Am. J. Respir. Crit. Care Med., Volume 156, Number 6, December 1997, 1897-1901

Antioxidative and Clinical Effects of High-dose N-Acetylcysteine in Fibrosing Alveolitis
Adjunctive Therapy to Maintenance Immunosuppression

JÜRGEN BEHR, KONRAD MAIER, BARBARA DEGENKOLB, FRITZ KROMBACH, and CLAUS VOGELMEIER

Abteilung für Pneumologie, Medizinische Klinik I, and Institut für Chirurgische Forschung, Klinikum Grosshadern der Ludwig-Maximilians-Universität München, München; and Institut für Inhalationsbiologie, GSF Forschungszentrum für Umwelt und Gesundheit, Neuherberg, Germany

In fibrosing alveolitis (FA), activated phagocytes cause excessive oxidative stress in the lower respiratory tract. Additionally, levels of glutathione, a major antioxidant of the human lung, are markedly reduced. Since N-acetylcysteine (NAC) is a known precursor for glutathione synthesis, we investigated the effect of NAC on redox balance and lung function in FA. Eighteen patients with an established diagnosis of FA were treated with 600 mg NAC three times daily for 12 wk in addition to their latest immunosuppressive therapy. Before and after NAC therapy, pulmonary function tests (PFTs) and bronchoalveolar lavage (BAL) were performed. BAL fluid was analyzed with regard to cell differential, glutathione status, and methionine sulfoxide content of BAL proteins (Met(O)), as an indicator of oxidative stress at the alveolar surface. There was an increase of total glutathione (GSH_t = GSH + 2 × GSSG: 3.43 ± 0.30 µM versus 4.20 ± 0.66 µM, p < 0.05) and of reduced glutathione (GSH: 2.58 ± 0.24 µM versus 3.42 ± 0.54 µM, p < 0.005) in native BAL fluid and in the epithelial lining fluid (GSH_t: 267.3 ± 26.0 µM versus 367.1 ± 36.0 µM, p < 0.005; GSH: 204.5 ± 20.7 µM versus 302.9 ± 32.2 µM, p < 0.005). The increase of GSH was accompanied by a decrease of Met(O) (6.83 ± 0.71% versus 4.60 ± 0.40%, p < 0.005). PFTs significantly improved during NAC treatment. We conclude that high-dose NAC significantly improved the antioxidant screen of the lungs by elevating GSH levels. Moreover, the decrease of Met(O) levels indicated an antioxidant effect at the alveolar surface. These biochemical changes were accompanied by an improvement of PFTs in patients under maintenance immunosuppression. NAC supplementation should, therefore, be considered as an adjunct therapy for FA.

This article has been cited by other articles:

				R. Kim and K. C. Meyer Review: Therapies for interstitial lung disease: past, present and future Therapeutic Advances in Respiratory Disease, October 1, 2008; 2(5): 319 - 338. [Abstract] [PDF]

				A U Wells, N Hirani, and on behalf of the BTS Interstitial Lung Disease Gui Interstitial lung disease guideline Thorax, September 1, 2008; 63(Suppl_5): v1 - v58. [Full Text] [PDF]

				J. Behr and J. H. Ryu Pulmonary hypertension in interstitial lung disease Eur. Respir. J., June 1, 2008; 31(6): 1357 - 1367. [Abstract] [Full Text] [PDF]

				P. Rogliani, M. Mura, M. Assunta Porretta, and C. Saltini Review: New perspectives in the treatment of idiopathic pulmonary fibrosis Therapeutic Advances in Respiratory Disease, April 1, 2008; 2(2): 75 - 93. [Abstract] [PDF]

				Y. Kabuyama, K. Oshima, T. Kitamura, M. Homma, J. Yamaki, M. Munakata, and Y. Homma Involvement of selenoprotein P in the regulation of redox balance and myofibroblast viability in idiopathic pulmonary fibrosis. Genes Cells, November 1, 2007; 12(11): 1235 - 1244. [Abstract] [Full Text] [PDF]

				P. K. Vayalil, K. E. Iles, J. Choi, A.-K. Yi, E. M. Postlethwait, and R.-M. Liu Glutathione suppresses TGF-beta-induced PAI-1 expression by inhibiting p38 and JNK MAPK and the binding of AP-1, SP-1, and Smad to the PAI-1 promoter Am J Physiol Lung Cell Mol Physiol, November 1, 2007; 293(5): L1281 - L1292. [Abstract] [Full Text] [PDF]

				N. Walter, H. R. Collard, and T. E. King Jr. Current perspectives on the treatment of idiopathic pulmonary fibrosis. Proceedings of the ATS, January 1, 2006; 3(4): 330 - 338. [Abstract] [Full Text] [PDF]

				M. Demedts, J. Behr, R. Buhl, U. Costabel, R. Dekhuijzen, H. M. Jansen, W. MacNee, M. Thomeer, B. Wallaert, F. Laurent, et al. High-Dose Acetylcysteine in Idiopathic Pulmonary Fibrosis. N. Engl. J. Med., November 24, 2005; 353(21): 2229 - 2242. [Abstract] [Full Text] [PDF]

				D. Bouros and K. M. Antoniou Current and future therapeutic approaches in idiopathic pulmonary fibrosis Eur. Respir. J., October 1, 2005; 26(4): 693 - 703. [Abstract] [Full Text] [PDF]

				V. L. Kinnula, C. L. Fattman, R. J. Tan, and T. D. Oury Oxidative Stress in Pulmonary Fibrosis: A Possible Role for Redox Modulatory Therapy Am. J. Respir. Crit. Care Med., August 15, 2005; 172(4): 417 - 422. [Abstract] [Full Text] [PDF]

				N. Khalil and R. O'Connor Idiopathic pulmonary fibrosis: current understanding of the pathogenesis and the status of treatment Can. Med. Assoc. J., July 20, 2004; 171(2): 153 - 160. [Abstract] [Full Text] [PDF]

				M. L. Rubio, M. C. Martin-Mosquero, M. Ortega, G. Peces-Barba, and N. Gonzalez-Mangado Oral N-Acetylcysteine Attenuates Elastase-Induced Pulmonary Emphysema in Rats Chest, April 1, 2004; 125(4): 1500 - 1506. [Abstract] [Full Text] [PDF]

				R.-M. Liu, Y. Liu, H. J. Forman, M. Olman, and M. M. Tarpey Glutathione regulates transforming growth factor-{beta}-stimulated collagen production in fibroblasts Am J Physiol Lung Cell Mol Physiol, January 1, 2004; 286(1): L121 - L128. [Abstract] [Full Text] [PDF]

				M. Mata, A. Ruiz, M. Cerda, M. Martinez-Losa, J. Cortijo, F. Santangelo, A. Serrano-Mollar, A. Llombart-Bosch, and E.J. Morcillo Oral N-acetylcysteine reduces bleomycin-induced lung damage and mucin Muc5ac expression in rats Eur. Respir. J., December 1, 2003; 22(6): 900 - 905. [Abstract] [Full Text] [PDF]

				C. Neurohr, A-G. Lenz, I. Ding, H. Leuchte, T. Kolbe, and J. Behr Glutamate-cysteine ligase modulatory subunit in BAL alveolar macrophages of healthy smokers Eur. Respir. J., July 1, 2003; 22(1): 82 - 87. [Abstract] [Full Text] [PDF]

				A Serrano-Mollar, D Closa, J Cortijo, E J Morcillo, N Prats, M Gironella, J Panes, J Rosello-Catafau, and O Bulbena P-selectin upregulation in bleomycin induced lung injury in rats: effect of N-acetyl-L-cysteine Thorax, July 1, 2002; 57(7): 629 - 634. [Abstract] [Full Text] [PDF]

				K.M. Beeh, J. Beier, I.C. Haas, O. Kornmann, P. Micke, and R. Buhl Glutathione deficiency of the lower respiratory tract in patients with idiopathic pulmonary fibrosis Eur. Respir. J., June 1, 2002; 19(6): 1119 - 1123. [Abstract] [Full Text] [PDF]

				J. Behr, B. Degenkolb, F. Krombach, and C. Vogelmeier Intracellular glutathione and bronchoalveolar cells in fibrosing alveolitis: effects of N-acetylcysteine Eur. Respir. J., May 1, 2002; 19(5): 906 - 911. [Abstract] [Full Text] [PDF]

				B. Nemery, A. Bast, J. Behr, P.J.A. Borm, S.J. Bourke, Ph. Camus, P. De Vuyst, H.M. Jansen, V.L. Kinnula, D. Lison, et al. Interstitial lung disease induced by exogenous agents: factors governing susceptibility Eur. Respir. J., July 1, 2001; 18(32_suppl): 30S - 42s. [Abstract] [Full Text] [PDF]

				J. Cortijo, M. Cerda-Nicolas, A. Serrano, G. Bioque, J.M. Estrela, F. Santangelo, A. Esteras, A. Llombart-Bosch, and E.J. Morcillo Attenuation by oral N-acetylcysteine of bleomycin-induced lung injury in rats Eur. Respir. J., June 1, 2001; 17(6): 1228 - 1235. [Abstract] [Full Text] [PDF]

				M. Selman, T. E. King Jr., and A. Pardo Idiopathic Pulmonary Fibrosis: Prevailing and Evolving Hypotheses about Its Pathogenesis and Implications for Therapy Ann Intern Med, January 16, 2001; 134(2): 136 - 151. [Abstract] [Full Text] [PDF]

				S.-I. HAGIWARA, Y. ISHII, and S. KITAMURA Aerosolized Administration of N-Acetylcysteine Attenuates Lung Fibrosis Induced by Bleomycin in Mice Am. J. Respir. Crit. Care Med., July 1, 2000; 162(1): 225 - 231. [Abstract] [Full Text]

				J. BEHR, B. DEGENKOLB, T. BEINERT, F. KROMBACH, and C. VOGELMEIER Pulmonary Glutathione Levels in Acute Episodes of Farmer's Lung Am. J. Respir. Crit. Care Med., June 1, 2000; 161(6): 1968 - 1971. [Abstract] [Full Text]

				W. W. DOUGLAS, J. H. RYU, and D. R. SCHROEDER Idiopathic Pulmonary Fibrosis . Impact of Oxygen and Colchicine, Prednisone, or No Therapy on Survival Am. J. Respir. Crit. Care Med., April 1, 2000; 161(4): 1172 - 1178. [Abstract] [Full Text]

				S. Abe, H. Takizawa, I. Sugawara, and S. Kudoh Diesel Exhaust (DE)-Induced Cytokine Expression in Human Bronchial Epithelial Cells . A Study with a New Cell Exposure System to Freshly Generated DE In Vitro Am. J. Respir. Cell Mol. Biol., March 1, 2000; 22(3): 296 - 303. [Abstract] [Full Text]

				T. King Idiopathic Pulmonary Fibrosis: Diagnosis and Treatment . International Consensus Statement Am. J. Respir. Crit. Care Med., February 1, 2000; 161(2): 646 - 664. [Full Text]