Environmental toxicity, redox signaling and lung inflammation: The role of glutathione

Molecular Aspects of Medicine - Tập 30 Số 1-2 - Trang 60-76 - 2009
Saibal K. Biswas1, Irfan Rahman1
1Department of Environmental Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Box 850, Rochester, NY 14642, USA

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Antonicelli, 2002, Nacystelyn inhibits hydrogen peroxide mediated interleukin-8 expression in human alveolar epithelial cells, Free Rad. Biol. Med., 32, 492, 10.1016/S0891-5849(01)00820-6

Aoki, 1996, Modulation of ICAM-1 expression by extra-cellular glutathione in hyperoxia-exposed human pulmonary artery endothelial cells, Am. J. Resp. Cell Mol. Biol., 15, 319, 10.1165/ajrcmb.15.3.8810635

Arfsten, 2007, Distribution of radio-labeled N-acetyl-l-cysteine in Sprague–Dawley rats and its effect on glutathione metabolism following single and repeat dosing by oral gavage, Cutan. Ocul. Toxicol., 26, 113, 10.1080/15569520701212233

Aruoma, 1989, The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid, Free Radic. Biol. Med., 6, 593, 10.1016/0891-5849(89)90066-X

Asti, 1995, Effectiveness of carbocysteine lysine salt monohydrate on models of airway inflammation and hyperresponsiveness, Pharmacol. Res., 31, 387, 10.1016/1043-6618(95)80094-8

Ault, 2003, Glutathione distribution in normal and oxidatively stressed cells, Exp. Cell Res., 285, 14, 10.1016/S0014-4827(03)00012-0

Azzi, 1998, Molecular basis of α-tocopherol control of smooth muscle cell proliferation, Biofactors, 7, 3, 10.1002/biof.5520070102

Bakin, 2005, Smad3-ATF3 signaling mediates TGF-beta suppression of genes encoding phase II detoxifying proteins, Free Radic. Biol. Med., 38, 375, 10.1016/j.freeradbiomed.2004.10.033

Banhegyi, 2003, Evidence for the transport of glutathione through ryanodine receptor channel type 1, Biochem. J., 376, 807, 10.1042/bj20031419

Banhegyi, 1999, Preferential transport of glutathione versus glutathione disulfide in rat liver microsomal vesicles, J. Biol. Chem., 274, 12213, 10.1074/jbc.274.18.12213

Beck, 2001, Spatial glutathione and cysteine distribution and chemical modulation in the early organogenesis-stage Rat Conceptus in utero, Toxicol. Sci., 62, 92, 10.1093/toxsci/62.1.92

Beeh, 2002, Glutathione deficiency of the lower respiratory tract in patients with idiopathic pulmonary fibrosis, Eur. Respir. J., 19, 1119, 10.1183/09031936.02.00262402

Beeh, 2004, Increased glutathione disulfide and nitrosothiols in sputum of patients with stable COPD, Chest, 126, 1116, 10.1378/chest.126.4.1116

Bindoli, 2008, Thiol chemistry in peroxidase catalysis and redox signaling, Antioxid. Redox Signal., 10, 1549, 10.1089/ars.2008.2063

Biswas, 2005, Curcumin induces glutathione biosynthesis and inhibits NF-kappaB activation and interleukin-8 release in alveolar epithelial cells: mechanism of free radical scavenging activity, Antioxid. Redox Signal., 7, 32, 10.1089/ars.2005.7.32

Borgstrom, 1990, Dose dependent pharmacokinetics of N-acetylcysteine after oral dosing to man, Biopharm. Drug Dispos., 11, 131, 10.1002/bdd.2510110205

Braga, 1982, Pharmacokinetic behaviour of S-carboxymethyl-cysteine-lys in patients with chronic bronchitis, Clin. Ther., 4, 480

Bridgeman, 1994, Effect of N-acetyl cysteine on the concentrations of thiols in plasma bronchoalveolar lavage fluid and lining tissue, Thorax, 49, 670, 10.1136/thx.49.7.670

Bunnell, 1993, Oxidized glutathione is increased in alveolar fluid of patients with ARDS, Am. Rev. Resp. Dis., 148, 1174, 10.1164/ajrccm/148.5.1174

Burgunder, 1989, Effect of N-acetylcysteine on plasma cysteine and glutathione following paracetamol administration, Eur. J. Clin. Pharmacol., 36, 127, 10.1007/BF00609183

Butterworth, 1993, Elevation of cysteine and replenishment of glutathione in rat lung slices by cysteine isopropylester and other cysteine precursors, Biochem. Pharmacol., 45, 1769, 10.1016/0006-2952(93)90432-V

Cantin, 1990, Extracellular glutathione suppresses human lung fibroblast proliferation, Am. J. Respir. Cell Mol. Biol., 3, 79, 10.1165/ajrcmb/3.1.79

Chakravarthi, 2006, The role of glutathione in disulphide bond formation and endoplasmic-reticulum-generated oxidative stress, EMBO Rep., 7, 271, 10.1038/sj.embor.7400645

Chan, 2000, Impaired expression of glutathione synthetic enzyme genes in mice with targeted deletion of the Nrf2 basic-leucine zipper protein, Biochim. Biophys. Acta, 1517, 19, 10.1016/S0167-4781(00)00238-4

Chan, 2001, An important function of Nrf2 in combating oxidative stress: detoxification of acetaminophen, Proc. Natl. Acad. Sci. USA, 98, 4611, 10.1073/pnas.081082098

Chappell, S., Daly, L., Mogan, K., Guetta-Baranes, T., Roca, J., Rabonivich, R., Lotya, J., Millar, A.B., Donnelly, S.C., Keatings, V., MacNee, W., Stolk, J., Hiemstra, P.S., Miniati, M., Monti, S., O’Connor, C.M., Kalsheker, N., 2008. Genetic varients of microsomal epoxide hydrolase and glutamate-cysteine ligase in COPD. Eur. Respir. J., in press, doi:10.1183/09031936.00065308.

Chen, 2000, 1-Cys peroxiredoxin, a bifunctional enzyme with glutathione peroxidase and phospholipase A2 activities, J. Biol. Chem., 275, 28421, 10.1074/jbc.M005073200

Chen, 2003, Nrf1 is critical for redox balance and survival of liver cells during development, Mol. Cell. Biol., 23, 4673, 10.1128/MCB.23.13.4673-4686.2003

Chuang, 2007, N-Acetylcysteine attenuates the acute lung injury caused by phorbol myristate acetate in isolated rat lungs, Pulm. Pharmacol. Ther., 20, 726, 10.1016/j.pupt.2006.08.010

Church, 1985, Free-radical chemistry of cigarette smoke and its toxicological implications, Environ. Health Perspect., 64, 111, 10.2307/3430003

Colombo, 1994, Stimulation of Cl-secretion by the mucoactive drug S-carboxymethylcysteine lysine-salt in the isolated rabbit trachea, Eur. Resp. J., 7, 1622, 10.1183/09031936.94.07091622

Cotgreave, 1997, N-Acetylcysteine: pharmacological considerations and experimental and clinical applications, Adv. Pharmacol., 38, 205, 10.1016/S1054-3589(08)60985-0

Cotgreave, 1987, Gastrointestinal metabolism of N-acetylcysteine in the rat, including an assay for sulfite in biological systems, Biopharm. Drug Dispos., 8, 377, 10.1002/bdd.2510080408

Crouch, 2005, Intravenous administration of N-acetylcysteine, Ann. Emerg. Med., 46, 207, 10.1016/j.annemergmed.2005.02.027

Crystal, 1991, Oxidants and respiratory tract epithelial injury: pathogenesis and strategies for therapeutic intervention, Am. J. Med., 91, 39S, 10.1016/0002-9343(91)90282-3

Das, 2001, C-Jun NH2-terminal kinase-mediated redox dependent degradation of I-κB: role of Trx in NF-κB activation, J. Biol. Chem., 276, 4662, 10.1074/jbc.M006206200

De Benedetto, 2005, Long-term oral N-acetylcysteine reduces exhaled hydrogen peroxide in stable COPD, Pulm. Pharmacol. Ther., 2005, 41, 10.1016/j.pupt.2004.09.030

de Boer, 1998, Transforming growth factor 1 and recruitment of macrophages and mast cells in airways in chronic obstructive pulmonary disease, Am. J. Respir. Crit. Care Med., 158, 1, 10.1164/ajrccm.158.6.9803053

De Caro, 1989, Pharmacokinetics and bioavailability of oral acetylcysteine in healthy volunteers, Arzneimittelforschung, 39, 382

Decramer, 2001, The bronchitis randomized on NAC cost-utility study (BRONCUS): hypothesis and design, BRONCUS-trial Committee. Eur. Respir. J., 17, 329, 10.1183/09031936.01.17303290

Decramer, 2005, Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (bronchitis randomized on NAC cost-utility study, BRONCUS): a randomized placebo-controlled trial, Lancet, 365, 1552, 10.1016/S0140-6736(05)66456-2

Dekhuijzen, 2004, Antioxidant properties of N-acetylcysteine: their relevance in relation to chronic obstructive pulmonary disease, Eur. Respir. J., 23, 629, 10.1183/09031936.04.00016804

Deleve, 1990, Importance of regulation of hepatic glutathione, Semin. Liver Dis., 10, 251, 10.1055/s-2008-1040481

Dickinson, 2003, Curcumin alters EpRE and AP-1 binding complexes and elevates glutamate–cysteine ligase gene expression, FASEB J., 17, 473, 10.1096/fj.02-0566fje

Dinkova-Kostova, 2002, Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants, Proc. Natl. Acad. Sci. USA, 99, 11908, 10.1073/pnas.172398899

Drost, 2005, Oxiative stress and airway inflammation in severe exacerbations of COPD, Thorax, 60, 293, 10.1136/thx.2004.027946

Dueholm, 1992, N-Acetylcysteine by metred dose inhaler in the treatment of chronic bronchitis: a multi-centre study, Respir. Med., 86, 89, 10.1016/S0954-6111(06)80220-9

Ekberg-Jansson, 1999, N-Isobutyrylcysteine, a donor of systemic thiols, does not reduce the exacerbation rate in chronic bronchitis, Eur. Respir. J., 13, 829, 10.1034/j.1399-3003.1999.13d22.x

Erickson, 2002, Identification of a variant antioxidant response element in the promoter of the human glutamate–cysteine ligase modifier subunit gene, J. Biol. Chem., 277, 30730, 10.1074/jbc.M205225200

Forman, 2003, Oxidative signaling and glutathione synthesis, Biofactors, 17, 1, 10.1002/biof.5520170101

Galloway, 1997, Regulation of human γ-glutamylcysteine synthetase: co-ordinate induction of the catalytic and regulatory subunits in HepG2 cells, Biochem. J., 328, 99, 10.1042/bj3280099

Gerrits, 2003, N-Acetylcysteine reduces the risk of re-hospitalization among patients with chronic obstructive pulmonary disease, Eur. Respir. J., 21, 795, 10.1183/09031936.03.00063402

Gillissen, 1997, Nacystelyn a novel lysine salt of N-acetylcysteine, to augment cellular antioxidant defence in vitro, Respir. Med., 91, 159, 10.1016/S0954-6111(97)90052-4

Goven, D., Boutten, A., Lecon-Malas, V., Marchal-Somme, J., Amara, N., Crestani, B., Fournier, M., Leseche, G., Soler, P., Boczkowski, J., Bonay, M., 2008. Altered Nrf2/Keap1-Bach1 equilibrium in pulmonary emphysema. Thorax., in press, doi:10.1136/thx.2007.091181.

Grandjean, 2000, Efficacy and oral long-term N-acetylcysteine in chronic bronchopulmonary disease: a meta-analysis of published double-blind, placebo-controlled clinical trials, Clin. Ther., 22, 209, 10.1016/S0149-2918(00)88479-9

Grigg, 1993, Bronchoalveolar lavage glutathione in intubated premature infants, Arch. Dis. Child., 69, 49, 10.1136/adc.69.1_Spec_No.49

Guidot, 2000, Mitochondrial glutathione replacement restores surfactant synthesis and secretion in alveolar epithelial cells of ethanol-fed rats, Alcohol. Clin. Exp. Res., 24, 1070, 10.1111/j.1530-0277.2000.tb04652.x

Haddad, 2002, Differential effects of ebselen on neutrophil recruitment, chemokine, and inflammatory mediator expression in a rat model of lipopolysaccharide-induced pulmonary inflammation, J. Immunol., 169, 974, 10.4049/jimmunol.169.2.974

Halliwell, 1999

Harju, 2002, Diminished immunoreactivity of gamma-glutamylcysteine synthetase in the airways of smokers’ lung, Am. J. Respir. Crit. Care Med., 166, 754, 10.1164/rccm.2112014

Harper, 2001, Activation of nuclear factor-kB transcriptional activity in airway epithelial cells by thioredoxin but not by N-acetyl-L-cysteine and glutathione, Am. J. Respir Cell Mol. Biol., 25, 178, 10.1165/ajrcmb.25.2.4471

Hayes, 1999, Glutathione and glutathione-dependent enzymes represent a co-ordinately regulated defense against oxidative stress, Free Radic. Res., 31, 273, 10.1080/10715769900300851

He, 2008, Suppression of oxidant-induced glutathione synthesis by erythromycin in human bronchial epithelial cells, Respiration, 75, 202, 10.1159/000111569

Holdiness, 1991, Clinical pharmacokinetics of N-acetylcysteine, Clin. Pharmacokinet., 20, 123, 10.2165/00003088-199120020-00004

Huang, 1993, Catalytic and regulatory properties of the heavy subunit of rat kidney – glutamylcysteine synthetase, J. Biol. Chem., 268, 19675, 10.1016/S0021-9258(19)36569-X

Hwang, 1992, Oxidized redox state of glutathione in the endoplasmic reticulum, Science, 257, 1496, 10.1126/science.1523409

Inci, 2007, N-Acetylcysteine attenuates lung ischemia-reperfusion injury after lung transplantation, Ann. Thorac. Surg., 84, 240, 10.1016/j.athoracsur.2007.03.082

Ishibashi, 2001, Effects of carbocysteine on airway inflammation and related events in SO2-exposed rats, Nihon Kokyuki Gakkai Zasshi, 39, 17

Itoh, 1999, Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain, Genes Dev., 13, 76, 10.1101/gad.13.1.76

Janssen, 1993, Cell and tissue responses to oxidative damage, Lab. Invest., 69, 261

Jardine, 2002, Molecular mechanism of TGF-β1-induced glutathione depletion in alveolar epithelial cells involvement of AP-1/ARE and Fra-1, J. Biol. Chem., 277, 21158, 10.1074/jbc.M112145200

Jessop, 2004, Glutathione directly reduce an oxidoreductase in the endoplasmic reticulum of mammalian cells, J. Biol. Chem., 279, 55341, 10.1074/jbc.M411409200

Jeyapaul, 2000, Nrf2 and c-Jun regulation of antioxidant response element (ARE)-mediated expression and induction of gamma-glutamylcysteine synthetase heavy subunit gene, Biochem. Pharmacol., 59, 1433, 10.1016/S0006-2952(00)00256-2

Kang, 2004, Scaffolding of Keap1 to the actin cytoskeleton controls the function of Nrf2 as key regulator of cytoprotective phase 2 genes, Proc. Natl. Acad. Sci. USA, 101, 2046, 10.1073/pnas.0308347100

Kasielski, 2001, Long-term administration of N-acetylcysteine decreases hydrogen peroxide exhalation in subjects with chronic obstructive pulmonary disease, Respir. Med., 95, 448, 10.1053/rmed.2001.1066

Katayama, 2001, Effects of carbocysteine on antigen-induced increases in cough sensitivity and bronchial responsiveness in guinea pigs, J. Pharmacol. Exp. Ther., 297, 975

Kidd, 1985, The free radical oxidant toxins of polluted air, 69

Kim, 2003, Thioredoxin-dependent redox regulation of the antioxidant responsive element (ARE) in electrophile response, Oncogene, 22, 1860, 10.1038/sj.onc.1206369

Kinnula, 1992, Oxidants and antioxidants in alveolar epithelial type II cells: in situ, freshly isolated, and cultured cells, Am. J. Physiol., 262, L69

Kinnula, 1992, Hydrogen peroxide release from alveolar macrophages and alveolar type II cells during adaptation to hyperoxia in vivo, Exp. Lung Res., 18, 655, 10.3109/01902149209031700

Kinnula, 1995, Generation and disposal of reactive oxygen metabolites in the lung, Lab. Invest., 73, 3

Kinnula, 2007, Thiol proteins, redox modulation and parenchymal lung disease, Curr. Med. Chem., 14, 213, 10.2174/092986707779313345

Kobayashi, 2005, Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation, Antioxid. Redox Signal., 7, 385, 10.1089/ars.2005.7.385

Kode, 2008, Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells, Am. J. Physiol. Lung Cell Mol. Physiol., 294, L478, 10.1152/ajplung.00361.2007

Koike, 2007, Glutathione redox regulates airway hyperresponsiveness and airway inflammation in mice, Am. J. Respir. Cell Mol. Biol., 37, 322, 10.1165/rcmb.2006-0423OC

Komatsu, 2005, Inhibition of endotoxin- and antigen-induced airway inflammation by fudosteine, a mucoactive agent, Pulm. Pharmacol. Ther., 18, 121, 10.1016/j.pupt.2004.11.002

Krzywanski, 2004, Variable regulation of glutamate cysteine ligase subunit proteins affects glutathione biosynthesis in response to oxidative stress, Arch. Biochem. Biophys., 423, 116, 10.1016/j.abb.2003.11.004

Kwong, 1999, The CNC basic leucine zipper factor, Nrf1, is essential for cell survival in response to oxidative stress inducing agents, J. Biol. Chem., 274, 37491, 10.1074/jbc.274.52.37491

Lee, 2008, Adaptive response to GSH depletion and resistance to l-buthionine-(S,R)-sulfoximine: involvement of Nrf2 activation, Mol. Cell. Biochem., 1573

Lee, 2003, Identification of the NF-E2-related factor-2-dependent genes conferring protection against oxidative stress in primary cortical astrocytes using oligonucleotide microarray analysis, J. Biol. Chem., 278, 12029, 10.1074/jbc.M211558200

Lee, 2007, A novel thiol compound, N-acetylcysteine amide, attenuates allergic airway disease by regulating activation of NF-kappaB and hypoxia-inducible factor-1alpha, Exp. Mol. Med., 39, 756, 10.1038/emm.2007.82

Leonard, 2006, Reoxygenation-specific activation of the antioxidant transcription factor Nrf2 mediates cytoprotective gene expression in ischemia-reperfusion injury, FASEB J., 20, 2624, 10.1096/fj.06-5097fje

Liu, 2008, NF-κB/p65 antagonizes Nrf2-ARE pathway by depriving CBP from Nrf2 and facilitating recruitment of HDAC3 to MafK, Biochim. Biophys. Acta., 1783, 713, 10.1016/j.bbamcr.2008.01.002

Liu, 2004, Glutathione regulates transforming growth factor beta stimulated collagen production in fibroblasts, Am. J. Physiol. Lung Cell Mol. Physiol., 286, L121, 10.1152/ajplung.00231.2003

Lomaestro, 1995, Glutathione in health and disease: pharmacotherapeutic issues, Ann. Pharmacother., 29, 1263, 10.1177/106002809502901213

Lowry, 2008, Lung lining fluid glutathione attenuates IL-13 induced asthma, Am. J. Respir. Cell Mol. Biol., 38, 509, 10.1165/rcmb.2007-0128OC

Lu, 1999, Regulation of hepatic glutathione synthesis: current concepts and controversies, FASEB J., 13, 1169, 10.1096/fasebj.13.10.1169

Luppi, 2005, Effects of cigarette smoke condensate on proliferation and wound closure of bronchial epithelial cells in vitro: role of glutathione, Resp. Res., 6, 140, 10.1186/1465-9921-6-140

Malhotra, D., Thimmulappa, R., Navas-Acien, A., Sandford, A., Elliott, M., Singh, A., Chen, L., Zhuang, X., Hogg, J., Pare, P., Tuder, R.M., Biswal, S., 2008. Decline in Nrf2 regulated antioxidants in COPD lungs due toloss of its positive regulator DJ-1. Am. J. Respir. Crit. Care Med., in press, doi:10.1164/recm.200803-380OC.

Mattes, 2006, Tissue and species distribution of the glutathione pathway transcriptome, Xenobiotica, 36, 1081, 10.1080/00498250600861793

McKone, 2006, Variants in the glutamate–cysteine-ligase gene are associated with cystic fibrosis lung disease, Am. J. Respir. Crit. Care Med., 174, 415, 10.1164/rccm.200508-1281OC

Meister, 1983, Glutathione, Ann. Rev. Biochem., 52, 711, 10.1146/annurev.bi.52.070183.003431

Meyer, 1993, Hydrogen peroxide and antioxidants have opposite effects on activation of NF-kB and AP-1 in intact cells: AP-1 as secondary antioxidant-responsive factor, EMBO J., 12, 2005, 10.1002/j.1460-2075.1993.tb05850.x

Miao, 2005, Transcriptional regulation of NF-E2 p45-related factor (NRF2) expression by the aryl hydrocarbon receptor-xenobiotic response element signaling pathway: direct cross-talk between phase I and II drug-metabolizing enzymes, J. Biol. Chem., 280, 20340, 10.1074/jbc.M412081200

Monova, 1998, An electrophile response element (EpRE) regulates –naphthoflavone induction of the human -glutamylcysteine synthetase regulatory subunit gene: Constitutive expression is mediated by an adjacent AP-1 site, J. Biol. Chem., 273, 14683, 10.1074/jbc.273.24.14683

Moran, 2002, Differential induction of mafF, mafG and mafK expression by electrophile-response-element activators, Biochem J., 361, 371, 10.1042/0264-6021:3610371

Moretti, 2004, The effect of longterm treatment with erdosteine on chronic obstructive pulmonary disease: the EQUALIFE study, Drugs Exp. Clin. Res., 30, 143

Moretti, 2007, An overview of drdosterine antioxidant activity in experimental research, Pharmacol. Res., 55, 249, 10.1016/j.phrs.2006.12.006

Mulcahy, 1997, Constitutive and β-napthoflavonone-induced expression of the human γ-glutamylcysteine synthetase heavy subunit gene is regulated by a distal antioxidant response element/TRE sequence, J. Biol. Chem., 272, 7445, 10.1074/jbc.272.11.7445

Nakayama, 1989, Quantitative analysis of the hydrogen peroxide formed in aqueous cigarette tar extracts, Free Radic. Biol. Med., 7, 9, 10.1016/0891-5849(89)90094-4

Pacht, 1991, Deficiency of alveolar fluid glutathione of patients with sepsis and ARDS, Chest, 100, 1397, 10.1378/chest.100.5.1397

Paget, 1998, ΣR, an RNA polymerase sigma factor that modulates expression of the thioredoxin system in response to oxidative stress in Streptomyces coelicolor A3(2), EMBO J., 17, 5776, 10.1093/emboj/17.19.5776

Park, 1998, Oxidative damage in tissues of rats exposed to cigarette smoke, Free Radic. Biol. Med., 25, 79, 10.1016/S0891-5849(98)00041-0

Parmentier, 2000, Regulation of LPS-mediated IL-1beta release by N-acetyl-l-cysteine in THP-1 cells, Eur. Respir. J., 16, 933, 10.1183/09031936.00.16593300

Peltoniemi, 2006, Modulation of glutaredoxin in the lung and sputum of cigarette smokers and chronic obstructive pulmonary disease, Respir. Res., 7, 133, 10.1186/1465-9921-7-133

Pietarinen-Runtti, 1998, Antioxidant enzyme regulation and resistance to oxidants of human bronchial epithelial cells cultured under hypoxic conditions, Am. Respir. Cell Mol. Biol., 19, 286, 10.1165/ajrcmb.19.2.2836

Pinkus, 1996, Role of oxidants and antioxidants in the induction of AP-1, NF-κB and glutathione S-transferase gene expression, J. Biol. Chem., 271, 13422, 10.1074/jbc.271.23.13422

Poole, 2001, Oral mucolytic drugs for exacerbations of chronic obstructive pulmonary disease: systematic review, BMJ, 322, 1271, 10.1136/bmj.322.7297.1271

Poole, 2003, Preventing exacerbations of chronic bronchitis and COPD: therapeutic potential of mucolytic agents, Am. J. Respir. Med., 2, 367, 10.1007/BF03256664

Rahman, 2005, The role of oxidative stress in the pathogenesis of COPD: implications for therapy, Treat. Respir. Med., 4, 175, 10.2165/00151829-200504030-00003

Rahman, 1996, Transcriptional regulation of γ-glutamylcysteine synthetase-heavy subunit by oxidants in human alveolar epithelial cells, Biochem. Biophys. Res. Commun., 229, 832, 10.1006/bbrc.1996.1888

Rahman, 2006, Assay for quantitative determination of glutathione and glutathione disulfide levels using enzymatic recycling method, Nat. Protoc., 1, 3159, 10.1038/nprot.2006.378

Rahman, 1996, Role of oxidants/antioxidants in smoking-induced lung diseases, Free Radic. Biol. Med., 21, 669, 10.1016/0891-5849(96)00155-4

Rahman, 2000, Regulation of redox glutathione levels and gene transcription in lung inflammation: therapeutic approaches, Free Radic. Biol. Med., 28, 1405, 10.1016/S0891-5849(00)00215-X

Rahman, 2000, Oxidative stress and regulation of glutathione in lung inflammation, Eur. Respir. J., 16, 534, 10.1034/j.1399-3003.2000.016003534.x

Rahman, 2001, Oxidant-mediated lung epithelial cell tolerance. the role of intracellular glutathione and nuclear factor-κB, Biochem. Pharmacol., 62, 787, 10.1016/S0006-2952(01)00702-X

Rahman, 1999, Systemic and pulmonary oxidative stress in idiopathic pulmonary fibrosis, Free. Radic. Biol. Med., 27, 60, 10.1016/S0891-5849(99)00035-0

Rasmusse, 1988, Reduction in days of illness after long-term treatment with N-acetylcysteine controlled-release tablets in patients with chronic bronchitis, Eur. J. Respir. Dis., 1, 351, 10.1183/09031936.93.01040351

Reddy, 2007, Deficiency in Nrf2-GSH signaling impairs type II cell growth and enhances sensitivity to oxidants, Am. J. Respir. Cell Mol. Biol., 37, 3, 10.1165/rcmb.2007-0004RC

Reynaert, 2007, Modulation of glutaredoxin-1 expression in a mouse model of allergic airway disease, Am. J. Respir. Cell Mol. Biol., 36, 147, 10.1165/rcmb.2006-0259RC

Rhee, C.K., Kang, C.M., You, M.B., Yoon, H.K., Kim, Y.K., Kim, K.H., Moon, H.S., Park, S.H., Song, J.S., 2008. Effect of fudosteine on mucin production. Eur. Respir. J., in press, doi:10.1183/09031936.00018508.

Rhee, 1999, A family of novel peroxidases, peroxiredoxins, Biofactors, 10, 207, 10.1002/biof.5520100218

Roum, 1993, Systemic deficiency of glutathione in cystic fibrosis, J. Appl. Physiol., 75, 2419, 10.1152/jappl.1993.75.6.2419

Rutkowski, 2007, Reactive oxygen and nitrogen species in inflammatory process, Pol. Merkur. Lekarski., 23, 131

Sadowska, 2007, Antioxidant and anti-inflammatory efficacy of NAC in the treatment of COPD: discordant in vitro and in vivo dose-effects: a review, Pulm. Pharmac. Ther., 20, 9, 10.1016/j.pupt.2005.12.007

Shi, 1994, Quinone-induced oxidative stress elevates glutathione and induces γ-glutamylcysteine synthetase activity in rat lung epithelial L2 cells, J. Biol. Chem., 269, 26512, 10.1016/S0021-9258(18)47224-9

Shin, 2007, NRF2 modulates aryl hydrocarbon receptor signaling: influence on adipogenesis, Mol. Cell. Biol., 27, 7188, 10.1128/MCB.00915-07

Siedlinski, 2008, Lung function loss, smoking, vitamin C intake, and polymorphisms of the glutamate–cysteine ligase genes, Am. J. Respir. Crit. Care Med., 178, 13, 10.1164/rccm.200711-1749OC

Singh, 2006, Glutathione peroxidase 2, the major cigarette smoke-inducible isoform of GPX in lungs, is regulated by Nrf2, Am. J. Respir. Cell Mol. Biol., 35, 639, 10.1165/rcmb.2005-0325OC

2007, Am. J. Respir. Cell Mol. Biol., 36, 642, 10.1165/ajrcmb.36.5.642

Smith, 1993, Increased levels of glutathione in bronchoalveolar lavage from patients with asthma, Am. Rev. Resp. Dis., 147, 1461, 10.1164/ajrccm/147.6_Pt_1.1461

Stey, 2000, The effect of oral N-acetylcysteine in chronic bronchitis: a quantitative systematic review, Eur. Respir. J., 16, 253, 10.1034/j.1399-3003.2000.16b12.x

Suter, 1994, NAC enhances recovery from acute lung injury in man, Chest, 105, 190, 10.1378/chest.105.1.190

Suzuki, M., Betsuyaku, T., Ito, Y., Nagai, K., Nasuhara, Y., Kaga, K., Kondo, S., Nishimura, M., 2008. Downregulated NF-E2-related Factor 2 in pulmonary macrophages of aged smokers and COPD patients. Am. J. Respir. Cell Mol. Biol., in press, doi:10.1165/rcmb.2007-0424OC.

Tanaka, 1998, Glutathione homeostasis in human hepatic cells: overexpression of γ-glutamylcysteine synthetase gene in cell lines resistant to buthionine sulfoximine: an inhibitor of glutathione synthesis, Biochem. Biophys. Res. Commun., 246, 398, 10.1006/bbrc.1998.8631

Tian, 1997, Increased transcription of the regulatory subunit of γ-glutamylcysteine synthetase in rat lung epithelial L2 cells exposed to oxidative stress or glutathione depletion, Arch. Biochem. Biophys., 342, 126, 10.1006/abbi.1997.9997

Tirouvanziam, 2006, High-dose oral N-acetylcysteine, a glutathione prodrug, modulates inflammation in cystic fibrosis, Proc. Natl. Acad. Sci. USA, 103, 4628, 10.1073/pnas.0511304103

Tomonari, 1997, Identification of cis-acting DNA elements of the human γ-glutamylcysteine synthetase heavy subunit gene, Biochem. Biophys. Res. Commun., 232, 522, 10.1006/bbrc.1997.6319

Trachootham, 2008, Redox regulation of cell survival, Antioxid. Redox Sign., 10, 1343, 10.1089/ars.2007.1957

Tsikas, 1998, Analysis of cysteine and N-acetylcysteine in human plasma by high-performance liquid chromatography at the basal state and after oral administration of N-acetylcysteine, J. Chromatogr. B. Biomed. Sci. Appl., 708, 55, 10.1016/S0378-4347(97)00670-1

Tu, 1998, Up-regulation of glutamate–cysteine ligase gene expression by butylated hyoxytoluene is mediated by transcription factor AP-1, Biochem. Biophys. Res. Commun., 244, 801, 10.1006/bbrc.1998.8345

Usatyuk, 2006, Redox regulation of 4-hydroxy-2-nonenal-mediated endothelial barrier dysfunction by focal adhesion, adherens, and tight junction proteins, J. Biol. Chem., 281, 35554, 10.1074/jbc.M607305200

Valko, 2007, Free radicals and antioxidants in normal physiological functions and human disease, Int. J. Biochem. Cell Biol., 39, 44, 10.1016/j.biocel.2006.07.001

van der Toorn, 2007, Cigarette smoke irreversibly modifies glutathione in airway epithelial cells, Am. J. Physiol. Lung Cell Mol. Physiol., 293, L1156, 10.1152/ajplung.00081.2007

Van Schooten, 2002, Effects of oral administration of N-acetyl-l-cysteine: a multibiomarker study in smokers, Cancer Epidemiol. Biomarkers Prev., 11, 167

Wakabayashi, 2004, Protection against electrophile and oxidant stress by induction of the phase 2 response: fate of cysteines of the Keap1 sensor modified by inducers, Proc. Natl. Acad. Sci. USA, 101, 2040, 10.1073/pnas.0307301101

Wang, 2006, Transgenic mice overexpressing peroxiredoxin 6 show increased resistance to lung injury in hyperoxia, Am. J. Respir. Cell Mol. Biol., 34, 481, 10.1165/rcmb.2005-0333OC

White, 1992, Reduction of glutathione is associated with growth restriction and enlargement of bovine pulmonary artery endothelial cells produced by transforming growth factor-β1, Am. J. Respir. Cell Mol. Biol., 6, 364, 10.1165/ajrcmb/6.4.364

Wild, 1999, Regulation of γ-glutamylcysteine synthetase subunit gene expression by the transcription factor Nrf2, J. Biol. Chem., 274, 33627, 10.1074/jbc.274.47.33627

Wood, 2003, Peroxiredoxin evolution and the regulation of hydrogen peroxide signaling, Science, 300, 650, 10.1126/science.1080405

Wood, 2003, Structure, mechanism and regulation of peroxiredoxins, Trends Biochem. Sci., 28, 32, 10.1016/S0968-0004(02)00003-8

Yang, 2005, Nrf1 and Nrf2 regulate rat glutamate-cysteine ligase catalytic subunit transcription indirectly via NF-kappaB and AP-1, Mol. Cell Biol., 25, 5933, 10.1128/MCB.25.14.5933-5946.2005

Yang, 2001, Cloning and characterization of the 5′-flanking region of the rat glutamate–cysteine ligase catalytic subunit, Biochem. J., 357, 447, 10.1042/0264-6021:3570447

Yang, 2002, Role of AP-1 in the coordinate induction of rat glutamate–cysteine ligase and glutathione synthetase by tert-butylhydroquinone, J. Biol. Chem., 277, 35232, 10.1074/jbc.M203812200

Yeh, 2007, Chronic alcoholism alters systemic and pulmonary glutathione redox status, Am. J. Respir. Crit. Care Med., 176, 270, 10.1164/rccm.200611-1722OC

Zhang, 2003, Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress, Mol. Cell Biol., 23, 8137, 10.1128/MCB.23.22.8137-8151.2003

Zhang, 2002, Ebselen suppresses late airway responses and airway inflammation in guinea pigs, Free Radic. Biol. Med., 32, 454, 10.1016/S0891-5849(01)00825-5

Zheng, J.P., Kang, J., Huang, S.G., Chen, P., Yao, W.Z., Yang, L., Bai, C.X., Wang, C.Z., Wang, C., Chen, B.Y., Shi, Y., Liu, C.T., Chen, P., Li, Q., Wang, Z.S., Huang, Y.J., Lui, Z.Y., Chen, F.P., Yuan, J.Z., Yuan, B.T., Qian, H.P., Zhi, R.C., Zhong, N.S., 2008. Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE Study): a randomized placebo-controlled study. Lancet 371, 2013–2018.