International Journal of Scientific & Technology Research

IJSTR@Facebook IJSTR@Twitter IJSTR@Linkedin
Home About Us Scope Editorial Board Blog/Latest News Contact Us

IJSTR >> Volume 7 - Issue 11, November 2018 Edition

International Journal of Scientific & Technology Research  
International Journal of Scientific & Technology Research

Website: http://www.ijstr.org

ISSN 2277-8616

Clinical Trials Of Glutathione Intended To Prevent The Outcomes Of Cystic Fibrosis And The Emerging Role Of GSH Precursors In Health Care And Therapeutics

[Full Text]



Amna Batool, Mahira Arooj



Cystic Fibrosis, clinical trials, Glutathione, Gemma-glutamylcysteine, N-Acetylcysteine



Current treatments aimed at controlling and alleviating the fatal symptoms of cystic fibrosis (CF) have directed their attention to draw valid inferences, by employing different strategies and agents for the absolute prevention of disease. Variety of CF clinical studies exploits the master antioxidant known as glutathione (GSH) and its precursors to improve the health status of CF patients and to develop the ultimate role of therapeutics. The practical usage of GSH in various clinical trials is assessed by its ability to improve numerous clinical endpoints and surrogate markers of CF, which are yet to be determined. More recently a precursor of GSH known as Gemma-glutamylcysteine (GGC) is gaining larger acceptance, ascertained by its efficacious role in ameliorating the health status of various patients. This review has two main focuses: to identify different clinical trials elucidating the role of GSH in the etiology of CF. Secondly to unravel the beneficial effects of N-Acetylcysteine (NAC) and GGC to discern novel clinical interventions and therapies to annihilate the disastrous effects of CF successfully.



[1] V. Saint-Criq, M.A. Gray, Role of CFTR in epithelial physiology. Cellular and Molecular Life Sciences, 74(1), 93-115, 2016, doi:10.1007/s00018-016-2391-y

[2] R.K. Rowntree, A. Harris, The Phenotypic Consequences of CFTR Mutations. Annals of Human Genetics, 67(5), 471-485, 2003, doi:10.1046/j.1469-1809.2003.00028.x

[3] A.M. Cantin, T.B. White, C.E. Cross, H.J. Forman, R.J. Sokol, D. Borowitz, Antioxidants in cystic fibrosis☆Conclusions from the CF Antioxidant Workshop, Bethesda, Maryland, November 11-12, 2003. Free Radical Biology and Medicine, 42(1), 15-31, 2007, doi:10.1016/j.freeradbiomed.2006.09.022

[4] J.H. Roum, R. Buhl, N.G. McElvaney, Z. Borok, R.G. Crystal, Systemic deficiency of glutathione in cystic fibrosis. Journal of Applied Physiology, 75(6), 1993, 2419–2424.

[5] A. Hector, M. Griese, D. Hartl, Oxidative stress in cystic fibrosis lung disease: an early event, but worth targeting? European Respiratory Journal, 44(1), 17-19, 2014, doi:10.1183/09031936.00038114

[6] I. Lee, C. Yang, Role of NADPH oxidase/ROS in pro-inflammatory mediators-induced airway and pulmonary diseases. Biochemical Pharmacology, 84(5), 581-590, 2012, doi:10.1016/j.bcp.2012.05.005

[7] M. Kleme, E. Levy, Cystic Fibrosis-Related Oxidative Stress and Intestinal Lipid Disorders. Antioxidants & Redox Signaling, 22(7), 614-631, 2015, doi:10.1089/ars.2014.6012

[8] J.D. Malhotra, R.J. Kaufman, Endoplasmic Reticulum Stress and Oxidative Stress: A Vicious Cycle or a Double-Edged Sword? Antioxidants & Redox Signaling, 9(12), 2277-2294, 2007, doi:10.1089/ars.2007.1782

[9] F. Antigny, C. Norez, F. Becq, C. Vandebrouck, Calcium homeostasis is abnormal in cystic fibrosis airway epithelial cells but is normalized after rescue of F508del-CFTR. Cell Calcium, 43(2), 175-183, 2008, doi:10.1016/j.ceca.2007.05.002

[10] E. Lai, T. Teodoro, A. Volchuk, Endoplasmic Reticulum Stress: Signaling the Unfolded Protein Response. Physiology, 22(3), 193-201, 2007, doi:10.1152/physiol.00050.2006

[11] A.J. Kettle, T. Chan, I. Osberg, R. Senthilmohan, A.L. Chapman, T.J. Mocatta, J.S. Wagener, Myeloperoxidase and Protein Oxidation in the Airways of Young Children with Cystic Fibrosis. American Journal of Respiratory and Critical Care Medicine, 170(12), 1317-1323, 2004, doi:10.1164/rccm.200311-1516oc

[12] E. Thomson, S. Brennan, R. Senthilmohan, C.L. Gangell, A.L. Chapman, P.D. Sly, A.J. Kettle, E. Williamson, Identifying peroxidases and their oxidants in the early pathology of cystic fibrosis. Free Radical Biology and Medicine, 49(9):1354-60, 2010, doi:10.1016/j.freeradbiomed.2010.07.010

[13] C.C. Winterbourn, A.J. Kettle, Redox Reactions and Microbial Killing in the Neutrophil Phagosome. Antioxidants & Redox Signaling, 18(6), 642-660, 2013, doi:10.1089/ars.2012.4827

[14] D. Harwood, A. Kettle, C. Winterbourn, Production of glutathione sulfonamide and dehydroglutathione from GSH by myeloperoxidase-derived oxidants and detection using a novel LC–MS/MS method. Biochemical Journal, 399(1), 161-168, 2006, doi:10.1042/bj20060978

[15] A.J. Kettle, R. Turner, C.L. Gangell, D.T. Harwood, I.S. Khalilova, A.L. Chapman, P.D. Sly, Oxidation contributes to low glutathione in the airways of children with cystic fibrosis. European Respiratory Journal, 44, 122-129, 2014, doi:10.1183/09031936.00170213

[16] M.J. Davies, The oxidative environment and protein damage. Biochimica et Biophysica Acta - Proteins and Proteomics, 1703(2), 93-109, 2005, doi:10.1016/j.bbapap.2004.08.007

[17] B. Arif, J.M. Ashraf, J. Ahmad, Z. Arif, K. Alam, Structural and immunological characterization of Amadori-rich human serum albumin: Role in diabetes mellitus. Archives of Biochemistry and Biophysics, 522(1), 17-25, 2012, doi:10.1016/j.abb.2012.04.005

[18] I., Sadowska-Bartosz, S., Galiniak, G., Bartosz, M. Rachel, Oxidative Modification of Proteins in Pediatric Cystic Fibrosis with Bacterial Infections. Oxidative Medicine and Cellular Longevity, 2014, 1-10, 2014, doi:10.1155/2014/389629

[19] N. Marczin, M. Yacoub, Disease markers in exhaled breath: basic mechanisms and clinical applications. Amsterdam: IOS Press, 2002.

[20] Y.M. Go, D.P. Jones, Intracellular Proatherogenic Events and Cell Adhesion Modulated by Extracellular Thiol/Disulfide Redox State. Circulation, 111(22), 2973-2980, 2005, doi:10.1161/circulationaha.104.515155

[21] A. Ramirez, B. Ramadan, J.D. Ritzenthaler, H.N. Rivera, D.P. Jones, J. Roman, Extracellular cysteine/cystine redox potential controls lung fibroblast proliferation and matrix expression through upregulation of transforming growth factor-beta. American Journal of Physiology-Lung Cellular and Molecular Physiology, 293(4), L972–L981, 2007, doi: 10.1152/ajplung.00010.2007

[22] N. Breusing, T. Grune, L. Andrisic, M. Atalay, G. Bartosz, F. Biasi, C.M. Spickett, An inter-laboratory validation of methods of lipid peroxidation measurement in UVA-treated human plasma samples. Free Radical Research, 44(10), 1203-1215, 2010, doi:10.3109/10715762.2010.499907

[23] A. Negre-Salvayre, N. Auge, V. Ayala, H. Basaga, J. Boada, R. Brenke, N. Zarkovic, Pathological aspects of lipid peroxidation. Free Radical Research, 44(10), 1125-1171, 2010, doi:10.3109/10715762.2010.498478

[24] L.G. Wood, D.A. Fitzgerald, P.G. Gibson, D.M. Cooper, C.E. Collins, M.L. Garg, Oxidative Stress in Cystic Fibrosis: Dietary and Metabolic Factors. Journal of the American College of Nutrition, 20(2), 157-165, 2001, doi:10.1080/07315724.2001.10719028

[25] P. Montuschi, M. Corradi, G. Ciabattoni, J. Nightingale, S. Kharitonov, P. Barnes, Increased 8-Isoprostane, a Marker of Oxidative Stress, in Exhaled Condensate of Asthma Patients. American Journal of Respiratory and Critical Care Medicine, 160(1), 216-220, 1999, doi:10.1164/ajrccm.160.1.9809140

[26] E.I. Back, C. Frindt, D. Nohr, J. Frank, R. Ziebach, M. Stern, M. Ranke, H.K. Biesalski, Antioxidant deficiency in cystic fibrosis: when is the right time to take action?. The American Journal of Clinical Nutrition, 80(2), 374-384, 2004.

[27] A. Lezo, F. Biasi, P. Massarenti, R. Calabrese, G. Poli, B. Santini, E. Bignamini, Oxidative stress in stable cystic fibrosis patients: Do we need higher antioxidant plasma levels? Journal of Cystic Fibrosis, 12(1), 35-41, 2013, doi:10.1016/j.jcf.2012.06.002

[28] D.G. Jiménez, J.D. Martín, R.A. Llorente, C.B. García, Oxidative Stress in Cystic Fibrosis. Cystic Fibrosis in the Light of New Research, 2015, doi:10.5772/60661

[29] P. Schönfeld, L. Wojtczak, Fatty acids as modulators of the cellular production of reactive oxygen species. Free Radical Biology and Medicine, 45(3), 231-241, 2008, doi:10.1016/j.freeradbiomed.2008.04.029

[30] N. Louhelainen, M. Myllärniemi, I. Rahman V.L. Kinnula, Airway biomarkers of the oxidant burden in asthma and chronic obstructive pulmonary disease: current and future perspectives. International Journal of Chronic Obstructive Pulmonary Disease, 3(4), 585–603, 2008.

[31] P.J. Barnes, B. Chowdhury, S.A. Kharitonov, H. Magnussen, C.P. Page, D. Postma, M. Saetta, Pulmonary Biomarkers in Chronic Obstructive Pulmonary Disease. American Journal of Respiratory and Critical Care Medicine, 174(1), 6-14, 2006, doi:10.1164/rccm.200510-1659pp

[32] A. Koutsokera, K. Kostikas, L.P. Nicod, J. Fitting, Pulmonary biomarkers in COPD exacerbations: a systematic review. Respiratory Research, 14(1), 111, 2013, doi:10.1186/1465-9921-14-111

[33] B. Antus, Oxidative Stress Markers in Sputum. Oxidative Medicine and Cellular Longevity, 2016, 1-12., 2016, doi:10.1155/2016/2930434

[34] C.M. Grant, Role of the glutathione/glutaredoxin and thioredoxin systems in yeast growth and response to stress conditions. Molecular Microbiology, 39(3), 533-541, 2001, doi:10.1046/j.1365-2958.2001.02283.x

[35] C. Jacob, I. Knight, P.G. Winyard, Aspects of the biological redox chemistry of cysteine: from simple redox responses to sophisticated signalling pathways. Biological Chemistry, 387(10-11), 1385-1397, 2006, doi:10.1515/bc.2006.174

[36] Y. Morel, R. Barouki, Influence du stress oxydant sur la régulation des gènes. Médecine sciences, 14(6-7), 713-721, 1998, doi:10.4267/10608/1126

[37] S. Biswas, A.S. Chida, I. Rahman, Redox modifications of protein–thiols: Emerging roles in cell signaling. Biochemical Pharmacology, 71(5), 551-564, 2006, doi:10.1016/j.bcp.2005.10.044

[38] R. Masella, R.D. Benedetto, R. Varì, C. Filesi, C. Giovannini, Novel mechanisms of natural antioxidant compounds in biological systems: involvement of glutathione and glutathione-related enzymes. The Journal of Nutritional Biochemistry, 16(10), 577-586, 2005, doi:10.1016/j.jnutbio.2005.05.013

[39] A. Pastore, G. Federici, E. Bertini, F. Piemonte, Analysis of glutathione: implication in redox and detoxification. Clinica Chimica Acta, 333(1), 19-39, 2003, doi:10.1016/s0009-8981(03)00200-6

[40] Y. Nzengue, Comparaison des Mécanismes de Toxicité Redox du Cadmium, du Cuivre et du Zinc: Place des Métallothionéines et de p53. Grenoble, France: Joseph Fournier, 299, 2008.

[41] J.D. Peterson, L.A. Herzenberg, K. Vasquez, C. Waltenbaugh, Glutathione levels in antigen-presenting cells modulate Th1 versus Th2 response patterns. Proceedings of the National Academy of Sciences, 95(6), 3071-3076, 1998, doi:10.1073/pnas.95.6.3071

[42] L.A. Boxer, J.M. Oliver, S.P. Spielberg, J.M. Allen, J.D. Schulman, Protection of Granulocytes by Vitamin E in Glutathione Synthetase Deficiency. New England Journal of Medicine, 301(17), 901-905, 1979, doi:10.1056/nejm197910253011702

[43] L.J. Galietta, C. Folli, C. Marchetti, L. Romano, D. Carpani, M. Conese, O. Zegarra-Moran, Modification of transepithelial ion transport in human cultured bronchial epithelial cells by interferon-gamma. American Journal of Physiology, 278, L1186–L1194, 2000.

[44] T.J. Kelley, M.L. Drumm, Inducible nitric oxide synthase expression is reduced in cystic fibrosis murine and human airway epithelial cells. Journal of Clinical Investigation, 102(6), 1200-1207, 1998, doi:10.1172/jci2357

[45] I. Rahman, W. Macnee, Regulation of redox glutathione levels and gene transcription in lung inflammation: therapeutic approaches. Free Radical Biology and Medicine, 28(9), 1405-1420, 2000, doi:10.1016/s0891-5849(00)00215-x

[46] C.K. Sen, S. Khanna, A.Z. Reznick, S. Roy, L. Packer, Glutathione Regulation of Tumor Necrosis Factor-α-Induced NF-κB Activation in Skeletal Muscle-Derived L6 Cells. Biochemical and Biophysical Research Communications, 237(3), 645-649, 1997, doi:10.1006/bbrc.1997.7206

[47] J.J. Haddad, R.E. Olver, S.C. Land, Antioxidant/Pro-oxidant Equilibrium Regulates HIF-1α and NF-κB Redox Sensitivity. Journal of Biological Chemistry, 275(28), 21130-21139, 2000, doi:10.1074/jbc.m000737200

[48] C. Tanaka, H. Kamata, H. Takeshita, H. Yagisawa, H. Hirata, Redox Regulation of Lipopolysaccharide(LPS)-Induced Interleukin-8 (IL-8) Gene Expression Mediated by NFκB and AP-1 in Human Astrocytoma U373 Cells. Biochemical and Biophysical Research Communications, 232(2), 568-573, 1997, doi:10.1006/bbrc.1997.6264

[49] G. Chen, S.H. Wang, T.D. Warner, Regulation of iNOS mRNA levels in endothelial cells by glutathione, a double-edged sword. Free Radical Research, 32(3), 223-234, 2000, doi:10.1080/10715760000300231

[50] T.A. Vos, H.V. Goor, L. Tuyt, A.D. Jager-Krikken, R. Leuvenink, F. Kuipers, H. Moshage, Expression of inducible nitric oxide synthase in endotoxemic rat hepatocytes is dependent on the cellular glutathione status. Hepatology, 29(2), 421-426, 1999, doi:10.1002/hep.510290231

[51] S.P. Singh, J.S. Wishnok, M. Keshive, W.M. Deen, S.R. Tannenbaum, The chemistry of the S-nitrosoglutathione/glutathione system. Proceedings of the National Academy of Sciences, 93(25), 14428-14433, 1996, doi:10.1073/pnas.93.25.14428

[52] C. Bishop, V.M. Hudson, S.C. Hilton, C. Wilde, A Pilot Study of the Effect of Inhaled Buffered Reduced Glutathione on the Clinical Status of Patients With Cystic Fibrosis. Chest, 127(1), 308-317, 2005, doi:10.1378/chest.127.1.308

[53] J.B. Owen, D.A. Butterfield, Measurement of Oxidized/Reduced Glutathione Ratio. Methods in Molecular Biology Protein Misfolding and Cellular Stress in Disease and Aging, 269-277, 2010, doi:10.1007/978-1-60761-756-3_18

[54] C. Hu, A.L. Eggler, A.D. Mesecar, R.B. Breemen, Modification of Keap1 Cysteine Residues by Sulforaphane. Chemical Research in Toxicology, 24(4), 515-521, 2011, doi:10.1021/tx100389r

[55] A.M. Cantin, S.L. North, R.C. Hubbard, R.G. Crystal, Normal alveolar epithelial lining fluid contains high levels of glutathione. Journal of Applied Physiology, 63(1), 152–157, 1987.

[56] C.B. Pocernich, D.A. Butterfield, Elevation of glutathione as a therapeutic strategy in Alzheimer disease. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1822(5), 625-630, 2012, doi:10.1016/j.bbadis.2011.10.003

[57] R. Quintana-Cabrera, S. Fernandez-Fernandez, V. Bobo-Jimenez, J. Escobar, J. Sastre, A. Almeida, J.P. Bolaños, γ-Glutamylcysteine detoxifies reactive oxygen species by acting as glutathione peroxidase-1 cofactor. Nature Communications, 3, 718, 2012, doi:10.1038/ncomms1722

[58] B.W. Ramsey, T.F. Boat, Outcome measures for clinical trials in cystic fibrosis Summary of a Cystic Fibrosis Foundation Consensus Conference. The Journal of Pediatrics, 124(2), 177-192, 1994, doi:10.1016/s0022-3476(94)70301-9

[59] D.R. Vandevanter, M.W. Konstan, Outcome measures for clinical trials assessing treatment of cystic fibrosis lung disease. Clinical Investigation, 2(2), 163-175, 2012, doi:10.4155/cli.11.174

[60] C.G. Cote, V.M. Pinto-Plata, J.M. Marin, H. Nekach, L.J. Dordelly, B.R. Celli, The modified BODE index: validation with mortality in COPD. European Respiratory Journal, 32(5), 1269-1274, 2008, doi:10.1183/09031936.00138507

[61] A. Visca, C.T. Bishop, S. Hilton, V.M. Hudson, Oral Reduced L-Glutathione Improves Growth in Pediatric Cystic Fibrosis Patients. Journal of Pediatric Gastroenterology and Nutrition, 60(6), 802-810, 2015, doi:10.1097/mpg.0000000000000738

[62] D. Hartl, M. Griese, T. Nicolai, G. Zissel, C. Prell, N. Konstantopoulos, S. Krauss-Etschmann, Pulmonary chemokines and their receptors differentiate children with asthma and chronic cough. Journal of Allergy and Clinical Immunology, 115(4), 728-736, 2005, doi:10.1016/j.jaci.2004.11.049

[63] M. Griese, M. Kappler, C. Eismann, M. Ballmann, S. Junge, E. Rietschel, A.Hector, Inhalation Treatment with Glutathione in Patients with Cystic Fibrosis. A Randomized Clinical Trial. American Journal of Respiratory and Critical Care Medicine, 188(1), 83-89, 2013, doi:10.1164/rccm.201303-0427oc

[64] A.D. Rogerio, C.A. Sorgi, R. Sadikot, T. Carlo, The Role of Lipids Mediators in Inflammation and Resolution. BioMed Research International, 2015, 1-2, 2015, doi:10.1155/2015/605959

[65] K.S. Kuhn, A.I. Krasselt, P. Furst, Glutathione and glutathione metabolites in small tissue samples and mucosal biopsies. Clinical Chemistry, 46, 1003 – 1005, 2000.

[66] B.F.Becker, Towards the physiological function of uric acid. Free Radical Biology and Medicine, 14(6), 615-631, 1993, doi:10.1016/0891-5849(93)90143-i

[67] K. Suzuki, H. Ota, S. Sasagawa, T. Sakatani, T. Fujikura, Assay method for myeloperoxidase in human polymorphonuclear leukocytes. Analytical Biochemistry, 132(2), 345-352, 1983, doi:10.1016/0003-2697(83)90019-2

[68] J. Yang, J.P. Eiserich, C.E. Cross, B.M. Morrissey, B.D. Hammock, Metabolomic profiling of regulatory lipid mediators in sputum from adult cystic fibrosis patients. Free Radical Biology and Medicine, 53(1), 160-171, 2012, doi:10.1016/j.freeradbiomed.2012.05.001

[69] A. Corti, M. Franzini, S. Cianchetti, G. Bergamini, E. Lorenzini, P. Melotti, A. Pompella, Contribution by Polymorphonucleate Granulocytes to Elevated Gamma-Glutamyltransferase in Cystic Fibrosis Sputum. PLoS ONE, 7(4), 2012, doi:10.1371/journal.pone.0034772

[70] R.M. Girón-Moreno, J.L. Justicia, S. Yamamoto, C. Valenzuela, C. Cisneros, R.M. Gómez-Punter, J. Ancochea, Role of C-reactive protein as a biomarker for prediction of the severity of pulmonary exacerbations in patients with cystic fibrosis. BMC Pulmonary Medicine, 14(150), 2014, doi:10.1186/1471-2466-14-150

[71] H.J. Fuchs, D.S. Borowitz, D.H. Christiansen, E.M. Morris, M.L. Nash, B.W. Ramsey, M.E. Wohl, Effect of Aerosolized Recombinant Human DNase on Exacerbations of Respiratory Symptoms and on Pulmonary Function in Patients with Cystic Fibrosis. New England Journal of Medicine, 331(10), 637-642, 1994, doi:10.1056/nejm199409083311003

[72] I. Baiardini, F. Braido, O. Fassio, F. Tarantini, M. Pasquali, F. Tarchino, G.W. Canonica, A new tool to assess and monitor the burden of chronic cough on quality of life: Chronic Cough Impact Questionnaire. Allergy, 60(4), 482-488, 2005, doi:10.1111/j.1398-9995.2005.00743.x

[73] F. Monti, F. Lupi, F. Gobbi, F. Agostini, A. Miano, L. Gee, J. Abbott, Validation of the Italian version of the Cystic Fibrosis Quality of Life Questionnaire (CFQoL), a disease specific measure for adults and adolescents with cystic fibrosis. Journal of Cystic Fibrosis, 7(2), 116-122, 2008, doi:10.1016/j.jcf.2007.06.003

[74] I. Horváth, J. Hunt, P.J. Barnes, K. Alving, A. Antczak, E. Baraldi, H. Wirtz, Exhaled breath condensate: methodological recommendations and unresolved questions. European Respiratory Journal, 26(3), 523-48, 2005, doi: 10.1183/09031936.05.00029705

[75] M.R. Cesarone, G. Belcaro, M. Carratelli, U. Cornelli, M.T. De Sanctis, L. Incandela, A. Barsotti, R. Terranova, A. Nicolaides, A simple test to monitor oxidative stress. International Angiology, 18(2), 127-30, 1999.

[76] C. Calabrese, A. Tosco, P. Abete, V. Carnovale, C. Basile, A. Magliocca, V. Raia, Randomized, single blind, controlled trial of inhaled glutathione vs placebo in patients with cystic fibrosis. Journal of Cystic Fibrosis, 14(2), 203-210, 2015, doi:10.1016/j.jcf.2014.09.014

[77] M. Rosenfeld, An Overview of Endpoints for Cystic Fibrosis Clinical Trials: One Size Does Not Fit All. Proceedings of the American Thoracic Society, 4(4), 299-301, 2007, doi:10.1513/pats.200611-178ht

[78] C. Kariya, H. Leitner, E. Min, C.V. Heeckeren, A.V. Heeckeren, B.J. Day, A role for CFTR in the elevation of glutathione levels in the lung by oral glutathione administration. AJP: Lung Cellular and Molecular Physiology, 292(6), 1590-1597, 2007, doi:10.1152/ajplung.00365.2006

[79] J.N. Snouwaert, K.K. Brigman, A.M. Latour, N.N. Malouf, R.C. Boucher, O. Smithies, B.H. Koller, An Animal Model for Cystic Fibrosis Made by Gene Targeting. Science, 257(5073), 1083-1088, 1992, doi:10.1126/science.257.5073.1083

[80] L. Zhou, C. Dey, S. Wert, M. Duvall, R. Frizzell, J. Whitsett, Correction of lethal intestinal defect in a mouse model of cystic fibrosis by human CFTR. Science, 266(5191), 1705-1708, 1994, doi:10.1126/science.7527588

[81] J. Prousky, The Treatment of Pulmonary Diseases and Respiratory-Related Conditions with Inhaled (Nebulized or Aerosolized) Glutathione. Evidence-Based Complementary and Alternative Medicine, 5(1), 27-35, 2008, doi:10.1093/ecam/nem040

[82] W. Moller, W. Barth, M. Kohlhaufl, K. Haussinger, W. Stahlhofen, J. Heyder, Human alveolar long-term clearance of ferromagnetic iron oxide microparticles in healthy and diseased subjects. Experimental Lung Research. 27, 547–568, 2001.

[83] P. Brand, I. Friemel, T. Meyer, H. Schulz, J. Heyder, K. Häuβinger, Total Deposition of Therapeutic Particles During Spontaneous and Controlled Inhalations. Journal of Pharmaceutical Sciences, 89(6), 724-731, 2000, doi:10.1002/(sici)1520-6017(200006)89:6<724::aid-jps3>3.0.co;2-b

[84] M. Griese, J. Ramakers, A. Krasselt, V. Starosta, S.V. Koningsbruggen, R. Fischer, G. Scheuch, Improvement of Alveolar Glutathione and Lung Function but Not Oxidative State in Cystic Fibrosis. American Journal of Respiratory and Critical Care Medicine, 169(7), 822-828, 2004, doi:10.1164/rccm.200308-1104oc

[85] D. Hartl, V. Starosta, K. Maier, I. Beck-Speier, C. Rebhan, B. Becker, M. Griese, Inhaled glutathione decreases PGE2 and increases lymphocytes in cystic fibrosis lungs. Free Radical Biology and Medicine, 39(4), 463-472, 2005, doi:10.1016/j.freeradbiomed.2005.03.032

[86] D.A. Mahler, C.K. Wells, Evaluation of Clinical Methods for Rating Dyspnea. Chest, 93(3), 580-586, 1988, doi:10.1378/chest.93.3.580

[87] P.A. Flume, P.J. Mogayzel, K.A. Robinson, C.H. Goss, R.L. Rosenblatt, R.J. Kuhn, B.C. Marshall, Cystic Fibrosis Pulmonary Guidelines. American Journal of Respiratory and Critical Care Medicine, 180(9), 802-808, 2009, doi:10.1164/rccm.200812-1845pp

[88] A. Corti, P. Melotti, C. Sorio, G. Bergamini, A. Hector, M. Griese, A. Pompella, GSH inhalation therapies in CF: how useful, how safe? Set-up of a CF murine model for monitoring of inflammation in vivo and assessment of convenient alternatives. Postdoc Journal, 22-24, 2016.

[89] W. Klare, T. Das, A. Ibugo, E. Buckle, M. Manefield, J. Manos, Glutathione-Disrupted Biofilms of Clinical Pseudomonas aeruginosa Strains Exhibit an Enhanced Antibiotic Effect and a Novel Biofilm Transcriptome. Antimicrobial Agents and Chemotherapy, 60(8), 4539-4551, 2016, doi:10.1128/aac.02919-15

[90] M. D’Orazio, F. Pacello, A. Battistoni, Extracellular Glutathione Decreases the Ability of Burkholderia cenocepacia to Penetrate into Epithelial Cells and to Induce an Inflammatory Response. PLoS ONE, 7(10), 2012, doi:10.1371/journal.pone.0047550

[91] Y. Zhang, K. Duan, Glutathione exhibits antibacterial activity and increases tetracycline efficacy against Pseudomonas aeruginosa. Science in China Series C: Life Sciences, 52(6), 501-505, 2009, doi:10.1007/s11427-009-0074-8

[92] M. Zafarullah, W.Q. Li, J. Sylvester, M. Ahmad, Molecular mechanisms of N -acetylcysteine actions. Cellular and Molecular Life Sciences , 60(1), 6-20, 2003, doi:10.1007/s000180300001

[93] L. Bonanomi, A. Gazzaniga, Toxicological, pharmacokinetic and metabolic studies on acetylcysteine. European Journal of Respiratory Diseases. Supplement, 111:45-51, 1980.

[94] R. Tirouvanziam, C.K. Conrad, T. Bottiglieri, L.A. Herzenberg, R.B. Moss, L.A. Herzenberg, High-dose oral N-acetylcysteine, a glutathione prodrug, modulates inflammation in cystic fibrosis. Proceedings of the National Academy of Sciences, 103(12), 4628-4633, 2006, doi:10.1073/pnas.0511304103

[95] K.R. Atkuri, J.J. Mantovani, L.A. Herzenberg, L.A. Herzenberg, N-Acetylcysteine—a safe antidote for cysteine/glutathione deficiency. Current Opinion in Pharmacology, 7(4), 355-359, 2007, doi:10.1016/j.coph.2007.04.005

[96] G. Ferguson, W. Bridge, Glutamate cysteine ligase and the age-related decline in cellular glutathione: The therapeutic potential of γ-glutamylcysteine. Archives of Biochemistry and Biophysics, 593, 12-23, 2016, doi:10.1016/j.abb.2016.01.017

[97] E. Pileblad, T. Magnusson, Increase in rat brain glutathione following intracerebroventricular administration of γ-glutamylcysteine. Biochemical Pharmacology, 44(5), 895-903, 1992, doi:10.1016/0006-2952(92)90121-x

[98] T.M. Le, H. Jiang, G.R. Cunningham, J.A. Magarik, W.S. Barge, M.C. Cato, M.L. Summar, γ-Glutamylcysteine ameliorates oxidative injury in neurons and astrocytes in vitro and increases brain glutathione in vivo. NeuroToxicology, 32(5), 518-525, 2011, doi:10.1016/j.neuro.2010.11.008

[99] J. Drake, J. Kanski, S. Varadarajan, M. Tsoras, D.A. Butterfield, Elevation of brain glutathione by ?-glutamylcysteine ethyl ester protects against peroxynitrite-induced oxidative stress. Journal of Neuroscience Research, 68(6), 776-784, 2002, doi:10.1002/jnr.10266

[100] J. Drake, R. Sultana, M. Aksenova, V. Calabrese, D.A. Butterfield, Elevation of mitochondrial glutathione by ?-glutamylcysteine ethyl ester protects mitochondria against peroxynitrite-induced oxidative stress. Journal of Neuroscience Research, 74(6), 917-927, 2003, doi:10.1002/jnr.10810

[101] Y.K. Nakamura, M.A. Dubick, S.T. Omaye, Modulation of oxidative stress by γ-glutamylcysteine (GGC) and conjugated linoleic acid (CLA) isomer mixture in human umbilical vein endothelial cells. Food and Chemical Toxicology, 50(6), 1854-1859, 2012, doi:10.1016/j.fct.2012.03.066

[102] E. Ristoff, C. Hebert, R. Njålsson, S. Norgren, O. Rooyackers, A. Larsson, Glutathione synthetase deficiency: is gamma-glutamylcysteine accumulation a way to cope with oxidative stress in cells with insufficient levels of glutathione?. Journal of Inherited Metabolic Disease, 25(7), 577-84, 2002.

[103] M.H. Zarka, W.J. Bridge, Oral administration of γ-glutamylcysteine increases intracellular glutathione levels above homeostasis in a randomised human trial pilot study. Redox Biology, 11, 631-636, 2017, doi:10.1016/j.redox.2017.01.014