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 (GSHt = GSH +/- 2 x GSSG: 3.43 +/- 0.30 microM versus 4.20 +/- 0.66 microM, p < 0.05) and of reduced glutathione (GSH: 2.58 +/- 0.24 microM versus 3.42 +/- 0.54 microM, p < 0.005) in native BAL fluid and in the epithelial lining fluid (GSHt: 267.3 +/- 26.0 microM versus 367.1 +/- 36.0 microM, p < 0.005; GSH: 204.5 +/- 20.7 microM versus 302.9 +/- 32.2 microM, 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.