease Prevention and Health Promotion (US) Office on Smoking and Health. The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General. Atlanta (GA): Centers for Disease Control and Prevention (US); 2014 (2007) Beyond the lungs a new view of COPD. The Lancet 370(9589):713CrossRefGoogle Scholar
  15. 15.
    Homa DM, Neff LJ, King BA, Caraballo RS, Bunnell RE, Babb SD, Garrett BE, Sosnoff CS, Wang L (2015) Vital signs: disparities in nonsmokers’ exposure to secondhand smoke—United States, 1999–2012. Morb Mortal Wkly Rep 64(4):103–108Google Scholar
  16. 16.
    Wang J, Bao L, Yu B, Liu Z, Han W, Deng C, Guo C (2015) Interleukin-1beta promotes epithelial-derived alveolar elastogenesis via αvβ6 integrin-dependent TGF-β activation. Cell Physiol Biochem 36:2198–2216PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Denic V, Quan EM, Weissman JS (2006) A luminal surveillance complex that selects misfolded glycoproteins for ER-associated degradation. Cell 126:349–359PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Yamada Y, Tomaru U, Ishizu A, Ito T, Kiuchi T, Ono A, Miyajima S, Nagai K, Higashi T, Matsuno Y, Dosaka-Akita H, Nishimura M, Miwa S, Kasahara M (2015) Decreased proteasomal function accelerates cigarette smoke-induced pulmonary emphysema in mice. Lab Investig 95:625–634PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Brashier BB, Kodgule R (2012) Risk factors and pathophysiology of chronic obstructive pulmonary disease (COPD). J Assoc Physicians India 60(Suppl):17–21PubMedPubMedCentralGoogle Scholar
  20. 20.
    Barreiro E, Peinado VI, Galdiz JB, Ferrer E, Marin-Corral J, Sanchez F, Gea J, Barbera JA, Project EiC (2010) Cigarette smoke-induced oxidative stress: a role in chronic obstructive pulmonary disease skeletal muscle dysfunction. Am J Respir Crit Care Med 182:477–488CrossRefGoogle Scholar
  21. 21.
    Mannino DM, Buist AS (2007) Global burden of COPD: risk factors, prevalence, and future trends. Lancet 370:765–773PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    U.S. Department of Health and Human Services (2014) The health consequences of smoking: 50 years of progress. A report of the surgeon general. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, Atlanta, GA.
  23. 23.
    Pryor WA, Stone K (1993) Oxidants in cigarette smoke. Radicals, hydrogen peroxide, peroxynitrate, and peroxynitrite. Ann N Y Acad Sci 686:12–27PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Rahman I, Adcock IM (2006) Oxidative stress and redox regulation of lung inflammation in COPD. Eur Respir J 28:219–242PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Morrow JD, Frei B, Longmire AW, Gaziano JM, Lynch SM, Shyr Y, Strauss WE, Oates JA, Roberts LJ 2nd (1995) Increase in circulating products of lipid peroxidation (F2-isoprostanes) in smokers. Smoking as a cause of oxidative damage. N Engl J Med 332:1198–1203PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Reznick AZ, Cross CE, Hu ML, Suzuki YJ, Khwaja S, Safadi A, Motchnik PA, Packer L, Halliwell B (1992) Modification of plasma proteins by cigarette smoke as measured by protein carbonyl formation. Biochem J 286(Pt 2):607–611PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Park EM, Park YM, Gwak YS (1998) Oxidative damage in tissues of rats exposed to cigarette smoke. Free Radic Biol Med 25:79–86PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Lung function testing: selection of reference values and interpretative strategies. American Thoracic Society (1991) Am Rev Respir Dis 144:1202–1218Google Scholar
  29. 29.
    Rahman I (2005) The role of oxidative stress in the pathogenesis of COPD: implications for therapy. Treat Respir Med 4:175–200PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Louhelainen N, Rytilä P, Haahtela T, Kinnula VL, Djukanović R (2009) Persistence of oxidant and protease burden in the airways after smoking cessation. BMC Pulm Med 9(25):1471–2466Google Scholar
  31. 31.
    Montano M, Cisneros J, Ramirez-Venegas A, Pedraza-Chaverri J, Mercado D, Ramos C, Sansores RH (2010) Malondialdehyde and superoxide dismutase correlate with FEV(1) in patients with COPD associated with wood smoke exposure and tobacco smoking. Inhal Toxicol 22:868–874PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Birben E, Sahiner UM, Sackesen C, Erzurum S, Kalayci O (2012) Oxidative stress and antioxidant defense. World Allergy Organ J 5:9–19PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Rahman I, MacNee W (1996) Role of oxidants/antioxidants in smoking-induced lung diseases. Free Radic Biol Med 21:669–681CrossRefGoogle Scholar
  34. 34.
    Poli G, Leonarduzzi G, Biasi F, Chiarpotto E (2004) Oxidative stress and cell signalling. Curr Med Chem 11:1163–1182PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Wynder EL, Hoffman D (1971) Tobaco and tobacco smoke. Acdemic Press, New York, pp 423–424Google Scholar
  36. 36.
    Mǖller T, Haussmann H-J, Schepers G (1997) evidence for peroxynitrite as an oxidative stress-indocing compound of aquous cigarette smoke fractions. Carcinogenesis 18(2):295–301PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Koyani CN, Flemmig J, Malle E, Arnhold J (2015) Myeloperoxidase scavenges peroxynitrite: a novel anti-inflammatory action of the heme enzyme. Arch Biochem Biophys 571:1–9PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Martins AB, Ximenes VF, da Fonseca LM (2013) Serum myeloperoxidase level is increased in heavy smokers. Open J Clin Diagn 3:5–8CrossRefGoogle Scholar
  39. 39.
    Gorska KR, Domagala-Kulawik J, Korcznski P, Nejman-Gryz P, Kosciuch J, Hildebrand K, Chazan R (2008) Comparison of cellular and bichemical markers of airway inflammation in patients with mild -to-moderate asthma and chronic obstructive pulmonary disease: an induced sputum and bronchoalveolar lavage fluid study. J Physiol Pharmacol 59:271–283PubMedPubMedCentralGoogle Scholar
  40. 40.
    Louhelainen N, Stark H, Mazur W, Rytila P, Djukanovic R, Kinnula VL (2010) Elevation of sputum matrix metalloproteinase-9 persists up to 6 months after smoking cessation: a research study. BMC Pulm Med 10:13–21PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Merchant RK, Schwartz DA, Helmers RA, Dayton CS, Hunninghake GW (1992) Bronchoalveolar lavage cellularity. The distribution in normal volunteers. Am Rev Respir Dis 146:448–453PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Ollerenshaw SL, Woolcock AJ (1992) Characteristics of the inflammation in biopsies from large airways of subjects with asthma and subjects with chronic airflow limitation. Am Rev Respir Dis 145:922–927PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Eidelman D, Saetta MP, Ghezzo H, Wang NS, Hoidal JR, King M, Cosio MG (1990) Cellularity of the alveolar walls in smokers and its relation to alveolar destruction. Functional implications. Am Rev Respir Dis 141:1547–1552PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Wiggs BR, Bosken C, Pare PD, James A, Hogg JC (1992) A model of airway narrowing in asthma and in chronic obstructive pulmonary disease. Am Rev Respir Dis 145:1251–1258PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Kaplanski G, Marin V, Fabrigoule M, Boulay V, Benoliel AM, Bongrand P, Kaplanski S, Farnarier C (1998) Thrombin-activated human endothelial cells support monocyte adhesion in vitro following expression of intercellular adhesion molecule-1 (ICAM-1; CD54) and vascular cell adhesion molecule-1 (VCAM-1; CD106). Blood 92:1259–1267PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Nordskog BK, Blixt AD, Morgan WT, Fields WR, Hellmann GM (2003) Matrix-degrading and pro-inflammatory changes in human vascular endothelial cells exposed to cigarette smoke condensate. Cardiovasc Toxicol 3:101–117PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    McMullen CB, Fleming E, Clarke G, Armstrong MA (2000) The role of reactive oxygen intermediates in the regulation of cytokine-induced ICAM-1 surface expression on endothelial cells. Mol Cell Biol Res Commun 3:231–237PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Agusti AG (2005) Systemic effects of chronic obstructive pulmonary disease. Proc Am Thorac Soc 2:367–370; discussion 371–362Google Scholar
  49. 49.
    Barnes PJ, Shapiro SD, Pauwels RA (2003) Chronic obstructive pulmonary disease: molecular and cellular mechanisms. Eur Respir J 22:672–688PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Masubuchi T, Koyama S, Sato E, Takamizawa A, Kubo K, Sekiguchi M, Nagai S, Izumi T (1998) Smoke extract stimulates lung epithelial cells to release neutrophil and monocyte chemotactic activity. Am J Pathol 153:1903–1912PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Palmblad J (1984) The role of granulocytes in inflammation. Scand J Rheumatol 13:163–172PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Drost EM, Selby C, Lannan S, Lowe GD, MacNee W (1992) Changes in neutrophil deformability following in vitro smoke exposure: mechanism and protection. Am J Respir Cell Mol Biol 6:287–295PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Di Stefano A, Maestrelli P, Roggeri A, Turato G, Calabro S, Potena A, Mapp CE, Ciaccia A, Covacev L, Fabbri LM, Saetta M (1994) Upregulation of adhesion molecules in the bronchial mucosa of subjects with chronic obstructive bronchitis. Am J Respir Crit Care Med 149:803–810PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Lehr HA, Kress E, Menger MD, Friedl HP, Hubner C, Arfors KE, Messmer K (1993) Cigarette smoke elicits leukocyte adhesion to endothelium in hamsters: inhibition by CuZn-SOD. Free Radic Biol Med 14:573–581PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Barnes PJ, Adcock IM, Ito K (2005) Histone acetylation and deacetylation: importance in inflammatory lung diseases. Eur Respir J 25:552–563PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Rahman I, Mulier B, Gilmour PS, Watchorn T, Donaldson K, Jeffery PK, MacNee W (2001) Oxidant-mediated lung epithelial cell tolerance: the role of intracellular glutathione and nuclear factor-kappaB. Biochem Pharmacol 62:787–794PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Rahman I, MacNee W (2000) Regulation of redox glutathione levels and gene transcription in lung inflammation: therapeutic approaches. Free Radic Biol Med 28:1405–1420PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Barnes PJ (2009) Role of HDAC2 in the pathophysiology of COPD. Annu Rev Physiol 71:451–464PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Rahman I, Marwick J, Kirkham P (2004) Redox modulation of chromatin remodeling: impact on histone acetylation and deacetylation, NF-kappaB and pro-inflammatory gene expression. Biochem Pharmacol 68:1255–1267PubMedCrossRefGoogle Scholar
  60. 60.
    Hoshimoto A, Suzuki Y, Katsuno T, Nakajima H, Saito Y (2002) Caprylic acid and medium-chain triglycerides inhibit IL-8 gene transcription in Caco-2 cells: comparison with the potent histone deacetylase inhibitor trichostatin A. Br J Pharmacol 136:280–286PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Adcock IM, Caramori G (2001) Cross-talk between pro-inflammatory transcription factors and glucocorticoids. Immunol Cell Biol 79:376–384PubMedCrossRefGoogle Scholar
  62. 62.
    Ohno Y, Lee J, Fusunyan RD, MacDermott RP, Sanderson IR (1997) Macrophage inflammatory protein-2: chromosomal regulation in rat small intestinal epithelial cells. Proc Natl Acad Sci USA 94:10279–10284PubMedCrossRefGoogle Scholar
  63. 63.
    Vanden Berghe W, De Bosscher K, Boone E, Plaisance S, Haegeman G (1999) The nuclear factor-kappaB engages CBP/p300 and histone acetyltransferase activity for transcriptional activation of the interleukin-6 gene promoter. J Biol Chem 274:32091–32098CrossRefGoogle Scholar
  64. 64.
    Nam HS, Izumchenko E, Dasgupta S, Hoque MO (2017) Mitochondria in chronic obstructive pulmonary disease and lung cancer: where are we now? Biomark Med 11:475–489PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Nunnari J, Suomalainen A (2012) Mitochondria: in sickness and in health. Cell 148:1145–1159PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Repine JE, Bast A, Lankhorst I (1997) Oxidative stress in chronic obstructive pulmonary disease. Oxidative Stress Study Group. Am J Respir Crit Care Med 156:341–357PubMedCrossRefGoogle Scholar
  67. 67.
    Janssen-Heininger YM, Persinger RL, Korn SH, Pantano C, McElhinney B, Reynaert NL, Langen RC, Ckless K, Shrivastava P, Poynter ME (2002) Reactive nitrogen species and cell signaling: implications for death or survival of lung epithelium. Am J Respir Crit Care Med 166:S9–S16PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Lanzetti M, da Costa CA, Nesi RT, Barroso MV, Martins V, Victoni T, Lagente V, Pires KM, e Silva PM, Resende AC, Porto LC, Benjamim CF, Valenca SS (2012) Oxidative stress and nitrosative stress are involved in different stages of proteolytic pulmonary emphysema. Free Radic Biol Med 53:1993–2001PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Białas AJ, Sitarek P, Miłkowska-Dymanowska J, Piotrowski WJ, Górski P (2016) The role of mitochondria and oxidative/antioxidative imbalance in pathobiology of chronic obstructive pulmonary disease. Oxidative Med Cell Longev 2016:7808576. ReviewCrossRefGoogle Scholar
  70. 70.
    McGuinness AJ, Sapey E (2017) Oxidative stress in COPD: sources, markers, and potential mechanisms. J Clin Med 6(2):21–39PubMedCentralCrossRefPubMedGoogle Scholar
  71. 71.
    Youle RJ, Narendra DP (2011) Mechanisms of mitophagy. Nat Rev Mol Cell Biol 12(1):9–14PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Ahmad T, Sundar IK, Lerner CA, Gerloff J, Tormos AM, Yao H, Rahman I (2015) Impaired mitophagy leads to cigarette smoke stress-induced cellular senescence: implications for chronic obstructive pulmonary disease. FASEB J 29(7):2912–2929PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Wiegman CH, Michaeloudes C, Haji G, Narang P, Clarke CJ, Russell KE, Bao W, Pavlidis S, Barnes PJ, Kanerva J, Bittner A, Rao N, Murphy MP, Kirkham PA, Chung KF, Adcock IM, Copdmap (2015) Oxidative stress-induced mitochondrial dysfunction drives inflammation and airway smooth muscle remodeling in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol 136:769–780PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Hoffmann RF, Zarrintan S, Brandenburg SM, Kol A, de Bruin HG, Jafari S, Dijk F, Kalicharan D, Kelders M, Gosker HR, Ten Hacken NH, van der Want JJ, van Oosterhout AJ, Heijink IH (2013) Prolonged cigarette smoke exposure alters mitochondrial structure and function in airway epithelial cells. Respir Res 14:97PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Soulitzis N, Neofytou E, Psarrou M, Anagnostis A, Tavernarakis N, Siafakas N, Tzortzaki EG (2012) Downregulation of lung mitochondrial prohibitin in COPD. Respir Med 106:954–961PubMedCrossRefGoogle Scholar
  76. 76.
    Houghton AM (2013) Mechanistic links between COPD and lung cancer. Nat Rev Cancer 13:233–245PubMedCrossRefGoogle Scholar
  77. 77.
    Taivassalo T, Hussain SN (2016) Contribution of the mitochondria to locomotor muscle dysfunction in patients with COPD. Chest 149:1302–1312PubMedCrossRefGoogle Scholar
  78. 78.
    Remels AH, Gosker HR, Schrauwen P, Langen RC, Schols AM (2008) Peroxisome proliferator-activated receptors: a therapeutic target in COPD? Eur Respir J 31:502–508PubMedCrossRefGoogle Scholar
  79. 79.
    DeMeo DL, Mariani T, Bhattacharya S, Srisuma S, Lange C, Litonjua A, Bueno R, Pillai SG, Lomas DA, Sparrow D, Shapiro SD, Criner GJ, Kim HP, Chen Z, Choi AM, Reilly J, Silverman EK (2009) Integration of genomic and genetic approaches implicates IREB2 as a COPD susceptibility gene. Am J Hum Genet 85:493–502PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Cloonan SM, Glass K, Laucho-Contreras ME, Bhashyam AR, Cervo M, Pabon MA, Konrad C, Polverino F, Siempos II, Perez E, Mizumura K, Ghosh MC, Parameswaran H, Williams NC, Rooney KT, Chen ZH, Goldklang MP, Yuan GC, Moore SC, Demeo DL, Rouault TA, D'Armiento JM, Schon EA, Manfredi G, Quackenbush J, Mahmood A, Silverman EK, Owen CA, Choi AM (2016) Mitochondrial iron chelation ameliorates cigarette smoke-induced bronchitis and emphysema in mice. Nat Med 22:163–174PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Kang MJ, Lee CG, Lee JY, Dela Cruz CS, Chen ZJ, Enelow R, Elias JA (2008) Cigarette smoke selectively enhances viral PAMP- and virus-induced pulmonary innate immune and remodeling responses in mice. J Clin Invest 118:2771–2784PubMedPubMedCentralGoogle Scholar
  82. 82.
    Kang MJ, Yoon CM, Kim BH, Lee CM, Zhou Y, Sauler M, Homer R, Dhamija A, Boffa D, West AP, Shadel GS, Ting JP, Tedrow JR, Kaminski N, Kim WJ, Lee CG, Oh YM, Elias JA (2015) Suppression of NLRX1 in chronic obstructive pulmonary disease. J Clin Invest 125:2458–2462PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Lei Y, Wen H, Yu Y, Taxman DJ, Zhang L, Widman DG, Swanson KV, Wen KW, Damania B, Moore CB, Giguere PM, Siderovski DP, Hiscott J, Razani B, Semenkovich CF, Chen X, Ting JP (2012) The mitochondrial proteins NLRX1 and TUFM form a complex that regulates type I interferon and autophagy. Immunity 36:933–946PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Arnoult D, Soares F, Tattoli I, Castanier C, Philpott DJ, Girardin SE (2009) An N-terminal addressing sequence targets NLRX1 to the mitochondrial matrix. J Cell Sci 122:3161–3168PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Halliwell B (1996) Antioxidants in human health and disease. Annu Rev Nutr 16:33–50PubMedCrossRefGoogle Scholar
  86. 86.
    Rahman I, MacNee W (1999) Lung glutathione and oxidative stress: implications in cigarette smoke-induced airway disease. Am J Phys 277:L1067–L1088Google Scholar
  87. 87.
    Kensler TW, Wakabayashi N, Biswal S (2007) Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol 47:89–116CrossRefGoogle Scholar
  88. 88.
    Boutten A, Goven D, Boczkowski J, Bonay M (2010) Oxidative stress targets in pulmonary emphysema: focus on the Nrf2 pathway. Expert Opin Ther Targets 14:329–346PubMedCrossRefGoogle Scholar
  89. 89.
    Duthie GG, Arthur JR, James WP (1991) Effects of smoking and vitamin E on blood antioxidant status. Am J Clin Nutr 53:1061S–1063SPubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Cantin AM, North SL, Hubbard RC and Crystal RG (1987) Normal alveolar epithelial lining fluid contains high levels of glutathione. J Appl Physiol (1985) 63:152–157PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Baskaran S, Lakshmi S, Prasad PR (1999) Effect of cigarette smoke on lipid peroxidation and antioxidant enzymes in albino rat. Indian J Exp Biol 37(12):1196–1200PubMedPubMedCentralGoogle Scholar
  92. 92.
    Mukherjee S, Woods L, Weston Z, Williams AB, Das SK (1993) The effect of mainstream and sidestream cigarette smoke exposure on oxygen defense mechanisms of guinea pig erythrocytes. J Biochem Toxicol 8:119–125PubMedCrossRefGoogle Scholar
  93. 93.
    Chow CK, Thacker RR, Changchit C, Bridges RB, Rehm SR, Humble J, Turbek J (1986) Lower levels of vitamin C and carotenes in plasma of cigarette smokers. J Am Coll Nutr 5:305–312PubMedCrossRefGoogle Scholar
  94. 94.
    Chytil F (1992) The lung and vitamin A. Am J Phys 262:J517–L527CrossRefGoogle Scholar
  95. 95.
    Das SK, Sinha Roy S, Mukherjee S, Ong DE (2014) Lung retinoid metabolism and signaling in chronic pulmonary disease. Indian J Biochem Biophys 51:499–505PubMedGoogle Scholar
  96. 96.
    Nair CR, Davis MM, Das SK (1988) Effect of vitamin A deficiency on pulmonary defense systems of guinea pig lung. Int J Vitam Nutr Res 58:375–380PubMedGoogle Scholar
  97. 97.
    Morabia A, Menkes MJ, Comstock GW, Tockman MS (1990) Serum retinol and airway obstruction. Am J Epidemiol 132:77–82PubMedCrossRefGoogle Scholar
  98. 98.
    Paiva SA, Godoy I, Vannucchi H, Favaro RM, Geraldo RR, Campana AO (1996) Assessment of vitamin A status in chronic obstructive pulmonary disease patients and healthy smokers. Am J Clin Nutr 64:928–934PubMedCrossRefGoogle Scholar
  99. 99.
    Mukherjee S, Nayyar T, Chytil F, Das SK (1995) Mainstream and sidestream cigarette smoke exposure increases retinol in guinea pig lungs. Free Radic Biol Med 18:507–514PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Rennard SI, Togo S, Holz O (2006) Cigarette smoke inhibits alveolar repair: a mechanism for the development of emphysema. Proc Am Thorac Soc 3(8):703–708PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Pinnock CB, Douglas RM, Martin AJ, Badcock NR (1988) Vitamin A status of children with respiratory syncytial virus infection in infancy. Aust Pediatr J 24:286–289Google Scholar
  102. 102.
    Edge R, McGarvey DJ, Truscott TG (1997) The carotenoids as anti-oxidants: a review. J Photochem Photobiol B 41:189–200PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Agler AH, Kurth T, Gaziano JM, Buring JE, Cassano PA (2011) Randomised vitamin E supplementation and risk of chronic lung disease in the Women's Health Study. Thorax 66(4):320–325PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Granado F, Olmedilla B, Blanco I (2003) Nutritional and clinical relevance of lutein in human health. Br J Nutr 90(3):487–502PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Schünemann HJ, McCann S, Grant BJB, Trevisan M, Muti P, Freudenheim JL (2002) Lung function in relation to intake of carotenoids and other antioxidant vitamins in a population-based study. Am J Epidemiol 155(5):463–471PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Grievink L, de Waart FG, Schouten EG, Kok FJ (2000) Serum carotenoids,α-tocopherol, and lung function among Dutch elderly. Am Respir Crit Care Med 161(3):790–795CrossRefGoogle Scholar
  107. 107.
    Schäffer MW, Roy SS, Mukherjee S, Das SK (2013) Vitamin A, vitamin E, lutein and β-carotene in lung tissues from subjects with chronic obstructive pulmonary disease and emphysema. Open J Respir Dis 03(02):8Google Scholar
  108. 108.
    Frankenberger M, Heimbeck I, Möller W, Mamidi S, Kassner G, Pukelsheim K, Wjst M, Neiswirth M, Kroneberg P, Lomas D, Halsall D, Iadarola P, Fertl A, Häussinger K, Ziegler-Heitbrock L (2009) Inhaled all-trans retinoic acid in an individual with severe emphysema. Eur Respir J 34:1487–1489PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Morabia A, Sorenson A, Kumanyika SK, Abbey H (1989) Vitamin A, cigarette smoking and airway obstruction. Am Rev Resp Dis 140:1312–1316PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Mata JR, Mata NL, Tsin ATC (1998) Substrate specificity of retinyl ester hydrolase activity in retinal pigment epithelium. J Lipid Res 39:604–612PubMedPubMedCentralGoogle Scholar
  111. 111.
    Biesalski HK, Reifen R, Fürst P, Edris M (1999) Retinyl palmitate supplementation by inhalation of an aerosol improves vitamin A status of preschool children in Gondar (Ethiopia). Br J Nutr 82:179–182PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Kohlhäufl M, Häussinger K, Stanzel F, Markus A, Tritschler J, Mühlhöfer A, Morresi-Hauf A, Golly I, Scheuch G, Jany BH, Biesalski HK (2002) Inhalation of aerosolized vitamin A: reversibility of metaplasia and dysplasia of human respiratory epithelia a prospective pilot study. Eur J Med Res 7:72–78PubMedPubMedCentralGoogle Scholar
  113. 113.
    Mahabir S, Schendel K, Dong YQ, Barrera SL, Spitz MR, Forman MR (2008) Dietary α-, β-, γ- and δ-tocopherols in lung cancer risk. Int J Cancer 123:1173–1180PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Napoli JL, McCormick AM, O’Meara B, Dratz EA (1988) VitaminA metabolism: alpha-tocopherol modulates tissue retinol levelsin vivo, and retinyl palmitate hydrolysis in vitro. Arch Biochem Biophys 230:194–202CrossRefGoogle Scholar
  115. 115.
    Melo van Lent D, Leermakers ETM, Hofman A, Stricker BH, Brusselle GG, Franco OH, Lahousse L, Kiefte-de Jong JC (2017) Association between lutein intake and lung function in adults: the Rotterdam Study. Br J Nutr 117(5):720–730PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Zingg J-M (2015) Vitamin E: a role in signal transduction. Annu Rev Nutr 35:135–173PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Roca-Ferrer J, Pujols L, Agusti C, Xaubet A, Mullol J, Gimferrer JM, Picado C (2011) Cyclooxigenase-2 levels are increased in the lung tissue and bronchial tumors of patients with chronic obstructive pulmonary disease. Arch Bronconeumol 47(12):584–589PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Peh HY, Tan WSD, Chan TK, Pow CW, Foster PS, Wong WSF (2017) Vitamin E isoform γ-tocotrienol protects against emphysema in cigarette smoke-induced COPD. Free Radic Biol Med 110:332–344PubMedCrossRefPubMedCentralGoogle Scholar
  119. 119.
    Das SK, Chakrabarti P, Tsao FH, Nayyar T, Mukherjee S (1992) Identification of calcium-dependent phospholipid-binding proteins (annexins) from guinea pig alveolar type II cells. Mol Cell Biochem 115:79–84.129PubMedPubMedCentralGoogle Scholar
  120. 120.
    Whitsett JA, Manton MA, Darovec-Beckerman C, Adams K (1981) II. Beta-adrenergic receptors and catecholamine sensitive adenylate cyclase in the developing rat lung. Life Sci 28:339–345PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    Das SK, Mukherjee S (1999) Role of peripheral benzodiazepine receptors on secretion of surfactant in guinea pig alveolar type II cells. Biosci Rep 19(5):461–471PubMedCrossRefPubMedCentralGoogle Scholar
  122. 122.
    Das SK, Tsao FH, Mukherjee S (2002) Mainstream and sidestream cigarette smoke exposure increases Ca2+−dependent phospholipid binding proteins in guinea pig alveolar type II cells. Mol Cell Biochem 231(1–2):37–42PubMedCrossRefPubMedCentralGoogle Scholar
  123. 123.
    Mukherjee S, Das SK (1992) Effects of cigarette smoke exp111osure on the binding capacity of β-adrenergic receptors in guinea pig alveolar type II cell. FASEB J 6:259Google Scholar
  124. 124.
    Wang W, Li X, Xu J (2015) Exposure to cigarette smoke downregulates β2-adrenergic receptor expression and upregulates inflammation in alveolar macrophages. Inhal Toxicol 27(10):488–494PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Gavish M, Cohen S, Nagler R (2016) Cigarette smoke effects on TSPO and VDAC expression in a cellular lung cancer model. Eur J Cancer Prev 25(5):361–367PubMedCrossRefPubMedCentralGoogle Scholar
  126. 126.
    Zhou Y, Zhang Y, Guo Y, Zhang Y, Xu M amd He B. (2014) β2-Adrenoceptor involved in smoking-induced airway mucus hypersecretion through β-arrestin-dependent signaling. PLoS One 9(6):e97788PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Henke MO, John G, Rheineck C, Chillappagari S, Naehrlich L, Rubin BK (2011) Serine proteases degrade airway mucins in cystic fibrosis. Infect Immun 79:3438–3444PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Abboud RT, Vimalanathan S (2008) Pathogenesis of COPD. Part I. The role of protease-antiprotease imbalance in emphysema. Int J Tuberc Lung Dis 12:361–367PubMedPubMedCentralGoogle Scholar
  129. 129.
    Crooks SW, Bayley DL, Hill SL, Stockley RA (2000) Bronchial inflammation in acute bacterial exacerbations of chronic bronchitis: the role of leukotriene B4. Eur Respir J 15:274–280PubMedCrossRefPubMedCentralGoogle Scholar
  130. 130.
    Owen CA (2005) Proteinases and oxidants as targets in the treatment of chronic obstructive pulmonary disease. Proc Am Thorac Soc 2:373–385; discussion 394–375PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Tuder RM, Yoshida T, Arap W, Pasqualini R, Petrache I (2006) State of the art. Cellular and molecular mechanisms of alveolar destruction in emphysema: an evolutionary perspective. Proc Am Thorac Soc 3:503–510PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Chillappagari S, Preuss J, Licht S, Muller C, Mahavadi P, Sarode G, Vogelmeier C, Guenther A, Nahrlich L, Rubin BK, Henke MO (2015) Altered protease and antiprotease balance during a COPD exacerbation contributes to mucus obstruction. Respir Res 16:85PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Pandey KC, De S, Mishra PK (2017) Role of proteases in chronic obstructive pulmonary disease. Front Pharmacol 8:512PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    MacNee W (2005) Pulmonary and systemic oxidant/antioxidant imbalance in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2:50–60PubMedCrossRefPubMedCentralGoogle Scholar
  135. 135.
    Sidhar SK, Lomas DA, Carrell RW, Foreman RC (1995) Mutations which impede loop/sheet polymerization enhance the secretion of human alpha 1-antitrypsin deficiency variants. J Biol Chem 270:8393–8396PubMedCrossRefPubMedCentralGoogle Scholar
  136. 136.
    Jonigk D, Al-Omari M, Maegel L, Muller M, Izykowski N, Hong J, Hong K, Kim SH, Dorsch M, Mahadeva R, Laenger F, Kreipe H, Braun A, Shahaf G, Lewis EC, Welte T, Dinarello CA, Janciauskiene S (2013) Anti-inflammatory and immunomodulatory properties of alpha1-antitrypsin without inhibition of elastase. Proc Natl Acad Sci USA 110:15007–15012PubMedCrossRefPubMedCentralGoogle Scholar
  137. 137.
    Lee KH, Lee CH, Jeong J, Jang AH, Yoo CG (2015) Neutrophil elastase differentially regulates interleukin 8 (IL-8) and vascular endothelial growth factor (VEGF) production by cigarette smoke extract. J Biol Chem 290:28438–28445PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Damrich-Grampp B, Seidl A, Weigt A, Lang M, Hummer B, Hahn HL (1990) [Elastase-induced hyperfunction of submucous glands develops independent of elastase-induced emphysema]. Pneumologie 44(Suppl 1):420–421Google Scholar
  139. 139.
    An JK, Blomenkamp K, Lindblad D, Teckman JH (2005) Quantitative isolation of alphalAT mutant Z protein polymers from human and mouse livers and the effect of heat. Hepatology 41:160–167PubMedCrossRefPubMedCentralGoogle Scholar
  140. 140.
    Dahl M, Tybjaerg-Hansen A, Lange P, Vestbo J, Nordestgaard BG (2002) Change in lung function and morbidity from chronic obstructive pulmonary disease in alpha1-antitrypsin MZ heterozygotes: a longitudinal study of the general population. Ann Intern Med 136:270–279PubMedCrossRefPubMedCentralGoogle Scholar
  141. 141.
    Hersh CP, Dahl M, Ly NP, Berkey CS, Nordestgaard BG, Silverman EK (2004) Chronic obstructive pulmonary disease in alpha1-antitrypsin PI MZ heterozygotes: a meta-analysis. Thorax 59:843–849PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Demedts IK, Demoor T, Bracke KR, Joos GF, Brusselle GG (2006) Role of apoptosis in the pathogenesis of COPD and pulmonary emphysema. Respir Res 7:53PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Hirata H, Takahashi A, Kobayashi S, Yonehara S, Sawai H, Okazaki T, Yamamoto K, Sasada M (1998) Caspases are activated in a branched protease cascade and control distinct downstream processes in Fas-induced apoptosis. J Exp Med 187:587–600PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Tesfaigzi Y, Myers OB, Stidley CA, Schwalm K, Picchi M, Crowell RE, Gilliland FD, Belinsky SA (2006) Genotypes in matrix metalloproteinase 9 are a risk factor for COPD. Int J Chron Obstruct Pulmon Dis 1:267–278PubMedPubMedCentralGoogle Scholar
  145. 145.
    Zhou M, Huang SG, Wan HY, Li B, Deng WW, Li M (2004) Genetic polymorphism in matrix metalloproteinase-9 and the susceptibility to chronic obstructive pulmonary disease in Han population of south China. Chin Med J (Engl) 117:1481–1484Google Scholar
  146. 146.
    Joos L, He JQ, Shepherdson MB, Connett JE, Anthonisen NR, Pare PD, Sandford AJ (2002) The role of matrix metalloproteinase polymorphisms in the rate of decline in lung function. Hum Mol Genet 11:569–576PubMedCrossRefPubMedCentralGoogle Scholar
  147. 147.
    Haq I, Lowrey GE, Kalsheker N, Johnson SR (2011) Matrix metalloproteinase-12 (MMP-12) SNP affects MMP activity, lung macrophage infiltration and protects against emphysema in COPD. Thorax 66:970–976PubMedCrossRefPubMedCentralGoogle Scholar
  148. 148.
    Linder R, Ronmark E, Pourazar J, Behndig A, Blomberg A, Lindberg A (2015) Serum metalloproteinase-9 is related to COPD severity and symptoms - cross-sectional data from a population based cohort-study. Respir Res 16:28PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Kelsen SG (2016) The unfolded protein response in chronic obstructive pulmonary disease. Ann Am Thorac Soc 13(Suppl 2):S138–S145PubMedPubMedCentralGoogle Scholar
  150. 150.
    Min T, Bodas M, Mazur S, Vij N (2011) Critical role of proteostasis-imbalance in pathogenesis of COPD and severe emphysema. J Mol Med (Berl) 89:577–593CrossRefGoogle Scholar
  151. 151.
    Tran I, Ji C, Ni I, Min T, Tang D, Vij N (2015) Role of cigarette smoke-induced aggresome formation in chronic obstructive pulmonary disease-emphysema pathogenesis. Am J Respir Cell Mol Biol 53:159–173PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Hassan T, Carroll TP, Buckley PG, Cummins R, O'Neill SJ, McElvaney NG, Greene CM (2014) miR-199a-5p silencing regulates the unfolded protein response in chronic obstructive pulmonary disease and alpha1-antitrypsin deficiency. Am J Respir Crit Care Med 189:263–273PubMedCrossRefPubMedCentralGoogle Scholar
  153. 153.
    Geraghty P, Wallace A, D'Armiento JM (2011) Induction of the unfolded protein response by cigarette smoke is primarily an activating transcription factor 4-C/EBP homologous protein mediated process. Int J Chron Obstruct Pulmon Dis 6:309–319PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Kenche H, Ye ZW, Vedagiri K, Richards DM, Gao XH, Tew KD, Townsend DM, Blumental-Perry A (2016) Adverse outcomes associated with cigarette smoke radicals related to damage to protein-disulfide isomerase. J Biol Chem 291:4763–4778PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Tagawa Y, Hiramatsu N, Kato H, Sakoh T, Nakajima S, Hayakawa K, Saito Y, Johno H, Takahashi S, Gu L, Yao J, Kitamura M (2011) Induction of CCAAT/enhancer-binding protein-homologous protein by cigarette smoke through the superoxide anion-triggered PERK-eIF2alpha pathway. Toxicology 287:105–112PubMedCrossRefPubMedCentralGoogle Scholar
  156. 156.
    Kelsen SG, Duan X, Ji R, Perez O, Liu C, Merali S (2008) Cigarette smoke induces an unfolded protein response in the human lung: a proteomic approach. Am J Respir Cell Mol Biol 38:541–550PubMedCrossRefPubMedCentralGoogle Scholar
  157. 157.
    Jorgensen E, Stinson A, Shan L, Yang J, Gietl D, Albino AP (2008) Cigarette smoke induces endoplasmic reticulum stress and the unfolded protein response in normal and malignant human lung cells. BMC Cancer 8:229PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    van Rijt SH, Keller IE, John G, Kohse K, Yildirim AO, Eickelberg O, Meiners S (2012) Acute cigarette smoke exposure impairs proteasome function in the lung. Am J Physiol Lung Cell Mol Physiol 303:L814–L823PubMedCrossRefPubMedCentralGoogle Scholar
  159. 159.
    Monick MM, Powers LS, Walters K, Lovan N, Zhang M, Gerke A, Hansdottir S, Hunninghake GW (2010) Identification of an autophagy defect in smokers’ alveolar macrophages. J Immunol 185:5425–5435PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Chen ZH, Kim HP, Sciurba FC, Lee SJ, Feghali-Bostwick C, Stolz DB, Dhir R, Landreneau RJ, Schuchert MJ, Yousem SA, Nakahira K, Pilewski JM, Lee JS, Zhang Y, Ryter SW, Choi AM (2008) Egr-1 regulates autophagy in cigarette smoke-induced chronic obstructive pulmonary disease. PLoS One 3:e3316PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Kim HP, Wang X, Chen ZH, Lee SJ, Huang MH, Wang Y, Ryter SW, Choi AM (2008) Autophagic proteins regulate cigarette smoke-induced apoptosis: protective role of heme oxygenase-1. Autophagy 4:887–895PubMedCrossRefPubMedCentralGoogle Scholar
  162. 162.
    Toraldo DM, De Nuccio F, Scoditti E (2013) Systemic inflammation in chronic obstructive pulmonary disease: may diet play a therapeutic role? J Allergy Ther 2013:S2Google Scholar
  163. 163.
    Fujita M (2015) New therapies for chronic obstructive pulmonary disease, lung regeneration. World J Respirol 5(1):34–39CrossRefGoogle Scholar
  164. 164.
    Guan S, Xu W, Han F, Gu W, Song L, Ye W, Liu Q, Guo X (2017) Ginsenoside Rg1 attenuates cigarette smoke-induced pulmonary epithelial-mesenchymal transition via inhibition of the TGF-β1/Smad pathway. Biomed Res Int 2017:7171404PubMedPubMedCentralGoogle Scholar
  165. 165.
    Vézina FA, Cantin AM (2018) Antioxidants and chronic obstructive pulmonary disease. Chronic Obstruct Pulmon Dis 5(4):277–288CrossRefGoogle Scholar
  166. 166.
    Gao W, Guo Y, Yang H (2017) Platycodin D protects against cigarette smoke-induced lung inflammation in mice. Int Immunopharmacol 47:53–58PubMedCrossRefPubMedCentralGoogle Scholar
  167. 167.
    Rahman I (2006) Antioxidant therapies in COPD. Int J COPD 1(1):15–29CrossRefGoogle Scholar
  168. 168.
    Selim AO, Gouda ZA, Selim SA (2017) An experimental study of a rat model of emphysema induced by cigarette smoke exposure and the effect of Survanta therapy. Ann Anat 211:69–77PubMedCrossRefGoogle Scholar
  169. 169.
    Zeng Z, Yang D, Huang X, Xiao Z (2017) Effect of carbocisteine on patients with COPD: a systematic review and meta-analysis. Int J Chron Obstruct Pulmon Dis 12:2277–2283PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Lin L, Yin Y, Hou G, Han D, Kang J, Wang Q (2017) Ursolic acid attenuates cigarette smoke-induced emphysema in rats by regulating PERK and Nrf2 pathways. Pulm Pharmacol Ther 44:111–121PubMedCrossRefGoogle Scholar
  171. 171.
    Uray IP, Dmitrovsky E, Brown PW (2016) Retinoids and rexinoids in cancer prevention: from laboratory to clinic. Semin Oncol 43(1):49–64PubMedCrossRefGoogle Scholar
  172. 172.
    Nan H, Qu-Bei LI, Shan-Ye Z (2018) Effect of vitamin A as an adjuvant therapy for pneumonia in children: a Meta analysis. Chin J Contemp Ped 20(2):146–153Google Scholar
  173. 173.
    Abdoulhossein D, Taheri I, Saba MA, Akbari H, Shafagh S, Asemi Zataollah A (2018) Effect of vitamin C and vitamin E on lung contusion: a randomized clinical trial study. Ann Med Surg (Lond) 36:152–157CrossRefGoogle Scholar
  174. 174.
    Pirabbasi E, Shahar S, Manaf ZA, Rajab NF, Manap RA (2016) Efficacy of ascorbic acid (Vitamin C) and/N-acetylcysteine (NAC) supplementation on nutritional and antioxidant status of male chronic obstructive pulmonary disease (COPD) patients. J Nutr Sci Vitaminol (Tokyo) 62(1):54–61CrossRefGoogle Scholar
  175. 175.
    Rautalahti M, Virtamo J, Haukka J, Heinonen OP, Sundvall J, Albanes D, Huttunen JK (1997) The effect of alpha-tocopherol and beta-carotene supplementation on COPD symptoms. Am J Respir Crit Care Med 156(5):1447–1452PubMedCrossRefGoogle Scholar
  176. 176.
    Kentson M, Leanderson P, Jacobson P, Persson HL (2018) Oxidant status, iron homeostasis, and carotenoid levels of COPD patients with advanced disease and LTOT. Eur Clin Respir J 5(1):1447221PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Biswas S, Hwang JW, Kirkham PA, Rahman I (2013) Pharmacological and dietary antioxidant therapies for chronic obstructive pulmonary disease. Curr Med Chem 20(12):1496–1530PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Kaluza J, Larsson SC, Orsini N, Linden A, Wolk A (2017) Fruit and vegetable consumption and risk of COPD: a prospective cohort study of men. Thorax 22(6):500–509CrossRefGoogle Scholar
  179. 179.
    Neurohr C, Lenz AG, Ding I, Leuchte H, Kolbe T, Behr J (2003) Glutamate-cysteine ligase modulatory su.bunit in BAL alveolar macrophages of healthy smokers. Eur Respir J 22(1):82–87PubMedCrossRefPubMedCentralGoogle Scholar
  180. 180.
    Lamson DW (2000) The use of nebulized glutathione in the treatment of emphysema: a case report. Altern Med Rev 5(5):429–431PubMedPubMedCentralGoogle Scholar
  181. 181.
    Zuin R, Palamidese A, Negrin R, Catozzo L, Scarda A, Balbinot M (2005) High dose N–acetylcysteine in patients with exacerbations of chronic obstructive pulmonary disease. Clin Drug Investig 5(6):401–408CrossRefGoogle Scholar
  182. 182.
    Cazzola M, Calzetta L, Page C, Jardim J, Chuchalin AG, Rogliani P, Matera MG (2015) Influence of N-acetylcysteine on chronic bronchitis or COPD exacerbations: a meta-analysis. Eur Respir Rev 24(137):451–461PubMedCrossRefPubMedCentralGoogle Scholar
  183. 183.
    Gillissen A, Jaworska M, Orth M, Coffiner M, Maes P, App EM, Cantin AM, Schultze-Werninghaus G (1997) Nacystelyn, a novel lysine salt of N-acetylcysteine, to augment cellular antioxidant defence in vitro. Respir Med 91(3):159–168PubMedCrossRefPubMedCentralGoogle Scholar
  184. 184.
    Ekberg-Jansson A, Larson M, MacNee W, Tunek A, Wahlgren L, Wouters EF, Larsson S (1999) N-isobutyrylcysteine, a donor of systemic thiols, does not reduce the exacerbation rate in chronic bronchitis. Eur Respir J 13(4):829–834PubMedCrossRefPubMedCentralGoogle Scholar
  185. 185.
    Cazzola M, Rogliani P, Calzetta L, Hanania NA, Matera MG (2017) Impact of mucolytic agents on COPD exacerbations: a pair-wise and network meta-analysis. COPD 14(5):552–563PubMedCrossRefPubMedCentralGoogle Scholar
  186. 186.
    Wang W, Guan WJ, Huang RQ, Xie YQ, Zheng JP, Zhu SX, Chen M, Zhong NS (2016) Carbocisteine attenuates TNF-α-induced inflammation in human alveolar epithelial cells in vitro through suppressing NF-κB and ERK1/2 MAPK signaling pathways. Acta Pharmacol Sin 37(5):629–636PubMedPubMedCentralCrossRefGoogle Scholar
  187. 187.
    Dal Negro RW, Wedzicha JA, Iversen M, Fontana G, Page C, Cicero AF, Pozzi E, Calverley PMA on behalf of the RESTORE group (2017) Effect of erdosteine on the rate and duration of COPD exacerbations: the RESTORE study. Eur Respir J 50(4):1700711PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Calverley PMA, Page C, Dal Negro RW, Fontana G, Iversen M, Cicero AF, Pozz E, Wedzicha JA (2018) Effect of erdosteine in moderately severe COPD patients. Eur Respir J 52:PA776Google Scholar
  189. 189.
    Oostwoud LC, Gunasinghe P, Seow HJ, Ye JM, Selemidis S, Bozinovski S, Vlahos R (2016) Apocynin and ebselen reduce influenza A virus-induced lung inflammation in cigarette smoke-exposed mice. Sci Rep 6:20983PubMedPubMedCentralCrossRefGoogle Scholar
  190. 190.
    Ueno-Iio T, Shibakura M, Iio K, Tanimoto Y, Kanehiro A, Tanimoto M, Kataoka M (2013) Effect of fudosteine, a cysteine derivative, on airway hyperresponsiveness, inflammation, and remodeling in a murine model of asthma. Life Sci 92(20–21):1015–1023PubMedCrossRefPubMedCentralGoogle Scholar
  191. 191.
    Hodge S, Matthews G, Mukaro V, Ahern J, Shivam A, Hodge G, Holmes M, Jersmann H, Reynolds PN (2011) Cigarette smoke-induced changes to alveolar macrophage phenotype and function are improved by treatment with procysteine. Am J Respir Cell Mol Biol 44(5):673–681PubMedCrossRefPubMedCentralGoogle Scholar
  192. 192.
    Malhotra D, Thimmulappa R, Navas-Acien A, Sandford A, Elliott M, Singh A, Chen L, Zhuang X, Hogg J, Pare P, Tuder RM, Biswal S (2008) 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 178(6):592–604PubMedPubMedCentralCrossRefGoogle Scholar
  193. 193.
    Dianat M, Radan M, Badavi M, Mard SA, Bayati V, Ahmadizadeh M (2018) Crocin attenuates cigarette smoke-induced lung injury and cardiac dysfunction by anti-oxidative effects: the role of Nrf2 antioxidant system in preventing oxidative stress. Respir Res 19(1):58–70PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Jiao Z, Chang J, Li J, Nie D, Cui H, Guo D (2017) Sulforaphane increases Nrf2 expression and protects alveolar epithelial cells against injury caused by cigarette smoke extract. Mol Med Rep 16(2):1241–1247PubMedPubMedCentralCrossRefGoogle Scholar
  195. 195.
    Wise RA, Holbrook JT, Criner G, Sethi S, Rayapudi S, Sudini KR, Sugar EA, Burke A, Thimmulappa R, Singh A, Talalay P, Fahey JW, Berenson CS, Jacobs MR, Biswal S, Broccoli Sprout Extract Trial Research Group (2017) Correction: lack of effect of oral sulforaphane administration on Nrf2 expression in COPD: a randomized, double-blind, placebo controlled trial. PLoS One 2(3):e0175077. Scholar
  196. 196.
    Li J, Tong D, Liuc J, Chen F, Shen Y (2016) Oroxylin A attenuates cigarette smoke-induced lung inflammation by activating Nrf2. Int Immunopharmacol 40:524–529PubMedCrossRefPubMedCentralGoogle Scholar
  197. 197.
    Gao W, Guo Y, Yang H (2017) Platycodin D protects against cigarette smoke-induced lung inflammation in mic. Int Immunopharmacol 47:53–58PubMedCrossRefPubMedCentralGoogle Scholar
  198. 198.
    Li XY, Luo BL, Wang LJ, Zhang WD, Liu ZG (2015) 15-Deoxy-prostaglandin J2 anti-inflammation in a rat model of chronic obstructive pulmonary disease and human bronchial epithelial cells via Nrf2 activation. Genet Mol Res 14(4):14037–14042PubMedCrossRefPubMedCentralGoogle Scholar
  199. 199.
    Sussan TE, Rangasamy T, Blake DJ, Malhotra D, El-Haddad H, Bedja D, Yates MS, Kombairaju P, Yamamoto M, Liby KT, Sporn MB, Gabrielson KL, Champion HC, Tuder RM, Kensler TW, Biswal S (2009) Targeting Nrf2 with the triterpenoid CDDO-imidazolide attenuates cigarette smoke-induced emphysema and cardiac dysfunction in mice. Proc Natl Acad Sci USA 106(1):250–255PubMedCrossRefPubMedCentralGoogle Scholar
  200. 200.
    Arja C, Surapaneni KM, Raya P, Adimoolam C, Balisetty B, Kanala KR (2013) Oxidative stress and antioxidant enzyme activity in South Indian male smokers with chronic obstructive pulmonary disease. Respirology 18(7):1069–1075PubMedPubMedCentralGoogle Scholar
  201. 201.
    Gilks CB, Price K, Wright JL, Churg A (1998) Antioxidant gene expression in rat lung after exposure to cigarette smoke. Am J Pathol 152(1):269–278PubMedPubMedCentralGoogle Scholar
  202. 202.
    Cheng SE, Lee IT, Lin CC, Kou YR, Yang CM (2010) Cigarette smoke particle-phase extract induces HO-1 expression in human tracheal smooth muscle cells: role of the c-Src/NADPH oxidase/MAPK/Nrf2 signaling pathway. Free Radic Biol Med 48(10):1410–1422PubMedCrossRefPubMedCentralGoogle Scholar
  203. 203.
    Zhu A, Ge D, Zhang J, Yue Teng Y, Yuan C, Huang M, Adcock IM, Barnes PJ, Xin Y (2014) Sputum myeloperoxidase in chronic obstructive pulmonary disease. Eur J Med Res 19(1):12–23PubMedPubMedCentralCrossRefGoogle Scholar
  204. 204.
    Chang LY, Crapo JD (2002) Inhibition of airway inflammation and hyperreactivity by an antioxidant mimetic. Free Radic Biol Med 33(3):379–386PubMedCrossRefPubMedCentralGoogle Scholar
  205. 205.
    Smith KR, Uyeminami DL, Kodavanti UP, Crapo JD, Chang LY, Pinkerton KE (2002) Inhibition of tobacco smoke-induced lung inflammation by a catalytic antioxidant. Free Radic Biol Med 33(8):1106–1114PubMedCrossRefPubMedCentralGoogle Scholar
  206. 206.
    Sato A, Hoshino Y, Hara T, Muro S, Nakamura H, Mishima M, Yodoi J (2008) Thioredoxin-1 ameliorates cigarette smoke-induced lung inflammation and emphysema in mice. J Pharmacol Exp Ther 325(2):380–388PubMedCrossRefPubMedCentralGoogle Scholar
  207. 207.
    Hoidal JR, Fox RB, LeMarbe PA, Perri R, Repine JE (1981) Altered oxidative metabolic responses in vitro of alveolar macrophages from asymptomatic cigarette smokers. Am Rev Respir Dis 123:85–89PubMedPubMedCentralGoogle Scholar
  208. 208.
    Churg A, Marshall CV, Sin DD, Bolton S, Zhou S, Thain K, Cadogan EB, Maltby J, Soars MG, Mallinder PR, Wright JL (2012) Late intervention with a myeloperoxidase inhibitor stops progression of experimental chronic obstructive pulmonary disease. Am J Respir Crit Care Med 185(1):34–43PubMedCrossRefPubMedCentralGoogle Scholar
  209. 209.
    Cazzola M, Page CP, Calzetta L, Matera MG (2012) Emerging anti-inflammatory strategies for COPD. Eur Respir J 40:724–741PubMedCrossRefPubMedCentralGoogle Scholar
  210. 210.
    Guan S, Xu W, Han F, Gu W, Song L, Ye W, Liu Q, and Guo X (2017) Ginsenoside Rg1 attenuates cigarette smoke-induced pulmonary epithelial-mesenchymal transition via inhibition of the TGF-𝛽1/Smad pathway. BioMed Res Int 2017, Article ID 7171404, 12 pagesGoogle Scholar
  211. 211.
    Luo F, Jingyan L, Yan T, Mingxing M (2017) Salidroside alleviates cigarette smoke-induced COPD in mice. Biomed Pharmacother 86:155–161PubMedCrossRefPubMedCentralGoogle Scholar
  212. 212.
    Yu D, Liu X, Zhang G, Ming Z, Wang T (2018) Isoliquiritigenin inhibits cigarette smoke-induced COPD by attenuating inflammation and oxidative stress via the regulation of the Nrf2 and NF-κB signaling pathways. Front Pharmacol 9:1001–1009PubMedPubMedCentralCrossRefGoogle Scholar
  213. 213.
    Guan R, Wang J, Li Z, Ding M, Li D, Xu G, Wang T, Chen Y, Yang Q, Long Z, Cai Z, Zhang C, Liang X, Dong L, Zhao L, Zhang H, Sun D, Lu W (2018) Sodium tanshinone IIA sulfonate decreases cigarette smoke-induced inflammation and oxidative stress via blocking the activation of MAPK/HIF-1α signaling pathway. Front Pharmacol 9:263–276PubMedPubMedCentralCrossRefGoogle Scholar
  214. 214.
    Siedlinski M, Boer JM, Smit HA, Postma DS, Boezen HM (2012) Dietary factors and lung function in the general population: wine and resveratrol intake. Eur Respir J 39(2):385–391PubMedCrossRefPubMedCentralGoogle Scholar
  215. 215.
    Suzuki M, Betsuyaku T, Ito Y, Nagai K, Odajima N, Moriyama C, Nasuhara Y, Nishimura M (2009) Curcumin attenuates elastase- and cigarette smoke-induced pulmonary emphysema in mice. Am J Physiol Lung Cell Mol Physiol 296(4):L614–L623PubMedCrossRefPubMedCentralGoogle Scholar
  216. 216.
    Ng TP, Niti M, Yap KB, Tan WC (2012) Curcumins-rich curry diet and pulmonary function in Asian older adults. PLoS One 7(12):e51753PubMedPubMedCentralCrossRefGoogle Scholar
  217. 217.
    Zhai T, Li S, Hu W, Li D, Leng S (2018) Potential micronutrients and phytochemicals against the pathogenesis of chronic obstructive pulmonary disease and lung cancer. Nutrients 10(7):813–831PubMedCentralCrossRefGoogle Scholar
  218. 218.
    Bao MJ, Shen J, Jia YL, Li FF, Ma WJ, Shen HJ, Shen LL, Lin XX, Zhang LH, Dong XW, Xie YC, Zhao YQ, Xie QM (2013) Apple polyphenol protects against cigarette smoke-induced acute lung injury. Nutrition 29(1):235–243PubMedCrossRefPubMedCentralGoogle Scholar
  219. 219.
    Sharafkhaneh A, Velamuri S, Badmaev V, Lan C, Hanania N (2007) The potential role of natural agents in treatment of airway inflammation. Ther Adv Respir Dis 1(2):105–120PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2020

Authors and Affiliations

  • Anuradha Ratna
    • 1
    • 2
  • Shyamali Mukherjee
    • 3
  • Salil K. Das
    • 1
    Email author
  1. 1.Department of Biochemistry, Cancer Biology, Neuroscience and PharmacologyMeharry Medical CollegeNashvilleUSA
  2. 2.Department of MedicineUniversity of Massachusetts Medical SchoolWorcesterUSA
  3. 3.Department of Professional Medical EducationMeharry Medical CollegeNashvilleUSA

Personalised recommendations