The Role of Oxidative Stress in the Pathogenesis of COPD

Treatments in Respiratory Medicine - Tập 4 - Trang 175-200 - 2012
Irfan Rahman1
1Department of Environmental Medicine, Division of Lung Biology and Disease, University of Rochester Medical Center, Rochester, USA

Tóm tắt

Chronic inflammation and oxidative stress are important features in the pathogenesis of COPD. The increased oxidative stress in patients with COPD is the result of an increased burden of inhaled oxidants, as well as increased amounts of reactive oxygen species (ROS) generated by various inflammatory, immune and epithelial cells of the airways. Oxidative stress has important implications on several events of lung physiology and for the pathogenesis of COPD. These include oxidative inactivation of antiproteases and surfactants, mucus hypersecretion, membrane lipid peroxidation, mitochondrial respiration, alveolar epithelial injury, remodeling of extracellular matrix, and apoptosis. An increased level of ROS produced in the airways is reflected by increased markers of oxidative stress in the airspaces, sputum, breath, lungs, and blood in patients with COPD. The biomarkers of oxidative stress such as H2O2, F2-isoprostanes, malondialdehyde and 4-hydroxy-2-nonenal have been successfully measured in breath condensate. ROS and aldehydes play a key role in enhancing the inflammation through the activation of mitogen-activated protein kinases and redox-sensitive transcription factors such as nuclear factor kappa B and activator protein-1. Oxidative stress also alters nuclear histone acetylation and deacetylation leading to increased gene expression of pro-inflammatory mediators in the lung. Oxidative stress may play a role in the poor clinical efficacy of corticosteroids in the treatment of COPD. Since a variety of oxidants, free radicals, and aldehydes are implicated in the pathogenesis of COPD it is likely that a combination of antioxidants may be effective in the treatment of COPD. Antioxidant compounds may also be of therapeutic value in monitoring oxidative biomarkers indicating disease progression. Various approaches to enhance the lung antioxidant screen and the clinical effectiveness of antioxidant compounds in the treatment of COPD are discussed.

Tài liệu tham khảo

Gutteridge JM, Halliwell B. Free radicals and antioxidants in the year 2000: a historical look to the future. Ann N Y Acad Sci 2000; 899: 136–47 Richer C, Cogvadze V, Laffranchi R, et al. Oxidants in mitochondria: from physiology to diseases. Biochim Biophys Acta 1995; 127: 67–74 Rahman I, MacNee W. Role of transcription factors in inflammatory lung diseases. Thorax 1998; 53: 601–12 Guyton KZ, Liu Y, Gorospe M, et al. Activation of mitogen-activated protein kinase by H2O2. J Biol Chem 1996; 271: 4138–42 Rahman I, MacNee W. Role of oxidants/antioxidants in smoking-induced airways diseases. Free Radic Biol Med 1996; 21: 669–81 Rahman I, MacNee W. Lung glutathione and oxidative stress: implications in cigarette smoke-induced airways disease. Am J Physiol 1999; 277: L1067–88 Rahman I, MacNee W. Oxidative stress and regulation of glutathione synthesis in lung inflammation. Eur Respir J 2000; 16: 534–54 American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995; 152: S77–S120 Snider G. Chronic obstructive pulmonary disease: risk factors, pathophysiology and pathogenesis. Annu Rev Med 1989; 40: 411–29 Church T, Pryor WA. Free radical chemistry of cigarette smoke and its toxicological implications. Environ Health Perspect 1985; 64: 111–26 Pryor WA, Stone K. Oxidants in cigarette smoke: radicals, hydrogen peroxides, peroxynitrate, and peroxynitrite. Ann N Y Acad Sci 1993; 686: 12–28 Nakayama T, Church DF, Pryor WA. Quantitative analysis of the hydrogen peroxide formed in aqueous cigarette tar extracts. Free Radic Biol Med 1989; 7: 9–15 Repine JE, Bast A, Lankhorst I, et al. Oxidative stress in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1997; 156: 341–57 Jorres RA, Magnussen H. Oxidative stress in COPD. Eur Respir Rev 1997; 7: 131–5 Walsh GM. Advances in the immunobiology of eosinophils and their role in disease. Crit Rev Clin Lab Sci 1999; 36: 453–96 Eiserich JP, Hristova M, Cross CE, et al. Formation of nitric oxide-derived inflammatory oxidants by myeloperoxidase in neutrophils. Nature 1998; 391: 393–7 MacPherson JC, Comhair SAAA, Eruzurum SC, et al. Eosinophils are a major source of nitric oxide-derived oxidants in severe asthma: characterization of pathways available to eosinophils for generating reactive nitrogen species. J Immunol 2001; 166: 5763–72 Wu W, Samoszuk MK, Comhair SAAA, et al. Eosinophils generate brominating oxidants in allergen-induced asthma. J Clin Invest 2000; 105: 1455–63 Halliwell B, Gutteridge JMC. Role of free radicals and catalytic metal ions in human disease: an overview. Methods Enzymol 1990; 186: 1–85 Zang LY, Stone K, Pryor WA. Detection of free radicals in aqueous extracts of cigarette tar by electron spin resonance. Free Radic Biol Med 1995; 19: 161–7 Rahman I, Morrison D, Donaldson K, et al. Systemic oxidative stress in asthma, COPD, and smokers. Am J Respir Crit Care Med 1996; 154: 1055–60 Aaron SD, Angel JB, Lunau M, et al. Granulocyte inflammatory markers and airway infection during acute exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 163: 349–55 Fiorini G, Crespi S, Rinaldi M, et al. Serum ECP and MPO are increased during exacerbations of chronic bronchitis with airway obstruction. Biomed Pharmacother 2000; 54: 274–8 Gompertz S, Bayley DL, Hill SL, et al. Relationship between airway inflammation and the frequency of exacerbations in patients with smoking related COPD. Thorax 2001; 56: 36–41 Morrison D, Rahman I, Lannan S, et al. Epithelial permeability, inflammation and oxidant stress in the airspaces of smokers. Am J Respir Crit Care Med 1999; 159: 473–9 Nakashima H, Ando M, Sugimoto M, et al. Receptor-mediated O2-release by alveolar macrophages and peripheral blood monocytes from smokers and nonsmokers. Am Rev Respir Dis 1987; 136: 310–5 Drath DB, Larnovsky ML, Huber GL. The effects of experimental exposure to tobacco smoke on the oxidative metabolism of alveolar macrophages. J Reticulendothel Soc 1970; 25: 597–604 Schaberg T, Klein U, Rau M, et al. Subpopulation of alveolar macrophages in smokers and nonsmokers: relation to the expression of CD11/CD18 molecules and Superoxide anion production. Am J Respir Crit Care Med 1995; 151: 1551–8 Mateos F, Brock JF, Perez-Arellano JL. Iron metabolism in the lower respiratory tract. Thorax 1998; 53: 594–600 Lapenna D, Gioia SD, Mezzetti A, et al. Cigarette smoke, ferritin, and lipid peroxidation. Am J Respir Crit Care Med 1995; 151: 431–5 Thompson AB, Bohling T, Heires A, et al. Lower respiratory tract iron burden is increased in association with cigarette smoking. J Lab Clin Med 1991; 117: 494–9 Wesselius LJ, Nelson ME, Skikne BS. Increased release of ferritin and iron by iron loaded alveolar macrophages in cigarette smokers. Am J Respir Crit Care Med 1994; 150: 690–5 Jeffery PK. Structural and inflammatory changes in COPD; a comparison with asthma. Thorax 1998; 53: 129–36 Saetta M. Airway inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999; 160: S17–20 Lacoste JY, Bousquet J, Chanez P, et al. Eosinophilic and neutrophilic inflammation in asthma, chronic bronchitis, and chronic obstructive pulmonary disease. J Allergy Clin Immunol 1993; 149: 803–10 Lebowitz MD, Postma DS. Adverse effects of smoking on the natural history of newly diagnosed chronic bronchitis. Chest 1995; 108: 55–61 Chan-Yeung M, Buncio AD. Leucocyte count, smoking and lung function. Am J Med 1984; 76: 31–7 Van Antwerpen VL, Theron AJ, Richards GA, et al. Vitamin E, pulmonary functions, and phagocyte-mediated oxidative stress in smokers and non-smokers. Free Radic Biol Med 1995; 18: 935–43 Chan-Yeung M, Abboud R, Dybuncio A, et al. Peripheral leucocyte count and longitudinal decline in lung function. Thorax 1988; 43: 426–68 Postma DS, Renkema TEJ, Noordhoek JA, et al. Association between nonspecific bronchial hyperreactivity and Superoxide anion production by polymorphonuclear leukocytes in chronic airflow obstruction. Am Rev Respir Dis 1988; 137: 57–61 Richards GA, Theron AJ, van der Merwe CA, et al. Spirometric abnormalities in young smokers correlate with increased chemiluminescence responses of activated blood phagocytes. Am Rev Respir Dis 1989; 139: 181–7 Rahman I, Skwarska E, MacNee W. Attenuation of oxidant/antioxidant imbalance during treatment of exacerbations of chronic obstructive pulmonary disease. Thorax 1997; 52: 565–8 Muns G, Rubinstein I, Bergmann KC. Phagocytosis and oxidative bursts of blood phagocytes in chronic obstructive airway disease. Scand J Infect Dis 1995; 27: 369–73 Noguera A, Busquets X, Sauleda J, et al. Expression of adhesion molecules and G-proteins in circulating neutrophils in COPD. Am J Respir Crit Care Med 1998; 158: 1664–8 Brown DM, Drost E, Donaldson K, et al. Deformability and CD11/CD18 expression of sequestered neutrophils in normal and inflamed lungs. Am J Respir Cell Mol Biol 1995; 13: 531–9 Pinamonti S, Muzzuli M, Chicca C, et al. Xanthine oxidase activity in bronchoalveolar lavage fluid from patients with chronic obstructive lung disease. Free Radic Biol Med 1996; 21: 147–55 Heunks LM, Vina J, van Herwaarden CL, et al. Xanthine oxidase is involved in exercise-induced oxidative stress in chronic obstructive pulmonary disease. Am J Physiol 1999; 277: R1697–704 Pinamonti S, Leis M, Barbieri A, et al. Detection of xanthine oxidase activity products by EPR and HPLC in bronchoalveolar lavage fluid from patients with chronic obstructive pulmonary disease. Free Radic Biol Med 1998; 25: 771–9 Rahman I, Biswas SK. Non-invasive biomarkers of oxidative stress: reproducibility and methodological issues. Redox Rep 2004; 9(3): 125–43 Rahman I. Reproducibility of oxidative stress biomarkers: are they reliable. Eur Respir J 2004; 23: 1–2 Rahman I, Kelly F. Non-invasive biomarkers in breath condensate: a promising new approach in free radical research. Free Radic Res 2003; 37: 1253–66 Nowak D, Kasielski M, Pietras T, et al. Cigarette smoking does not increase hydrogen peroxide levels in expired breath condensate of patients with stable COPD. Monaldi Arch Chest Dis 1998; 53: 268–73 Nowak D, Antczak A, Krol M, et al. Increased content of hydrogen peroxide in expired breath of cigarette smokers. Eur Respir J 1996; 9: 652–7 Dekhuijzen PNR, Aben KKH, Dekker I, et al. Increased exhalation of hydrogen peroxide in patients with stable and unstable chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996; 154: 813–6 Kharitonov SA, Barnes PJ. Exhaled markers of pulmonary disease. Am J Respir Crit Care Med 2001; 163: 1693–722 Sugiura H, Ichinose M, Yamagata S, et al. Correlation between change in pulmonary function and suppression of reactive nitrogen species production following steroid treatment in COPD. Thorax 2003; 58: 299–305 Montuschi P, Collins JV, Ciabattoni G, et al. Exhaled 8-isoprostane as an in vivo biomarker of lung oxidative stress in patients with COPD and healthy smokers. Am. J. Respir. Crit. Care Med 2000; 162: 1175–7 Corradi M, Rubinstein I, Andreoli RL, et al. Aldehydes in exhaled breath condensate of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003; 167: 1380–6 Nowak D, Kasielski M, Antczak A, et al. Increased content of thiobarbituric acid reactive substances in hydrogen peroxide in the expired breath condensate of patients with stable chronic obstructive pulmonary disease: no significant effect of cigarette smoking. Respir Med 1999; 93: 389–96 Tsukagoshi H, Shimizu Y, Iwamae S, et al. Evidence of oxidative stress in asthma and COPD: potential inhibitory effect of theophylline. Respir Med 2000; 94: 584–8 Maziak W, Loukides S, Culpitt S, et al. Exhaled nitric oxide in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 157: 998–1002 Corradi M, Majori M, Cacciani GC, et al. Increased exhaled nitric oxide in patients with stable chronic obstructive pulmonary disease. Thorax 1999; 54: 576–680 Delen FM, Sippel JM, Osborne ML, et al. Increased exhaled nitric oxide in chronic bronchitis: comparison with asthma and COPD. Chest 2000; 117: 695–701 Rutgers SR, van der Mark TW, Coers W, et al. Markers of nitric oxide metabolism in sputum and exhaled air are not increased in chronic obstructive pulmonary disease. Thorax 1999; 54: 576–680 Robbins RA, Millatmal T, Lassi K, et al. Smoking cessation is associated with an increase in exhaled nitric oxide. Chest 1997; 112: 313–8 Choi AM, Alam J. Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury. Am J Respir Cell Mol Biol 1996; 15: 9–19 Montuschi P, Kharitonov SA, Barnes PJ. Exhaled carbon monoxide and nitric oxide in COPD. Chest 2001; 120: 496–501 Petruzzelli S, Puntoni R, Mimotti P, et al. Plasma 3-nitrotyrosine in cigarette smokers. Am J Respir Crit Care Med 1997; 156: 1902–7 Van der Vliet A, Smith D, O’Neill CA, et al. Interactions of peroxynitrite and human plasma and its constituents: oxidative damage and antioxidant depletion. Biochem J 1994; 303: 295–301 Eiserich JP, van der Vliet A, Handelman GJ, et al. Dietary antioxidants and cigarette smoke-induced biomolecular damage: a complex interaction. Am J Clin Nutr 1995; 62: 1490S-500S Ichinose M, Sugiura H, Yamagata S, et al. Increase in reactive nitrogen species production in chronic obstructive pulmonary disease airways. Am J Respir Crit Care Med 2000; 162: 701–6 Pignatelli B, Li CG, Boffetta P, et al. Nitrated and oxidized plasma proteins in smokers and lung cancer patients. Cancer Res 2001; 61: 778–84 Kanazawa H, Shiraishi S, Hirata K, et al. Imabalance between levels of nitrogen oxides and peroxynitrite inihibitory activity in chronic obstructive pulmonary disease. Thorax 2003; 58: 106–9 Gutteridge JMC. Lipid peroxidation and antioxidants as biomarkers of tissue damage. Clin Chem 1995; 41: 1819–28 Uchida K, Shiraishi M, Naito Y, et al. Activation of stress signaling pathways by the end product of lipid peroxidation. J Biol Chem 1999; 274: 2234–42 Parola M, Bellomo G, Robino G, et al. 4-Hydroxynonenal as a biological signal: molecular basis and pathophysiological implications. Antioxidant Redox Signal 1999; 1: 255–84 Rahman I, Van Schadewijk AA, Crowther A, et al. 4-Hydroxy-2-nonenal, a specific lipid peroxidation product is elevated in lungs of patients with chronic obstructive pulmonary disease (COPD). Am J Respir Crit Care Med 2002; 166: 490–5 Morrow JD, Roberts LJ. The isoprostanes: unique bioactive products of lipid peroxidation. Prog Lipid Res 1997; 36: 1–21 Morrow JD, Hill KE, Burk RF, et al. A series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalyzed mechanism. Proc Natl Acad Sci U S A 1990; 87: 9383–7 Morrow JD, Roberts LJ. The isoprostanes: their role as an index of oxidant stress status in human pulmonary disease. Am J Respir Crit Care Med 2002; 166 (12 Pt 2): S25–30 Pratico D, Basili S, Vieri M, et al. Chronic obstructive pulmonary disease is associated with an increase in urinary levels of isoprostane F2α-III, an index of oxidant stress. Am J Respir Crit Care Med 1998; 158: 1709–14 Habib MP, Clements NC, Garewal HS. Cigarette smoking and ethane exhalation in humans. Am J Respir Crit Care Med 1995; 151: 1368–72 Euler DE, Dave SJ, Guo H. Effect of cigarette smoking on pentane excretion in alveolar breath. Clin Chem 1996; 42: 303–8 Paredi P, Kharitonov SA, Leak D, et al. Exhaled ethane, a marker of lipid peroxidation, is elevated in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000; 162: 369–673 Morrow JD, Frei B, Longmire AW, et al. Increase in circulating products of lipid peroxidation (F2-isoprostanes) in smokers: smoking as a cause of oxidative damage. N Engl J Med 1995; 332: 1198–203 Reilly M, Delanty N, Lawson JA, et al. Modulation of oxidant stress in vivo in chronic cigarette smokers. Circulation 1996; 94: 19–25 Fahn H, Wang L, Kao S, et al. Smoking-associated mitochondrial DNA mutation and lipid peroxidation in human lung tissue. Am J Respir Cell Mol Biol 1998; 19: 901–9 Britton JR, Pavord ID, Richards KA, et al. Dietary antioxidant vitamin intake and lung function in the general population. Am J Respir Crit Care Med 1995; 151: 1383–7 Rahman I, MacNee W. Oxidant/antioxidant imbalance in smokers and chronic obstructive pulmonary disease. Thorax 1996; 51: 348–50 Petruzzelli S, Hietanen E, Bartsch H, et al. Pulmonary lipid peroxidation in cigarette smokers and lung patients. Chest 1990; 98: 930–5 Bridges AB, Scott NA, Parry GJ, et al. Age, sex, cigarette smoking and indices of free radical activity in healthy humans. Eur J Med 1993; 2: 205–8 Duthie GG, Arthur JR, James WPT. Effects of smoking and vitamin E on blood antioxidant status. Am J Clin Nutr 1991; 53: 1061S–3S Mezzetti A, Lapenna D, Pierdomenico SD, et al. Vitamins E, C and lipid peroxidation in plasma and arterial tissue of smokers and non-smokers. Atherosclerosis 1995; 112: 91–9 van Antwerpen L, Theron AJ, Myer MS, et al. Cigarette smoke-mediated oxidant stress, phagocytes, vitamin C, vitamin E and tissue injury. Ann N Y Acad Sci 1993; 686: 53–65 Pelletier O. Vitamin C status of cigarette smokers and nonsmokers. Am J Clin Nutr 1970; 23: 520–8 Chow CK, Thacker R, Bridges RB, et al. Lower levels of vitamin C and carotenes in plasma of cigarette smokers. J Am Coll Nutr 1986; 5: 305–12 Bridges RB, Chow CK, Rehm SR. Micronutrients and immune functions in smokers. Ann N Y Acad Sci 1990; 587: 218–31 Theron AJ, Richards GA, Rensburg AJ, et al. Investigation of the role of phagocytes and antioxidant nutrients in oxidant stress mediated by cigarette smoke. Int J Vitam Nutr Res 1990; 60: 261–6 Barton GM, Roath OS. Leukocytic ascorbic acid in abnormal leukocyte states. Int J Vitam Nutr Res 1976; 46: 271–4 Pacht ER, Kaseki H, Mohammed JR, et al. Deficiency of vitamin E in the alveolar fluid of cigarette smokers, influence on alveolar macrophage cytotoxicity. J Clin Invest 1988; 77: 789–96 Cross CE, van der Vliet A, O’Neill CA, et al. Oxidants, antioxidants, and respiratory tract lining fluids. Environ Health Perspect 1994; 102 Suppl. 10: 185–91 Cross CE, O’Neill CA, Reznick AZ, et al. Cigarette smoke oxidation of human plasma constitutents. Ann N Y Acad Sci 1993; 686: 72–90 Dietrich M, Block G, Hudes M, et al. Antioxidant supplementation decreases lipid peroxidation biomarker F2-isoprostanes in plasma of smokers. Cancer Epidemiol Biomarkers Prev 2002; 11: 7–13 Zhang J, Jiang S, Watson RR. Antioxidant supplementation prevents oxidation and inflammatory responses induced by sidestream cigarette smoke in old mice. Environ Health Perspect 2001; 109: 1007–9 Smith KR, Uyeminami DL, Kodavanti UP, et al. Inhibition of tobacco smoke-induced lung inflammation by a catalytic antioxidant. Free Radic Biol Med 2002; 15: 1106–14 Cantin AM, North SL, Hubbard RC, et al. Normal alveolar epithelial lung fluid contains high levels of glutathione. J Appl Physiol 1987; 63: 152–7 Rahman I, Li XY, Donaldson K, et al. Glutathione homeostasis in alveolar epithelial cells in vitro and lung in vivo under oxidative stress. Am J Physiol 1995; 269: L285–92 Li XY, Donaldson K, Rahman I, et al. An investigation of the role of glutathione in the increased epithelial permeability induced by cigarette smoke in vivo and in vitro. Am J Respir Crit Care Med 1994; 149: 1518–25 Rahman I, Smith CAD, Lawson M, et al. Induction of gamma-glutamylcysteine synthetase by cigarette smoke condensate is associated with AP-1 in human alveolar epithelial cells. FEBS Lett 1996; 396: 21–5 Li XY, Rahman I, Donaldson K, et al. Mechanisms of cigarette smoke induced increased airspace permeability. Thorax 1996; 51: 465–71 Linden M, Hakansson L, Ohlsson K, et al. Glutathione in bronchoalveolar lavage fluid from smokers is related to humoral markers of inflammatory cell activity. Inflammation 1989; 13: 651–8 Harju T, Kaarteenaho-Wiik R, Soini Y, et al. Diminished immunoreactivity of γ-glutamylcysteine synthetase in the airways of smokers’ lung. Am J Respir Crit Care Med 2002; 166: 754–9 McCusker K, Hoidal J. Selective increase of antioxidant enzyme activity in the alveolar macrophages from cigarette smokers and smoke-exposed hamsters. Am Rev Respir Dis 1990; 141: 678–82 Kondo T, Tagami S, Yoshioka A, et al. Current smoking of elderly men reduces antioxidants in alveolar macrophages. Am J Respir Crit Care Med 1994; 149: 178–82 York GK, Pierce TH, Schwartz LS, et al. Stimulation by cigarette smoke of glutathione peroxidase system enzyme activities in rat lung. Arch Environ Health 1976; 31: 286–90 Toth KM, Berger EM, Buhler CJ, et al. Erythrocytes from cigarette smokers contain more glutathione and catalase and protect endothelial cells from hydrogen peroxide better than do erythrocytes from non-smokers. Am Rev Respir Dis 1986; 134: 281–4 Gadek J, Fells GA, Crystal RG. Cigarette smoking induces functional antiprotease deficiency in the lower respiratory tract of humans. Science 1979; 206: 1315–6 Carp H, Janoff A. Possible mechanisms of emphysema in smokers: in vitro suppression of serum elastase-inhibitory capacity by fresh cigarette smoke and its prevention by anti-oxidants. Am Rev Respir Dis 1978; 118: 617–21 Carp H, Janoff A. Inactivation of bronchial mucous proteinase inhibitor by cigarette smoke and phagocyte-derived oxidants. Exp Lung Res 1980; 1: 225–37 Hubbard RC, Ogushi F, Fells GA, et al. Oxidants spontaneously released by alveolar macrophages of cigarette smokers can inactivate the active site of α-1-antitrypsin rendering it ineffective as an inhibitor of neutrophil elastase. J Clin Invest 1987; 80: 1289–95 Kramps JA, van Twisk C, Dijkman DH. Oxidative inactivation of antileukoprotease is triggered by polymorphonuclear leucocytes. Clin Sci 1988; 75: 53–62 Johnson D, Travis J. The oxidative inactivation of human α1-proteinase inhibitor. Further evidence for methionine at the reactive center. J Biol Chem 1979; 254: 4022–6 Kramps JA, Rudolphus A, Stolk J, et al. Role of antileukoprotease in the lung. Ann N Y Acad Sci 1991; 624: 97–108 Vogelmeier C, Biedermann T, Maier K, et al. Comparative loss of activity of recombinant secretory leukoprotease inhibitor and alpha 1-protease inhibitor caused by different forms of oxidative stress. Eur Respir J 1997; 10: 2114–9 Carp H, Miller F, Hoidal JR, et al. Potential mechanisms of emphysema: α1-proteinase inhibitor recovered from lungs of cigarette smokers contains oxidised methionine and has decreased elastase inhibitory capacity. Proc Natl Acad Sci U S A 1982; 79: 2041–5 Wallaert B, Gressier B, Marquette CH, et al. Inactivation of alpha 1-proteinase inhibitor by alveolar inflammatory cells from smoking patients with or without emphysema. Am Rev Respir Dis 1993; 147: 1537–43 Wallaert B, Certs A, Gressier B, et al. Oxidative inactivation of α-1-proteinase inhibitor by alveolar epithelial type II cells. J Appl Physiol 1993; 75: 2376–82 Stone P, Calore JD, McGowan SE, et al. Functional alpha-1-protease inhibitor in the lower respiratory tract of smokers is not decreased. Science 1983; 221: 1187–9 Boudier C, Pelletier A, Pauli G, et al. The functional activity of alphal-proteinase inhibitor in bronchoalveolar lavage fluids from healthy human smokers and non smokers. Clin Chim Acta 1983; 131: 309–15 Abboud RT, Fera T, Richter A, et al. Acute effect of smoking on the functional activity of alpha-1-protease inhibitor in bronchoalveolar lavage fluid. Am Rev Respir Dis 1985; 131: 1187–9 Gadek JE, Hunninghake GW, Fells GA, et al. Evaluation of the protease-antiprotease theory of human destructive lung disease. Bull Eur Physiopathol Respir 1980; 16 Suppl.: 27–40 Nadel JA. Role of epidermal growth factor receptor activation in regulating mucin synthesis. Respir Res 2001; 2: 85–9 Takeyama K, Jung B, Shim JJ, et al. Activation of epidermal growth factor receptors is responsible for mucin synthesis induced by cigarette smoke. Am J Physiol Lung Cell Mol Physiol 2001; 280: L165–72 Leikauf GD, Borchers MT, Prows DR, et al. Mucin apoprotein expression in COPD. Chest 2002; 121: 166S–82S Adler KB, Holden-Stauffer WJ, Repine JE. Oxygen metabolites stimulate release of high-molecular-weight glycoconjugates by cell and organ cultures of rodent respiratory epithelium via an arachidonic acid-dependent mechanism. J Clin Invest 1990; 85: 75–85 Fischer BM, Voynow JA. Neutrophil elastase induces MUC5AC gene expression in airway epithelium via a pathway involving reactive oxygen species. Am J Respir Cell Mol Biol 2002; 26: 447–52 Tyagi SC. Homocysteine redox receptor and regulation of extracellular matrix components in vascular cells. Am J Physiol 1998; 274: C396–405 Lois M, Brown LA, Moss IM, et al. Ethanol ingestion increases activation of matrix metalloproteinases in rat lungs during acute endotoxemia. Am J Respir Crit Care Med 1999; 160: 1354–60 Fod HD, Rollo EE, Brown P, et al. Attenuation of oxidant-induced lung injury by the synthetic matrix metalloproteinase inhibitor BB-3103. Ann N Y Acad Sci 1999; 878: 650–3 Choi AM, Elbon CL, Bruce SA, et al. Messenger RNA levels of lung extracellular matrix proteins during ozone exposure. Lung 1994; 172: 15–30 Russell REK, Culpitt SV, DeMatos C, et al. Release and activity of matrix metalloproteinase-9 and tissue inhibitor of matalloproteinase-2 by alveolar macrophages from patients with COPD. Am J Respir Cell Mol Biol 2002; 26: 602–9 Rossi AG, Haslett C. Inflammation, cell injury, and apoptosis. In: Said SI, editor. Lung biology in health and disease: proinflammatory and antiinflammatory peptides. New York: Marcel Dekkar Inc, 1998: 9–21 Nakajima Y, Aoshiba K, Yasui S, et al. H2O2 induces apoptosis in bovine tracheal epithelial cells in vitro. Life Sci 1999; 64: 2489–96 Aoshiba K, Tamaoki J, Nagai A. Acute cigarette smoke exposure induces apoptosis of alveolar macrophages. Am J Physiol Lung Cell Mol Physiol 2001; 281: LI392–401 Hoshino Y, Mio T, Nagai S, et al. Cytotoxic effects of cigarette smoke extract on an alveolar type II cell-derived cell line. Am J Physiol Lung Cell Mol Physiol 2001; 281: L509–16 Vayssier M, Banzet N, Francois D, et al. Tobacco smoke induces both apoptosis and necrosis in mammalian cells: differential effects of HSP 70. Am J Physiol 1998; 275: L771–9 Wickenden JA, Clarke MC, Rossi AG, et al. Cigarette smoke prevents apoptosis through inhibition of caspase activation and induces necrosis. Am J Respir Cell Mol Biol 2003; 29: 562–70 Hall AG. Review: the role of glutathione in the regulation of apoptosis. Eur J Clin Invest 1999; 29: 238–45 Kasahara Y, Tuder RM, Cool CD, et al. Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysema. Am J Respir Crit Care Med 2001; 163: 737–44 Wang J, Wilcken DE, Wang XL. Cigarette smoke activates caspase-3 to induce apoptosis of human umbilical venous endothelial cells. Mol Genet Metab 2001; 72: 82–8 Kasahara Y, Tuder RM, Taraseviciene-Stewart L, et al. Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J Clin Invest 2000; 106: 1311–9 Mullick AE, McDonald JM, Melkonian G, et al. Reactive carbonyls from tobacco smoke increase arterial endothelial layer injury. Am J Physiol Heart Circ Physiol 2002; 283: H591–7 Tuder RM, Zhen L, Cho CY, 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 Rabinovich RA, Ardite E, Trooster T, et al. Reduced muscle redox capacity after endurance training in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 164: 1114–8 Engelen MP, Schols AM, Does JD, et al. Altered glutamate metabolism is associated with reduced muscle glutathione levels in patients with emphysema. Am J Respir Crit Care Med 2000; 161: 98–103 Ribera F, N’Guessan B, Zoll J, et al. Mitochondrial electron transport chain function is enhanced in inspiratory muscles of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 167: 873–879, 2003 Heunks LM, Dekhuijzen PN. Respiratory muscle function and free radicals: from cell to COPD. Thorax 2000; 55: 704–16 Sauleda J, Garcia-Palmer FJ, Gonzalez G, et al. The activity of cytochrome oxidase is increased in circulating lymphocytes of patients with chronic obstructive pulmonary disease, asthma, and chronic arthritis. Am J Respir Crit Care Med 2000; 161: 32–5 Agusti AG, Sauleda J, Miralles C, et al. Skeletal muscle apoptosis and weight loss in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002; 166: 485–9 Anderson R, Theron AJ, Richards GA, et al. Passive smoking by humans sensitizes circulating neutrophils. Am Rev Respir Dis 1991; 144: 570–4 Schunemann HJ, Muti P, Freudenheim JL, et al. Oxidative stress and lung function. Am J Epidemiol 1997; 146: 939–48 Sargeant LA, Jaeckel A, Wareham NJ. Interaction of vitamin C with the relation between smoking and obstructive airways disease in EPIC Norfolk. European Prospective Investigation into Cancer and Nutrition. Eur Respir J 2000; 16: 397–403 Britton JR, Pavord ID, Richards KA, et al. Dietary antioxidant vitamin intake and lung function in the general population. Am J Respir Crit Care Med 1995; 151: 1383–7 Grievink L, Smit HA, Ocke MC, et al. Dietary intake of antioxidant (pro)-vitamins, respiratory symptoms and pulmonary function: the MORGEN study. Thorax 1998; 53: 166–71 Shahar E, Folsom AR, Melnick SL, et al. Dietary n-3 polyunsaturated fatty acids and smoking-related chronic obstructive pulmonary disease: atherosclerosis risk in communities study investigators. N Engl J Med 1994; 331: 228–33 Shahar E, Boland LL, Folsom AR, et al. Docosahexaenoic Acid and smoking related chronic obstructive pulmonary disease. Atherosclerosis Risk in Communities Study Investigators. Am J Respir Crit Care Med 1999; 159: 1780–5 Sridhar MK, Galloway A, Lean MEJ, et al. An out-patient nutritional supplementation programme in COPD patients. Eur Respir J 1994; 7: 720–72 Do BK, Garewal HS, Clements Jr NC, et al. Exhaled ethane and antioxidant vitamin supplements in active smokers. Chest 1996; 110: 159–64 Habib MP, Tank LJ, Lane LC, et al. Effect of vitamin E on exhaled ethane in cigarette smokers. Chest 1999; 115: 684–90 Wyatt TA, Heires AJ, Sanderson SD, et al. Protein kinase C activation is required for cigarette smoke-enhanced C5a-mediated release of interleukin-8 in human bronchial epithelial cells. Am J Respir Cell Mol Biol 1999; 21: 283–8 Di Stefano A, Caramore G, Oates T, et al. Increased expression of nuclear factor-kB in bronchial biopsies from smokers and patients with COPD. Eur Respir J 2002; 20: 556–63 Caramori G, Romagnoli M, Casolari P, et al. Nuclear localization of p65 in sputum macrophages but not in sputum neutrophils during COPD exacerbations. Thorax 2003; 58: 348–51 Mochida-Nishimura K, Sureweicz K, Cross JV, et al. Differential activation of MAP kinase signaling pathways and nuclear factor-kappaB in bronchoalveolar cells of smokers and nonsmokers. Mol Med 2001; 7: 177–85 Keatings VM, Collins PD, Scott DM, et al. Differences in interleukin-8 and tumor necrosis factor-alpha in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med 1996; 153: 530–4 Wesselius LJ, Nelson ME, Bailey K, et al. Rapid lung cytokine accumulation and neutrophil recruitment after lipopolysaccharide inhalation by cigarette smokers and nonsmokers. J Lab Clin Med 1997; 129: 106–14 Hellermann GR, Nagy SB, Kong X, et al. Mechanism of cigarette smoke condensate-induced acute inflammatory response in human bronchial epithelial cells. Respir Res 2002; 3: 22–30 Anto RJ, Mukhopadhyay A, Shishodia S, et al. Cigarette smoke condensate activates nuclear transcription factor KB through phosphorylation and degradation of IκBα: correlation with induction of cyclooxygenase-2. Carcinogenesis 2002; 23: 1511–8 Gebel S, Muller T. The activity of NF-kappa B in Swiss 3T3 cells exposed to aqueous extracts of cigarette smoke is dependent on thioredoxin. Toxicol Sci 2001; 59: 75–81 Muller T, Gebel S. The cellular stress response induced by aqueous extracts of cigarette smoke is critically dependent on the intracellular glutathione concentration. Carcinogenesis 1998; 19: 797–801 Sugano N, Shimada K, Ito K, et al. Nicotine inhibits the production of inflammatory mediators in U937 cells through modulation of nuclear factor-kappaB activation. Biochem Biophys Res Commun 1998; 252: 25–8 Ouyang Y, Virasch N, Hao P, et al. Suppression of human IL-1beta, IL-2, IFN-gamma, and TNF-alpha production by cigarette smoke extracts. J Allergy Clin Immunol 2000; 16: 280–7 Vayssier M, Banzet N, Francois D, et al. Tobacco smoke induces both apoptosis and necrosis in mammalian cells: differential effects of HSP 70. Am J Physiol Lung Cell Mol Physiol 1998; 275: L771–9 Keatings VM, Collins PD, Scott DM, et al. Differences in interleukin 8 and tumour necrosis factor∞ in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med 1996; 153: 530–4 Antonicelli F, Parmentier M, Rahman I, et al. Nacystelyn inhibits hydrogen peroxide mediated interleukin-8 expression in human alveolar epithelial cells. Free Radic Biol Med 2002; 32: 492–502 Parmentier M, Hirani N, Rahman I, et al. Regulation of LPS-mediated IL-lβ by N-acetyl-L-cysteine in THP-1 cells. Eur Respir J 2000; 16: 933–9 Martey CA, Pollock SJ, Turner CK, et al. Cigarette smoke induces cyclooxygenase 2 and microsomal prostaglandin E2 synthase in human lung fibroblasts: Implications for lung inflammation and cancer. Am J Physiol Lung Cell Mol Physiol 2004; 287: 981–91 Mio T, Romberger DJ, Thompson AB, et al. Cigarette smoke induces interleukin-8 release from human bronchial epithelial cells. Am J Respir Crit Care Med 1997; 155: 1770–6 Wang H, Ye Y, Zhu M, et al. Increased interleukin-8 expression by cigarette smoke extract in endothelial cells. Environ Toxicol Pharmacol 2000; 9: 19–23 Masubuchi T, Koyama S, Sato E, et al. Smoke extract stimulates lung epithelial cells to release neutrophil and monocyte chemotactic activity. Am J Pathol 1998; 153: 1903–12 Witherden IR, Bon EJV, Goldstraw P, et al. Primary human alveolar type II epithelial cell chemokine release: effects of cigarette smoke and neutrophil elastase. Am J Respir Cell Mol Biol 2004; 30: 500–9 Rusznak C, Mills PR, Devalia JL, et al. Effect of cigarette smoke on the permeability and IL-1beta and sICAM-1 release from cultured human bronchial epithelial cells of never-smokers, smokers, and patients with chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 2000; 23: 530–6 Rahman I, Bel A, Mulier B, et al. Transcriptional regulation of [Unsupported Character]-glutamylcysteine synthetase-heavy subunit by oxidants in human alveolar epithelial cells. Biochem Biophys Res Commun 1996; 229: 832–7 Rahman I, Antonicelli F, MacNee W. Molecular mechanisms of the regulation of glutathione synthesis by tumour necrosis factor-α and dexamethasone in human alveolar epithelial cells. J Biol Chem 1999; 274: 5088–96 Gilks CB, Price K, Wright JL, et al. Antioxidant gene expression in rat lung after exposure to cigarette smoke. Am J Pathol 1998; 152: 269–78 Muller T, Gebel S. The cellular stress response induced by aqueous extracts of cigarette smoke is critically dependent on the intracellular glutathione concentration. Cardiogenesis 1998; 19: 797–801 Muller T. Expression of c-fos in quiescent Swiss 3T3 exposed to aqueous cigarette smoke fractions. Cancer Res 1995; 55: 1927–32 Ishii T, Matsuse T, Igarashi H, et al. Tobacco smoke reduces viability in human lung fibroblasts: protective effect of glutathione S-transferase P1. Am J Physiol Lung Cell Mol Physiol 2001; 280: L1189–95 Maestrelli P, Messlemani AHE, Fina OD, et al. Increased expression of heme oxygenease (HO)-1 in alveolar spaces and HO-2 in alveolar walls of smokers. Am J Respir Crit Care Med 2001; 164: 1508–13 Favatier F, Polla BS. Tobacco-smoke-inducible human haem oxygenase-1 gene expression: role of distinct transcription factors and reactive oxygen intermediates. Biochem J 2001; 353: 475–82 Vayssier M, Favatier F, Pinot F, et al. Tobacco smoke induces coordinate activation of HSF and inhibition of NF-κB in human monocytes: effects on TNFalpha release. Biochem Biophys Res Commun 1998; 252: 249–56 Yoo CG, Lee S, Lee CT, et al. Anti-inflammatory effect of heat shock protein induction is related to stabilization of I kappa B alpha through preventing I kappa B kinase activation in respiratory epithelial cells. J Immunol 2000; 164: 5416–23 Wu C. Chromatin remodeling and the control of gene expression. J Biol Chem 1997; 272: 28171–4 Imhof A, Wolffe AP. Transcription: gene control by targeted histone acetylation. Curr Biol 1998; 8: R422–4 Bannister AJ, Miska EA. Regulation of gene expression by transcription factor acetylation. Cell Mol Life Sci 2000; 57: 1184–92 Tikoo K, Lau SS, Monks TJ. Histone H3 phosphorylation is coupled to poly-(ADP-ribosylation) during reactive oxygen species-induces cell death in renal proximal tubular epithelial cells. Mol Pharmacol 2001; 60: 394–402 Miyata Y, Towatari M, Maeda T, et al. Histone acetylation induces by granulocyte colony-stimulating factor in a MAP kinase-dependent manner. Biochem Biophys Res Commun 2001; 283: 655–60 Bohm L, Schneeweiss FA, Sharan RN, et al. Influence of histone acetylation on the modification of cytoplasmic and nuclear proteins by ADP-ribosylation in response to free radicals. Biochim Biophys Acta 1997; 1334: 149–54 Rahman I, Gilmour P, Jimenez LA, et al. Oxidative stress and TNF-α induce histone acetylation and AP-1/NF-κB in alveolar epithelial cells: potential mechanism in inflammatory gene transcription. Mol Cell Biochem 2002; 234/ 235: 239–48 Berghe WV, Bosscher KD, Boone E, et al. The nuclear factor-κB engages CBP/ p300 and histone acetyltransferase activity for transcriptional activation of the interleukin-6 gene promoter. J Biol Chem 1999; 274: 32091–8 Ito K, Lim G, Caramori G, et al. Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression, and inhibits glucocorticoid actions in alveolar macrophages. FASEB J 2001; 15: 1110–2 Lakshminarayanan V, Drab-Weiss EA, Roebuck KA. H2O2 and TNF induce differential binding of the redox-responsive transcription factor AP-1 and NF-kB to the interleukin-8 promoter in endothelial and epithelial cells. J Biol Chem 1998; 273: 32670–8 Tomita K, Barnes PJ, Adcock IM. The effect of oxidative stress on histone acetylation and IL-8 release. Biochem Biophys Res Commun 2003; 301: 572–7 Adcock IM, Caramori G. Cross-talk between pro-inflammatory transcription factors and glucocorticoids. Immunol Cell Biol 2001; 79: 376–84 Culpitt SV, Rogers DF, Shah P, et al. Impaired inhibition by dexamethasone of cytokine release by alveolar macrophages from COPD patients. Am J Respir Crit Care Med 2002; 167: 24–31 Marwick JA, Giddings J, Buter K, et al. Cigarette smoke induces pro-inflammatory gene transcription in rat lungs. Am J Respir Cell Mol Biol 2004; 31: 633–42 Rahman I, Marwick JA, Kirkham PA. Redox modulation of histone acetylation and deacetylation: impact on NF-κB and pro-inflammatory gene expression. Biochem Pharmacol 2004; 68: 1255–67 Hogg JC. Childhood viral infection and the pathogenesis of asthma and chronic obstructive lung disease. Am J Respir Crit Care Med 1999; 160: S26–8 Retamales I, Elliott WM, Meshi B, et al. Amplication of inflammation emphysema and its association with latent adenoviral infection. Am J Respir Crit Care Med 2001; 164: 469–73 Keicho N, Higashimoto Y, Bondy GP, et al. Endotoxin-specific NF-kappaB activation in pulmonary epithelial cells harboring adenovirus E1A. Am J Physiol 1999; 277: L523–32 Higashimoto Y, Elliott WM, Behzad AR, et al. Inflammatory mediator mRNA expression by adenovirus E1A-transfected bronchial epithelial cells. Am J Respir Crit Care Med 2002; 166: 200–7 Gilmour PS, Rahman I, Donaldson K, et al. Environmental particle-mediated epithelial IL-8 release is regulated by histone acetylation. Am J Physiol Lung Cell Mol Physiol 2003; 284: L533–40 Metcalf JP. Adenovirus E1A 13S gene product upregulates tumor necrosis factor gene. Am J Physiol 1996; 270: L535–40 Silverman EK, Speizer FE. Risk factors for the development of chronic obstructive pulmonary disease. Med Clin North Am 1996; 80: 501–22 Sandford AJ, Weir TD, Pare PD. Genetic risk factors for chronic obstructive pulmonary disease. Eur Respir J 1997; 10: 1380–91 Barnes PJ. Genetics and pulmonary medicine: 9. molecular genetics of chronic obstructive pulmonary disease. Thorax 1999; 54: 245–52 Huang S-L, Su C-H, Chang S-C. Tumour necrosis factor-α gene polymorphism in chronic bronchitis. Am J Respir Crit Care Med 1997; 156: 1436–9 Smith CAD, Harrison DJ. Association between polymorphism in gene for microsomal epoxide hydrolase and susceptibility to emphysema. Lancet 1997; 350: 630–3 Yim JJ, Park GY, Lee CT, et al. Genetic susceptibility to chronic obstructive pulmonary disease in Koreans: combined analysis of polymorphic genotypes for microsomal epoxide hydrolase and glutathione S-transferase M1 and T 1. Thorax 2000; 55: 121–5 He JQ, Juan J, Connett JE, et al. Antioxidant gene polymorohisms and susceptibility to a rapid decline in lung function smokers. Am J Respir Crit Care Med 2002; 166: 323–8 Joos L, He JQ, Shepherdson MB, et al. The role of matrix metalloproteinase polymorphisms in the rate of decline in lung function. Hum Mol Genet 2002; 211: 569–678 Chabrier P-E, Auguet M, Spinnewyn B, et al. BN 80933, a dual inhibitor of neuronal nitric oxide synthase and lipid peroxidation: a promising neuroprotective strategy. Proc Natl Acad Sci U S A 1999; 96: 10824–9 Nishikawa M, Kakemizu N, Ito T, et al. Superoxide mediates cigarette smoke-induced infiltration of neutrophils into the airways through nuclear factor-κB activation and IL-8 mRNA expression in guinea pigs in vivo. Am J Respir Cell Mol Biol 1999; 20: 189–98 Rautalahti M, Virtamo J, Haukka J, et al. The effect of alpha-tocopherol and beta-carotene supplementation on COPD symptoms. Am J Respir Crit Care Med 1997; 156: 1447–52 Allard JP, Royall D, Kurian R, et al. Effects of beta-carotene supplementation on lipid peroxidation in humans. Am J Clin Nutr 1994; 59: 884–90 Aghdassi E, Royall D, Allard JP. Oxidative stress in smokers supplemented with vitamin C. Int J Vitam Nutr Res 1999; 69: 45–51 Steinberg FM, Chait A. Antioxidant vitamin supplementation and lipid peroxidation in smokers. Am J Clin Nutr 1998; 68: 319–27 Gerrits CMGM, Herings RMC, Leufkens HGM, et al. N-acetylcysteine reduces risk of re-hospitalisation among patients with COPD. Eur Respir J 2003; 21: 795–8 Poole PJ, Black PN. Oral mucylytic drugs for exacerbationsof chronic obstructive pulmonary disease: systematic review. BMJ 2001; 322: 1–16 Stey C, Steurer J, Bachmann S, et al. The effect of oral N-acetylcysteine in chronic bronchitis: a quantitative systematic review. Eur Respir J 2000; 16: 253–62 Grandjean EM, Berthet P, Ruffmann R, et al. Efficacy and oral long-term N-acetylcysteine in chronic bronchopulmonary disease: a meta-analysis of published double-blind, placebo-controlled clinical trials. Clin Ther 2000; 22: 209–21 Dekhuijzen PN. Antioxidant properties of N-acetylcysteine: their relevance in relation to chronic obstructive pulmonary disease. Eur Respir J 2004; 23: 629–36 Olsson B, Johansson M, Gabrielson J, et al. Pharmacokinetics of reduced and oxidised N-acetylcysteine. Eur J Clin Pharmacol 1988; 34: 77–82 Bridgeman MME, Marsden M, MacNee W, et al. Cysteine and glutathione concentrations in plasma and bronchoalveolar lavage fluid after treatment with N-acetylcysteine. Thorax 1991; 46: 39–42 Bridgemen MME, Marsden M, Selby C. Effect of N-acetyl cysteine on the concentrations of thiols in plasma bronchoalveolar lavage fluid and lining tissue. Thorax 1994; 49: 670–5 Boman G, Backer U, Larsson S, et al. Oral acetylcysteine reduces exaceration rate in chronic bronchitis. Eur J Respir Dis 1983; 64: 405–15 Rasmusse JB, Glennow C. Reduction in days of illness after long-term treatment with N-acetylcysteine controlled-release tablets in patients with chronic bronchitis. Eur J Respir Dis 1988; 1: 351–5 British Thoracic Society Research Committee. Oral N-acetylcysteine and exacerbation rates in patients with chronic bronchitis and severe airways obstruction. Thorax 1985; 40: 823–35 Dueholm M, Nielsen C, Thorshauge H, et al. N-acetylcysteine by metred dose inhaler in the treatment of chronic bronchitis: a multi-centre study. Respir Med 1992; 86: 98–2 Van Schooten FJ, Nia AB, De Flora S, et al. Effects of oral administration of N-acetyl-L-cysteine: a multi-biomarker study in smokers. Cancer Epidemiol Biomarkers Prev 2002; 11: 167–75 Nagy AM, Vanderbist F, Parij N, et al. Effect of the mucoactive drug Nacystelyn on the respiratory burst of human blood polymorphonuclear neutrophils. Pulm Pharmacol Ther 1997; 10: 287–92 Gillissen A, Jaworska M, Orth M, et al. Nacystelyn a novel lysine salt of N-acetylcysteine to augment cellular antioxidant defence in vitro. Respir Med 1997; 91: 159–68 Antonicelli F, Parmentier M, Drost EM, et al. Regulation of LPS-mediated inflammation in vivo and in vitro by the thiol anti-oxidant Nacystelyn. Am J Physiol Lung Cell Mol Physiol 2004; 286: L1319–27 Ekberg-Jansson A, Larson M, MacNee W, et al. N-isobutyrylcysteine, a donor of systemic thiols, does not reduce the exacerbation rate in chronic bronchitis. Eur Respir J 1999; 13: 829–34 Marrades RM, Roca J, Barbera A, et al. Nebulised glutathione induces bronchoconstriction in patients with mild asthma. Am J Respir Crit Care Med 1997; 156: 425–30 Buhl R, Vogelmeier C, Critenden M, et al. Augmentation of glutathione in the fluid lining the epithelium of the lower respiratory tract by directly administering glutathione aerosol. Proc Natl Acad Sci U S A 1990; 87: 4063–7 Roum JH, Borok Z, McElvaney NG, et al. Glutathione aerosol suppresses lung epithelial surface inflammatory cell-derived oxidants in cystic fibrosis. J Appl Physiol 1999; 87: 438–43 Borok Z, Buhl R, Grimes GJ, et al. Effect of glutathione aerosol on oxidant-antioxidant imbalance in idiopathic pulmonary fibrosis. Lancet 1991; 338: 215–6 Wendel A, Fausel M, Safayhi H, et al. A novel biologically active seleno-organic compound. II. Activity of PZ51 in relation to glutathione peroxidase. Biochem Pharmacol 1984; 33: 3241–5 Haddad el-B, McCluskie K, Birrell MA, et al. Differential effects of ebselen on neutrophil recruitment, chemokine, and inflammatory mediator expression in a rat model of lipopolysaccharide-induced pulmonary inflammation. J Immunol 2002; 169: 974–82 Zhang M, Nomura A, Uchida Y, et al. Ebselen suppresses late airway responses and airway inflammation in guinea pigs. Free Radic Biol Med 2002; 32: 454–64 Biswas SK, McClure D, Jimenez LA, et al. Curcumin induces glutathione biosynthesis and inhibits oxidant- and TNF-α-mediated NF-κB activation and chromatin remodeling in alveolar epithelial cells. Antioxid Redox Signal 2004; 7: 32–41 Culpitt SV, Rogers DF, Fenwick PS, et al. Inhibition by red wine extract, resveratrol, of cytokine release by alveolar macrophages in COPD. Thorax 2003; 58: 942–6 Donnelly LE, Newton R, Kennedy GE, et al. Anti-inflammatory effects of resveratrol in lung epithelial cells: molecular mechanisms. Am J Physiol Lung Cell Mol Physiol 2004 Oct; 287(4): L774–83 Howitz KT, Bitterman KJ, Cohen HY, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003; 425: 191–6