Abstract
The cystic fibrosis transmembrane regulator (CFTR) should no longer be viewed primarily as a ‘chloride channel’ but recognized as a channel that also controls the efflux of other physiologically important anions, such as glutathione (GSH) and bicarbonate. More effective approaches to cystic fibrosis treatment may result from this reconceptualization of the CFTR by researchers and clinicians. For example, oxidant damage in cystic fibrosis has been assumed to be a significant part of the pathophysiology of the disease. Generally speaking, antioxidant status in cystic fibrosis is compromised. However, until recently this was seen as secondary to the excessive chemoattraction of neutrophils in this disease caused by mutation of the CFTR protein, leading to a high oxidant burden. New findings suggest that the cystic fibrosis mutations in fact cause a primary dysfunction in the system of one of the body’s most important antioxidant and immune-signaling substances: the reduced GSH system. Cystic fibrosis mutations significantly decrease GSH efflux from cells without redundant channels to the CFTR; this leads to deficiency of GSH in the epithelial lining fluid of the lung, as well as in other compartments, including immune system cells and the gastrointestinal tract. This deficiency is exaggerated over time as the higher-than-normal oxidant burden of cystic fibrosis leads to successively larger decrements in GSH without the normal opportunity to fully recover physiologic levels. This GSH system dysfunction may be the trigger for initial depletion of other antioxidants and may also play a role in initiating the over-inflammation characteristic of cystic fibrosis. Proper GSH system functioning also affects immune system competence and mucus viscosity, both of relevance to cystic fibrosis pathophysiology. In a way, cystic fibrosis may be thought of as the first identified disease with GSH system dysfunction.
This overview provides a review of the most pertinent recent research findings in this area. Exogenous augmentation of GSH in the lung epithelial lining fluid is possible, and therapeutic approaches include administration of aerosolized buffered GSH, intravenous GSH, and oral GSH. However, it is important to remember that the pathophysiology of cystic fibrosis is multifactorial, and rectification of GSH system dysfunction in patients with cystic fibrosis will not eliminate all harmful effects of the disease. The promising results of two clinical trials of aerosolized buffered GSH in cystic fibrosis patients have been published or accepted for publication at the time of this writing. GSH depletion in lung epithelial lining fluid has also been noted in other respiratory diseases such as COPD, idiopathic pulmonary fibrosis, and adult respiratory distress syndrome, and therapies to augment GSH may also be contemplated in these diseases.
Similar content being viewed by others
Notes
1 The use of trade names is for product identification purposes only and does not imply endorsement.
References
Khan TZ, Wagener JS, Bost T, et al. Early pulmonary inflammation in infants with cystic fibrosis. Am J Respir Crit Care Med 1995 Apr; 151(4): 1075–82
Balough K, McCubbin M, Weinberger M, et al. The relationship between infection and inflammation in the early stages of lung disease from cystic fibrosis. Pediatr Pulmonol 1995 Aug; 20(2): 63–70
Muhlebach MS, Stewart PW, Leigh MW, et al. Quantitation of inflammatory responses to bacteria in young cystic fibrosis and control patients. Am J Respir Crit Care Med 1999 Jul; 160(1): 186–91
Noah TL, Black HR, Cheng PW, et al. Nasal and bronchoalveolar lavage fluid cytokines in early cystic fibrosis. J Infect Dis 1997 Mar; 175(3): 638–47
Osika E, Cavaillon JM, Chadelat K, et al. Distinct sputum cytokine profiles in cystic fibrosis and other chronic inflammatory airway diseases. Eur Respir J 1999 Aug; 14(2): 339–46
Tabary O, Escotte S, Couetil JP, et al. Genistein inhibits constitutive and inducible NFkappaB activation and decreases IL-8 production by human cystic fibrosis bronchial gland cells. Am J Pathol 1999 Aug; 155(2): 473–81
Dai Y, Dean TP, Church MK, et al. Desensitisation of neutrophil responses by systemic interleukin 8 in cystic fibrosis. Thorax 1994 Sep; 49(9): 867–71
Bonfield TL, Konstan MW, Berger M. Altered respiratory epithelial cell cytokine production in cystic fibrosis. J Allergy Clin Immunol 1999; 104(1): 72–8
Pilewski JM, Frizzell RA. Role of CFTR in airway disease. Physiol Rev 1999 Jan; 79Suppl. 1: S215–55
van der Vliet A, Eiserich JP, Marelich GP, et al. Oxidative stress in cystic fibrosis: does it occur and does it matter? Adv Pharmacol 1997; 38: 491–513
Tamada T, Hug M, Peters K, et al. Bicarbonate secretion in airway serous cells. Pediatr Pulmonol 2001 Oct; 22: 119–20
Coakley RD. Regulation of airway surface liquid pH in cystic fibrosis. Pediatr Pulmonol 2001 Oct; 22: 120–1
McShane D, Davies JC, Davies MG, et al. Airway surface pH in subjects with cystic fibrosis. Eur Respir J 2003; 21(1): 37–42
Jayaraman S, Joo NS, Reitz B, et al. Submucosal gland secretions in airways from cystic fibrosis patients have normal [NA(+)] and pH but elevated viscosity. Proc Natl Acad Sci U S A 2001; 98(14): 8119–23
Jayaraman S, Song Y, Verkman AS. Airway surface liquid pH regulation in well-differentiated airway epithelial cell cultures and mouse trachea. Am J Physiol Cell Physiol 2001; 281(5): C1504–11
Hudson VM. Rethinking cystic fibrosis pathology: the critical role of abnormal reduced glutathione (GSH) transport caused by CFTR mutation. Free Radic Biol Med 2001; 30(12): 1440–61
Benabdeslam H, Abidi H, Garcia I, et al. Lipid peroxidation and antioxidant defenses in cystic fibrosis patients. Clin Chem Lab Med 1999 May; 37(5): 511–6
Stocker R, Bowry VW, Frei B, et al. Ubiquinol-10 protects human low density lipoprotein more efficiently against lipid peroxidation than does alpha-tocopherol. Proc Natl Acad Sci U S A 1991 Mar; 88: 1646–50
Thomas SR, Neuzil J, Stocker R. Cosupplementation with coenzyme Q prevents the prooxidant effect of alpha-tocopherol and increases the resistance of LDL to transition metal-dependent oxidation initiation. Aterioscler Thromb Vasc Biol 1996 May; 16(5): 687–96
Thanislass J, Raveendran M, Devaraj H. Buthionine sulfoximine-induced glutathione depletion: its effect on antioxidants, lipid peroxidation and calcium homeostasis in the lung. Biochem Pharmacol 1995 Jul 17; 50(2): 229–34
Leedle RA, Aust SD. The effect of glutathione on the vitamin E requirement for inhibition of liver microsomal lipid peroxidation. Lipids 1990 May; 25(5): 241–5
Higuchi Y, Matsukawa S. Glutathione depletion induces giant DNA and high-molecular-weight DNA fragmentation associated with apoptosis through lipid peroxidation and protein kinase C activation in C6 glioma cells. Arch Biochem Biphys 1999 Mar 1; 363(1): 33–42
Scholz RW, Reddy PV, Wynn MK, et al. Glutathione-dependent factors and inhibition of rat liver microsomal lipid peroxidation. Free Radic Biol Med 1997; 23(5): 815–28
Hagiwara K, Naito K, Kurokawa Y, et al. Kidney injury induced by lipid peroxide produced by vitamin E deficiency and GSH depletion in rats. J Nutr Sci Vitaminol (Tokyo) 1991 Feb; 37(1): 99–107
Angelini P, Cirelli F, Quarticelli A, et al. Administration of glutathione and lipid peroxidation induced during fasting. Boll Soc Ital Biol Sper 1990 Nov; 66(11): 1097–104
Rosenblat M, Aviram M. Macrophage glutathione content and glutathione peroxidase activity are inversely related to cell-mediated oxidation of LDL: in vitro and in vivo studies. Free Radic Biol Med 1998 Jan 15; 24(2): 305–17
Chen Q, Galleano M, Cederbaum AI. Cytotoxicity and apoptosis produced by arachidonic acid in Hep G2 cells overexpressing human cytochrome P4502E1. J Biol Chem 1997 Jun 6; 272(23): 14532–41
Klatt P, Lamas S. Regulation of protein function by S-glutathiolation in response to oxidative and nitrosative stress. Eur J Biochem 2000 Aug; 267(16): 4928–44
Thomas JA, Mallis RJ. Aging and oxidation of reactive protein sulfhydryls. Exp Gerontol 2001 Sep; 36(9): 1519–26
Buhl R, Meyer A, Vogelmeier C. Oxidant-protease interaction in the lung: prospects for antioxidant therapy. Chest 1996 Dec; 110(6 Suppl.): 267S–72S
Gillissen A, Birrer P, McElvaney NG, et al. Recombinant secretory leukoprotease inhibitor augments glutathione levels in lung epithelial lining fluid. J Appl Physiol 1993 Aug; 75(2): 825–32
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 Sep; 10(9): 2114–9
Barbero GJ. Therapeutic approaches to cystic fibrosis. Bull World Health Organ 1994; 72(3): 341–52
Brenneisen P, Briviba K, Wlaschek M, et al. Hydrogen peroxide (H2O2) increases the steady-state mRNA levels of collagenase/MMP-1 in human dermal fibroblasts. Free Radic Biol Med 1997; 22(3): 515–24
Ogino T, Packer L, Maguire JJ. Neutrophil antioxidant capacity during the respiratory burst: loss of glutathione induced by chloramines. Free Radic Biol Med 1997; 23(3): 445–52
Bilzer M, Lauterberg BH. Glutathione metabolism in activated human neutrophils: stimulation of glutathione synthesis and consumption of glutathione by reactive oxygen species. Eur J Clin Invest 1991 Jun; 21(3): 316–22
Vanglarik CJ, Giron-Calle J, Matalon S, et al. Extracellular glutathione protects airway epithelial cells against oxidative damage caused by hypochlorous acid exposure. Pediatr Pulmonol 2001 Oct; 22: 276–7
Freeman ML, Huntley SA, Meredith MJ, et al. Destabilization and denaturation of cellular protein by glutathione depletion. Cell Stress Chaperones 1997 Sep; 2(3): 191–8
Calabreses V, Testa G, Ravagna A, et al. HSP70 induction in the brain following ethanol administration in the rat: regulation by glutathione redox state. Biochem Biophys Res Commun 2000 Mar 16; 269(2): 397–400
Liu H, Lightfoot R, Stevens JL. Activation of heat shock factor by alkylating agents is triggered by glutathione depletion and oxidation of protein thiols. J Biol Chem 1996 Mar 1; 271(9): 4805–12
Wilhelm D, Bender K, Knebel A, et al. The level of intracellular glutathione is a key regulator for the induction of stress-activated signal transduction pathways including Jun N-terminal protein kinases and p38 kinase by alkylating agents. Mol Cell Biol 1997 Aug; 17(8): 4792–800
Kirlin WG, Cai J, Thompson SA, et al. Glutathione redox potential in response to differentiation and enzyme inducers. Free Radic Biol Med 1999 Dec; 27(11-12): 1208–18
Lertratanangkoon K, Savaraj N, Scimeca JM, et al. Glutathione depletion-induced thymidylate insufficiency for DNA repair synthesis. Biochem Biophys Res Commun 1997 May 19; 234(2): 470–5
Asensi M, Garcia-Espana A, Pallardo FV, et al. Effect of nonprotein thiols on protein synthesis in isolated rat hepatocytes. Experientia 1996 Feb 15; 52(2): 111–4
Fussell JC, Kelly FJ. Effects of dexamethasone on lung protein turnover. Biochem J 1991 Jan 1; 273 (Pt 1): 93–7
Murthy MR. Protein synthesis in growing-rat tissues: II. Polyribosome concentration of brain and liver as a function of age. Biochim Biophys Acta 1966 Jun 22; 119(3): 599–613
Thanislass J, Raveendran M, Sivasithamparam N, et al. Effect of chronic glutathione deficiency on rat lung mitochondrial function. Pulm Pharmacol 1996 Apr; 9(2): 119–22
Rojas E, Valverde M, Kala SV, et al. Accumulation of DNA damage in the organs of mice deficient in gamma-glutamyltranspeptidase. Mutat Res 2000 Feb 14; 447(2): 305–16
Gilmont RR, Dardano A, Young M, et al. Effects of glutathione depletion on oxidant-induced endothelial cell injury. J Surg Res 1998 Nov; 80(1): 62–8
Fiorentini C, Falzano L, Rivabene R, et al. N-acetylcysteine protects epithelial cells against the antioxidant imbalance due to Clostridium difficile toxins. FEBS Lett 1999 Jun 18; 453(1-2): 124–8
Kamei H. Cystine starvation induces reversible large-body formation from nuclear bodies in T24 cells. Exp Cell Res 1997 Nov 25; 237(1): 207–16
Zuelke KA, Jones DP, Perreault SD. Glutathione oxidation is associated with altered microtubule function and disrupted fertilization in mature hamster oocytes. Biol Reprod 1997 Dec; 57(6): 1413–9
Jain A, Martensson J, Mehta T, et al. Ascorbic acid prevents oxidative stress in glutathione deficient mice: effects on lung type 2 cell lamellar bodies, lung surfactant, and skeletal muscle. Proc Natl Acad Sci U S A 1992 Jun; 89(11): 5093–7
Shaheen SO, Sterne JA, Songhurst CE, et al. Frequent paracetamol use and asthma in adults. Thorax 2000 Apr; 55(4): 266–70
Li XY, Donaldson K, Rahman I, et al. An investigation of the role of glutathione in increased epithelial permeability induced by cigarette smoke in vivo and in vitro. Am J Respir Crit Care Med 1994 Jun; 149(6): 1518–25
Remiao F, Carmo H, Carvalho FD, et al. Inhibition of glutathione reductase by isoproterenol oxidation products. J Enzyme Inhib 2000; 15(1): 47–61
Barker JE, Heales SJ, Cassidy A, et al. Depletion of brain glutathione results in a decrease of glutathione reductase activity: an enzyme susceptible to oxidative damage. Brain Res 1996 Apr 15; 16(1-2): 118–22
van Klaveren RJ, Hoet PH, Pype JL, et al. Increase in gamma-glutamyltransferase by glutathione depletion in rat type II pneumocytes. Free Radic Biol Med 1997; 22(3): 525–34
Smith CV, Jones DP, Guenthner TM, et al. Compartmentation of glutathione: implications for the study of toxicity and disease. Toxicol Appl Pharmacol 1996; 140: 1–12
Houtmeyers E, Gosselink R, Gayan-Ramirez G, et al. Regulation of mucociliary clearance in health and disease. Eur Respir J 1999 May; 13(5): 1177–88
King M, Rubin BK. Mucus-controlling agents: past and present. Respir Care Clin N Am 1999 Dec; 5(4): 575–94
Houtmeyers E, Gosselink R, Gayan-Ramirez G, et al. Effects of drugs on mucus clearance. Eur Respir J 1999 Aug; 14(2): 452–67
Connolly MA. Mucolytics and the critically ill patient: help or hindrance? AACN Clin Issues 1995 May; 6(2): 307–15
Clarke SW. Rationale of airway clearance. Eur Respir J Suppl 1989 Jul; 7: 599s–603s
Jiang N, Dreher KL, Dye JA, et al. Residual oil fly ash induces cytotoxicity and mucin secretion by guinea pig tracheal epithelial cells via an oxidant-mediated mechanism. Toxicol Appl Pharmacol 2000 Mar 15; 163(3): 221–30
Li JD, Feng W, Gallup M, et al. Activation of NF-kappaB via a Src-dependent Ras-MAPK-pp90rsk pathway is required for Pseudomonas aeruginosa-induced mucin overproduction in epithelial cells. Proc Natl Acad Sci U S A 1998; 95(10): 5718–23
Fischer B, Voynow J. Neutrophil elastase induces MUC5AC messenger RNA expression by an oxidant-dependent mechanism. Chest 2000 May; 117 (5 Suppl. 1): 317S–20S
Day BJ, van Heeckeren A, Velsor LW. Elevation of lung CFTR, MRP-2, and epithelial lining fluid glutathione in mice with Pseudomonas aeruginosa lung infection [abstract]. Am J Respir Crit Care Med 2003 Apr; 167(7): A916
Day BJ, van Heeckeren AM, Min E, et al. Role for cystic fibrosis transmembrane conductance regulator protein in a glutathione response to bronchopulmonary pseudomonas infection. Infect Immun 2004 Apr; 72(4): 2045–51
Boxer LA, Oliver JM, Speilberg SP, et al. Protection of granulocytes by vitamin E in glutathione synthetase deficiency. N Engl J Med 1979 Oct 25; 301(17): 901–5
Cho S, Urata Y, Ilada T, et al. Glutathione downregulates the phosphorylation of I kappa-B: autoloop regulation of the NF-kappa B-mediated expression of NF-kappa B subunits by TNF-alpha in mouse vascular endothelial cells. Biochem Biophys Res Commun 1998; 253(1): 104–8
Droge W, Eck HP, Gmunder H, et al. Modulation of lymphocyte functions and immune responses by cysteine and cysteine derivatives. Am J Med 1991 Sep 30; 91(3C): 140–3
Sen CK, Khanna S, Reznick AZ, et al. Glutathione regulation of tumor necrosis factor-alpha-induced NF-kappa B activation in skeletal muscle-derived L6 cells. Biochem Biophys Res Commun 1997 Aug 28; 237(3): 645–9
Desai A, Huang X, Warren JS. Intracellular glutathione redox status modulates MCP-1 expression in pulmonary granulomatous vasculitis. Lab Invest 1999 Jul; 79(7): 837–47
Luo Y, Hattori A, Munoz J, et al. Intrastriatal dopamine injection induces apoptosis through oxidation-involved activation of transcription factors AP-1 and NF-kappaB in rats. Mol Pharmacol 1999 Aug; 56(2): 254–64
Haddad JJ, Olver RE, Land SC. Antioxidant/pro-oxidant equilibrium regulates HIF-1alpha and NF-kappaB redox sensitivity: evidence for inhibition by glutathione oxidation in alveolar epithelial cells. J Biol Chem 2000; 275(28): 21130–9
Tanaka C, Kamata H, Takeshita H, et al. Redox regulation of lipopolysaccharide (LPS)-induced interleukin-8 (IL-8) gene expression mediated by NF kappa B and AP-1 in human astrocytoma U373 cells. Biochem Biophys Res Commun 1997 Mar 17; 232(2): 568–73
Rahman I, MacNee W. Regulation of redox glutathione levels and gene transcription in lung inflammation: therapeutic approaches. Free Radic Biol Med 2000 May 1; 28(9): 1405–20
Christman JW, Sadikot RT, Blackwell TS. The role of nuclear factor-kappa B in pulmonary diseases. Chest 2000; 117(5): 1482–7
Gosset P, Wallaert B, Tonnel AB, et al. Thiol regulation of the production of TNF-alpha, IL-6 and IL-8 by human alveolar macrophages. Eur Respir J 1999 Jul; 14(1): 98–105
Hashimoto S, Gon Y, Matsumoto K, et al. Regulation by intracellular glutathione of TNF-alpha-induced p38 MAP kinase activation and RANTES production by human pulmonary vascular endothelial cells. Allergy 2000 May; 55(5): 463–9
Yamauchi N, Watanabe N, Kuriyama H, et al. Suppressive effects of intracellular glutathione on hydroxyl radical production induced by tumor necrosis factor. Int J Cancer 1990 Nov 15; 46(5): 884–8
Peristeris P, Clark BD, Gatti S, et al. N-acetylcysteine and glutathione as inhibitors of tumor necrosis factor production. Cell Immunol 1992 Apr; 140(2): 390–9
Rovin BH, Dickerson JA, Tan LC, et al. Modulation of IL-1-induced chemokine expression in human mesangial cells through alterations in redox status. Cytokine 1997 Mar; 9(3): 178–86
Pena LR, Hill DB, McClain CJ. Treatment with glutathione precursor decreases cytokine activity. JPEN J Parenter Enteral Nutr 1999 Jan–Feb; 23(1): 1–6
Watson RW, Rotstein OD, Nathens AB, et al. Thiol-mediated redox regulation of neutrophil apoptosis. Surgery 1996 Aug; 120(2): 150–7
Nakatani T, Tawaramoto M, Opare Kennedy D, et al. Apoptosis induced by chelation of intracellular zinc is associated with depletion of cellular reduced glutathione level in rat hepatocytes. Chem Biol Interact 2000 Mar 15; 125(3): 151–63
Coppola S, Ghibelli L. GSH extrusion and the mitochondrial pathway of apoptotic signalling. Biochem Soc Trans 2000 Feb; 28(2): 56–61
Colell A, Garcia-Ruiz C, Miranda M, et al. Selective glutathione depletion of mitochondria by ethanol sensitizes hepatocytes to tumor necrosis factor. Gastroenterology 1998 Dec; 115(6): 1541–51
Nicole A, Santiard-Baron D, Ceballos-Picot I. Direct evidence for glutathione as mediator of apoptosis in neuronal cells. Biomed Pharmacother 1998; 52(9): 349–55
Rosenfeld ME. Inflammation, lipids, and free radicals: lessons learned from the atherogenic process. Semin Reprod Endrocrinol 1998; 16(4): 249–61
Hardwick SJ, Carpenter KL, Allen EA, et al. Glutathione (GSH) and the toxicity of oxidised low-density lipoprotein to human monocyte-macrophages. Free Radic Res 1999 Jan; 30(1): 11–9
Aoshiba K, Yasui S, Nishimura K, et al. Thiol depletion induces apoptosis in cultured lung fibroblasts. Am J Respir Cell Mol Biol 1999 Jul; 21(1): 54–64
Vahrmeijer AL, van Dierendonck JH, Schutrups J, et al. Effect of glutathione depletion on inhibition of cell cycle progression and induction of apoptosis by melphalan (L-phenylalanine mustard) in human colorectal cancer cells. Biochem Pharmacol 1999 Aug 15; 58(4): 655–64
Yang CF, Shen HM, Ong CN. Ebselen induces apoptosis in HepG (2) cells through rapid depletion of intracellular thiols. Arch Biochem Biophys 2000 Feb 15; 374(2): 142–52
Li Y, Maher P, Schubert D. A role for 12-lipoxygenase in nerve cell death caused by glutathione depletion. Neuron 1997 Aug; 19(2): 453–63
Iwata S, Hori T, Sato N, et al. Adult T cell leukemia (ATL)-derived factor/human thioredoxin prevents apoptosis of lymphoid cells induced by L-cystine and glutathione depletion: possible involvement of thiol-mediated redox regulation in apoptosis caused by pro-oxidant state. J Immunol 1997 Apr; 158(7): 3108–17
Wedner HJ, Simchowitz L, Stenson WF, et al. Inhibition of human polymorphonuclear leukocyte function by 2-cyclohexene-1-one: A role for glutathione in cell activation. J Clin Invest 1981 Aug; 68(2): 535–43
Aziz AS, Klesius PH, Frandsen JC. Effects of selenium on polymorphonuclear leukocyte function in goats. Am J Vet Res 1984 Sep; 45(9): 1715–8
Voetman AA, Loos JA, Roos D. Changes in the levels of glutathione in phagocytosing human neutrophils. Blood 1980 May; 55(5): 741–7
Peterson JD, Herzenberg LA, Vasquez K, et al. Glutathione levels in antigen-presenting cells modulate Th1 versus Th2 response patterns. Proc Natl Acad Sci U S A 1998 Mar 17; 95(6): 3071–6
Nathens AB, Rotstein OD, Dackiw AP, et al. The glutathione depleting agent diethylmaleate prolong renal allograft survival. J Surg Res 1998 Jun; 77(1): 75–9
Robinson MK, Rodrick ML, Jacobs DO, et al. Glutathione depletion in rats impairs T-cell and macrophage immune function. Arch Surg 1993 Jan; 128(1): 29–34
Ginn-Pease ME, Whisler RL. Optimal NF kappa B mediated transcriptional responses to Jurkat T cells exposed to oxidative stress are dependent on intracellular glutathione and costimulatory signals. Biochem Biophys Res Commun 1996 Sep 24; 226(3): 695–702
Jeannin P, Delneste Y, Lecoanet-Henchoz S, et al. Thiols decrease human interleukin (IL) 4 production and IL-4-induced immunoglobulin synthesis. J Exp Med 1995 Dec 1; 182(6): 1785–92
Rigacci S, Iantomasi T, Marraccini P, et al. Evidence for glutathione involvement in platelet-derived growth-factor-mediated signal. Biochem J 1997 Jun 15; 324 (Pt 3): 791–6
Smyth MJ. Glutathione modulates activation-dependent proliferation of human peripheral blood lymphocyte populations without regulating their activated function. J Immunol 1991 Mar 15; 146(6): 1921–7
Romero DL, Mounho BJ, Lauer FT, et al. Depletion of glutathione by benzo (a)pyrene metabolites, ionomycin, thapsigargin, and phorbol myristate in human peripheral blood mononuclear cells. Toxicol Appl Pharmacol 1997 May; 144(1): 62–9
Liang SM, Liang CM, Hargrove ME, et al. Regulation by glutathione of the effect of lymphokines on differentiation of primary activated lymphocytes: influence of glutathione on cytotoxic activity of CD3-AK-. J Immunol 1991 Mar 15; 146(6): 1909–13
Gmunder H, Droge W. Differential effects of glutathione depletion on T cell subsets. Cell Immunol 1991 Nov; 138(1): 229–37
Ting CC, Hargrove HE, Liang SM, et al. Dichotomy of glutathione regulation of the activation of resting and preactivated lymphocytes. Cell Immunol 1992 Jun; 142(1): 40–53
Gmunder H, Eck HP, Benninghoff B, et al. Macrophages regulate intracellular glutathione levels of lymphocytes: evidence for an immunoregulatory role of cysteine. Cell Immunol 1990 Aug; 129(1): 32–46
Galietta LJV, Folli C, Marchetti C, et al. Modification of transepithelial ion transport in human cultured bronchial epithelial cells by interferon-gamma. Am J Physiol Lung Cell Mol Physiol 2000 Jun; 278(6): L1186–94
van der Meide PH, de Labie MC, Botman CA, et al. Mercuric chloride down-regulates T cell interferon-gamma production in brown Norway but not in Lewis rats: role of glutathione. Eur J Immunol 1993 Mar; 23(3): 675–81
Sprietsma JE. Zinc-controlled Th1/Th2 switch significantly determines development of disease. Med Hypotheses 1997 Jul; 49(1): 1–14
Sprietsma JE. Cysteine, glutathione (GSH) and zinc and copper ions together are effective, natural, intracellular inhibitors of (AIDS) viruses. Med Hypotheses 1999 Jun; 52(6): 529–38
Spriestma JE. Modern diets and diseases: NO-zinc balance: under Th1, zinc and nitrogen monoxide (NO) collectively protect against viruses, AIDS, autoimmunity, diabetes, allergies, asthma, infectious diseases, atherosclerosis and cancer. Med Hypotheses 1999 Jul; 53(1): 6–16
Moser C, Johansen HK, Song Z, et al. Chronic pseudomonas aeruginosa lung infection is more severe in Th2 responding BALB/c mice compared to Th1 responding C3H/HeN mice. APMIS 1997 Nov; 105(11): 838–42
Chen G, Wang SH, Warner TD. Regulation of iNOS mRNA levels in endothelial cells by glutathione, a double-edged sword. Free Radic Res 2000 Mar; 32(3): 223–34
Kang KW, Pak YM, Kim ND. Diethylmaleate and buthionine sulfoximine, glutathione-depleting agents, differentially inhibit expression of inducible nitric oxide synthase in endotoxemic mice. Nitric Oxide 1999 Jun; 3(3): 265–71
Vos TA, Goor H, Tuyt L, et al. Expression of inducible nitric oxide synthase in endotoxemic rat hepatocytes is dependent on the cellular glutathione status. Hepatology 1999 Feb; 29(2): 421–6
Wang F, Wang LY, Wright D, et al. Redox imbalance differentially inhibits lipopolysaccharide-induced macrophage activation in the mouse liver. Infect Immun 1999 Oct; 67(10): 5409–16
Davidson CA, Kaminski PM, Wolin MS. NO elicits prolonged relaxation of bovine pulmonary arteries via endogenous peroxynitrite generation. Am J Physiol 1997 Aug; 273 (2 Pt 1): L437–44
Singh SP, Wishnok JS, Keshive M, et al. The chemistry of the S-nitrosoglutathione/glutathione system. Proc Natl Acad Sci U S A 1996 Dec; 93: 14428–33
D’Emilia DM, Lipton SA. Ratio of S-nitrosohomocyst(e)ine or other thiols determines neurotoxicity in rat cerebrocortical cultures. Neurosci Lett 1999; 265: 103–6
Stefanelli C, Pignatti C, Tantani B, et al. Nitric oxide can function as either a killer molecule or an antiapoptotic effector in cardiomyocytes. Biochim Biophys Acta 1999 Jul 8; 1450(3): 406–13
Rosenberg PA, Li Y, Ai S, et al. Intracellular redox state determines whether nitric oxide is toxic or protective to rat oligodendrocytes in culture. J Neurochem 1999 Aug; 73(2): 476–84
Chiueh CC, Rauhala P. The redox pathway of S-nitrisoglutathione, glutathione and nitric oxide in cell to neuron communications. Free Radic Res 1999 Dec; 31(6): 641–50
Jones KL, Bryan TW, Jinkins PA, et al. Superoxide released from neutrophils causes a reduction in nitric oxide gas. Am J Physiol 1998 Dec; 275(6): L1120–6
Zavodnik IB, Lapshina EA, Rekawiecka K, et al. Membrane effects of nitrite-induced oxidation of human red blood cells. Biochim Biophys Acta 1999 Oct 15; 1421(2): 306–16
Kelley TJ, Drumm ML. Inducible nitric oxide synthase expression is reduced in cystic fibrosis murine and human airway epithelial cell lines. J Clin Invest 1998 Sep; 102(6): 1200–7
Mayer B, Pfeiffer S, Schrammel A, et al. A new pathway of nitric oxide cyclic GMP signalling involving s-nitrosoglutathione. J Biol Chem 1998 Feb 6; 273(6): 3264–70
Belvisi MG, Ward JK, Mitchell JA, et al. Nitric oxide as a neurotransmitter in human airways. Arch Int Pharmacodyn Ther 1995 Jan–Feb; 329(1): 97–110
Gaston B, Drazen JM, Jansen A, et al. Relaxation of human bronchial smooth muscle by S-nitrosothiols in vitro. J Pharmacol Exp Ther 1994 Feb; 268(2): 978–84
Kamosinska B, Radomski MW, Duszyk M, et al. Nitric oxide activates chloride currents in human lung epithelial cells. Am J Physiol 1997 Jun; 272 (6 Pt 1): L1098–104
Dong YJ, Chao AC, Kouyama K, et al. Activation of CFTR chloride current by nitric oxide in human T lymphocytes. EMBO J 1995 Jun 15; 14(12): 2700–7
Runer T, Lindberg S. Ciliostimulatory effects mediated by nitric oxide. Acta Otolaryngol 1999; 119(7): 821–5
Linsdell P, Hanrahan JW. Glutathione permeability of CFTR. Am J Physiol 1998 Jul; 44(1): C323–6
Gao L, Kim KJ, Yankaskas JR, et al. Abnormal glutathione transport in cystic fibrosis airway epithelia. Am J Physiol 1999 Jul; 277(1): L113–8
Velsor LW, van Heeckeren A, Day BJ. Antioxidant imbalance in the lungs of cystic fibrosis transmembrane conductance regulator protein mutant mice. Am J Physiol Lung Cell Mol Physiol 2001 Jul; 281(1): L31–8
Kogan I, Ramjeesingh M, Kidd J, et al. Characterization of glutathione permeability through the CFTR channel pore. Pediatr Pulmonol 2002 Oct; 24: 189–90
Kogan I, Ramjessingh M, Li C, et al. CFTR directly mediates nucleotide-regulated glutathione flux. EMBO J 2003 May 1; 22(9): 1981–9
Finder JD, Engman CL, Kagan VE, et al. Bronchoalveolar lavage fluid from patients with cystic fibrosis have diminished levels of reduced glutathione [abstract]. Ped Pulm 2003; 239Suppl. 25: A158
Hull J, Vervaart P, Grimwood K, et al. Pulmonary oxidative stress response in young children with cystic fibrosis. Thorax 1997; 52: 557–60
Tirouvanziam R. CFTR, glutathione, and neutrophil function [online]. Available from URL: http://63.193.197.190/Subsets/tirouv/index.htm [Accessed 1999 Nov 13]
Neefjes VM, Evelo CT, Baars LG, et al. Erythrocyte glutathione S transferase as a marker of oxidative stress at birth. Arch Dis Child Fetal Neonatal Ed 1999 Sep; 81(2): F130–3
Brown RK, Wyatt H, Price JF, et al. Pulmonary dysfunction in cystic fibrosis is associated with oxidative stress. Eur Respir J 1996; 9: 334–9
Roum JH, Buhl R, McElvaney NG, et al. Systemic deficiency of glutathione in cystic fibrosis. J Appl Physiol 1993 Dec; 75(6): 2419–24
Tirouvanziam RM, Tjioe I, Moss RB, et al. Multiparameter study of CF blood and lung leukocytes using 3-laser, 11-color cytometry. Pediatr Pulmonol 2001 Oct; 22: 271–2
Abraham EH, Sterling KM, Kim RJH, et al. Erythrocyte membrane ATP binding cassette (ABC) proteins: MRP1 and CFTR as well as CD39 (ectoapyrase) involved in RBC ATP transport and elevated blood plasma ATP of cystic fibrosis. Blood Cells Mol Dis 2001 Jan–Feb; 27(1): 165–80
Dominguez C, Gartner S, Linan S, et al. Enhanced oxidative damage in cystic fibrosis patients. Biofactors 1998; 8(1-2): 149–53
Lloyd-Still JD, Ganther HE. Selenium and glutathione peroxidase levels in cystic fibrosis. Pediatrics 1980; 65: 1010–2
Carmagnol F, Sinet PM, Lenoir G, et al. Absence of modifications of the enzyme defense system against oxygen toxicity in cystic fibrosis. Pediatr Res 1983; 17: 181–2
Konstan MW, Berger M. Current understanding of the inflammatory process in cystic fibrosis: onset and etiology. Pediatr Pulmnol 1997 Aug; 24(2): 137–42
Tirouvanziam R, Khazaal I, Peault B. Primary inflammation in human cystic fibrosis small airways. Am J Physiol Lung Cell Mol Physiol 2002 Aug; 283(2): L445–51
Tirouvanziam R, de Bentzmann S, Hubeau C, et al. Inflammation and infection in naive human cystic fibrosis airway grafts. Am J Respir Cell Mol Biol 2000 Aug; 23(2): 121–7
Escotte S, Laplace V, Benoit S, et al. Basal KC production in tracheal surface liquid of CF mice engrafted in nude mice [abstract]. Pediatr Pulmonol 2001 Oct; 22: 227
Lancellotti L, D’Orazio C, Mastella G, et al. Deficiency of vitamins E and A in cystic fibrosis is independent of pancreatic function and current enzyme and vitamin supplementation. Eur J Pediatr 1996 Apr; 155(4): 281–5
Portal BC, Richard MJ, Faure HS, et al. Altered antioxidant status and increased lipid peroxidation in children with cystic fibrosis. Am J Clin Nutr 1995 Apr; 61(4): 843–7
Winklhofer-Roob BM, Ellemunter H, Fruhwirth M, et al. Plasma vitamin C concentrations in patients with cystic fibrosis: evidence of associations with lung inflammation. Am J Clin Nutr 1997 Jun; 65(6): 1858–66
Wood LG, Fitzgerald DA, Gibson PG, et al. Oxidative stress in cystic fibrosis: dietary and metabolic factors. Am Coll Nutr 2001 Apr; 20(2 Suppl.): 157–65
Madarasi A, Lugassi A, Greiner E, et al. Antioxidant status in patients with cystic fibrosis. Ann Nutr Metab 2000; 44(5-6): 207–11
Isabelle D, Puget M, Bellon G, et al. Antioxidant and peroxidative status in 312 patients with cystic fibrosis. Pediatr Pulmonol 2002 Oct; 24: 339
Birrer P, McElvaney NG, Rudeberg A, et al. Protease-antiprotease imbalance in the lungs of children with cystic fibrosis. Am J Respir Crit Care Med 1994 Jul; 150(1): 207–13
Griese M, Birrer P, Demirsoy A. Pulmonary surfactant in cystic fibrosis. Eur Respir J 1997 Sep; 10(9): 1983–8
DiMango E, Tabibi S, Ratner A, et al. Activation of NF-kappaB by adherent Pseudomonas aeruginosa in normal cystic fibrosis respiratory epithelial cells. J Clin Investig 1998; 101(11): 2598–605
Weber A, Nguyen B, Bryan R, et al. Effects of CFTR mutations on epithelial cytokine expression [abstract]. Pediatr Pulmonol 1999 Sep; Suppl. 19: 309–10
Elborn JS, Cordon SM, Western PJ, et al. Tumor necrosis-factor-alpha, resting energy expenditure and cachexia in cystic fibrosis. Clin Sci (Colch) 1993 Nov; 85(5): 563–8
Pfeffer KD, Huecksteadt TP, Hoidal JR. Expression and regulation of tumor necrosis factor in macrophages from cystic fibrosis patients. Am J Respir Cell Mol Biol 1993 Nov; 9(5): 511–9
Greally P, Hussain MJ, Vergani D, et al. Serum interleukin-1 alpha and soluble interleukin-2 receptor concentrations in cystic fibrosis. Arch Dis Child 1993 Jun; 68(6): 785–7
Wilmott RW, Frenzke M, Kociela V, et al. Plasma interleukin-1 alpha and beta, tumor necrosis factor-alpha, and lipopolysaccharide concentrations during pulmonary exacerbations of cystic fibrosis. Pediatr Pulmonol 1994 Jul; 18(1): 21–7
Lundberg JO, Nordvall SL, Weitzberg E, et al. Exhaled nitric oxide in paediatric asthma and cystic fibrosis. Arch Dis Child 1996; 75: 323–6
Kroesbergen A, Jobsis Q, Bel EH, et al. Flow-dependency of exhaled nitric oxide in children with asthma and cystic fibrosis. Eur Respir J 1999 Oct; 14(4): 871–5
Grasemann H, Michler E, Wallot M, et al. Decreased concentration of exhaled nitric oxide (NO) in patients with cystic fibrosis. Pediatr Pulmonol 1997; 24: 173–7
Balfour-Lynn IM, Laverty A, Dinwiddie R. Reduced upper airway nitric oxide in cystic fibrosis. Arch Dis Child 1996; 75: 319–22
Dotsch J, Demirakca S, Terbrack HG, et al. Airway nitric oxide in asthmatic children and patients with cystic fibrosis. Eur Respir J 1996; 9: 2537–40
Thomas SR, Kharitonov SA, Scott SF, et al. Nasal and exhaled nitric oxide is reduced in adult patients with cystic fibrosis and does not correlate with cystic fibrosis genotype. Chest 2000 Apr; 117(4): 1085–9
Ho LP, Innes JA, Greening AP. Nitrite levels in breath condensate of patients with cystic fibrosis is elevated in contrast to exhaled nitric oxide. Thorax 1998 Aug; 53(8): 680–4
Andersson C, Gaston B, Roomans G. S-Nitrosoglutathione induces functional deltaF508-CFTR in airway epithelial cells. Biochem Biophys Res Commun 2002 Sep 27; 297(3): 552–7
Snyder AH, McPherson ME, Hunt JF, et al. Acute effects of aerosolized S-nitrosoglutathione in cystic fibrosis. Am J Respir Crit Care Med 2002 Apr 1; 165(7): 922–6
Jungas T, Motta I, Duffieux F, et al. Glutathione levels and BAX activation during apoptosis due to oxidative stress in cells expressing wild-type and mutant cystic fibrosis transmembrane conductance regulator. J Biol Chem 2002 Aug 2; 277(31): 27912–8
Hosseini Nia T, Kubow S, Grey V, et al. Inhibition of Pseudomonas aeroginosa-mediated mortality and weight loss via ingestion of whey treated by hyperbaric pressure [abstract]. Pediatr Pulmonol 2002 Oct; 24: 276
Buhl R, Vogelmeier C, Critenden M, et al. Augmentation of the glutathione in the fluid lining the epithelium of the lower respiratory tract by directly administering glutathione. Proc Natl Acad Sci U S A 1990 Jun; 87: 4063–7
Buhl R, Holroyd K, Borok Z, et al. Reversal of the glutathione deficiency in the lower respiratory tract of HIV-seropositive individuals by glutathione aerosol therapy [abstract]. Clin Res 1990; 38(2): 596A
Holroyd KJ, Buhl R, Borok Z, et al. Correction of glutathione deficiency in the lower respiratory tract of HIV seropositive individuals by glutathione aerosol treatment. Thorax 1993 Oct; 48(10): 985–9
Borok Z, Buhl R, Grimes GJ, et al. Effect of glutathione aerosol on oxidant-antioxidant imbalance in idiopathic pulmonary fibrosis. Lancet 1991 Jul 17; 338: 215–6
Marrades RM, Roca J, Barbera JA, et al. Nebulized glutathione induces bronchoconstriction in patients with mild asthma. Am J Respir Crit Care Med 1997; 156: 425–30
Bernorio S, Pecis M, Zucchi A, et al. Glutathione in bronchial hyperresponsiveness. J Aerosol Med 1996; 9(2): 207–13
Testa B, Mesolella M, Testa D, et al. Glutathione in the upper respiratory tract. Ann Otol Rhinol Laryngol 1995; 104: 117–9
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 Jul; 87(1): 438–43
Bagnato GF, Gulli S, De Pasquale R, et al. Effect of inhaled glutathione on airway response to ‘Fog’ challenge in asthmatic patients. Respiration 1999 Nov-Dec; 66(6): 518–21
Griese M, Ramakers J, Krasselt A, et al. Optimized aerosol delivery of glutathione (GSH) to patients with cystic fibrosis (CF) increases alveolar GSH concentration [abstract]. Am J Respir Crit Care Med 2003 Apr; 167(7): A919
Griese M, Ramakers J, Krasselt A, et al. Improvement of alveolar glutathione and lung function but not oxidative state in cystic fibrosis. Am J Respir Crit Care Med 2004 Apr 1; 169(7): 822–8
Bishop C, Hudson VM, Hilton SC, et al. Effect of inhaled buffered glutathione (GSH) on the clinical status of cystic fibrosis patients [abstract]. Am J Respir Crit Care Med 2003 Apr; 167(7): A918
Bishop CT, Hudson VM, Hilton SC, Wilde C. A pilot study of the effect of inhaled buffered reduced glutathione on the clinical status of cystic fibrosis patients. Chest. In press
Aw TY, Wierzbicka G, Jones DP. Oral glutathione increases tissue glutathione in rats. Chem Biol Interact 1991; 80(1): 89–97
Iantomasi T, Favilli F, Marraccini P, et al. Glutathione transport system in human small intestine epithelial cells. Biochim Biophys Acta 1997 Dec 4; 1330(2): 274–83
Hunjan MK, Evered DF. Absorption of glutathione from the gastro-intestinal tract. Biochim Biophys Acta 1985 May 14; 815(2): 184–8
Favilli F, Marracini P, Iantomasi T, et al. Effect of orally administered glutathione on glutathione levels in some organs of rats: role of specific transporters. Br J Nutr 1997 Aug; 78(2): 293–300
Hagen TM, Wierzbicka GT, Sillau AH, et al. Bioavailability of dietary glutathione: effect on plasma concentration. Am J Physiol 1990 Oct; 259 (4 Pt 1): G524–9
Gao L, Broughman JR, Iwamoto T, et al. Synthetic chloride channel restores glutathione secretion in cystic fibrosis airway epithelia. Am J Physiol Lung Cell Mol Physiol 2001 Jul; 281(1): L24–30
Ciuchi E, Odetti P, Prando R. The effect of acute glutathione treatment on sorbitol level in erythrocytes from diabetic patients. Diabetes Metab 1997 Feb; 23(1): 58–60
Sechi G, Deledda MG, Bua G, et al. Reduced intravenous glutathione in the treatment of early Parkinson’s disease. Prog Neuropsychopharmacol Biol Psychiatry 1996 Oct; 20(7): 1159–70
Visca AG. Adherence to treatment and self-prescription on new drugs: an emerging problem [abstract]. Pediatr Pulmonol 2002 Oct; 24: 347
Acknowledgment
The authors have provided no information on sources of funding or conflicts of interest directly relevant to the content of this review.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hudson, V.M. New Insights Into the Pathogenesis of Cystic Fibrosis. Treat Respir Med 3, 353–363 (2004). https://doi.org/10.2165/00151829-200403060-00003
Published:
Issue Date:
DOI: https://doi.org/10.2165/00151829-200403060-00003