Lung macrophages may play a relevant role in oxidative processes producing both superoxide anion ðO À 2 Þ and NO. In this view, an antioxidant therapy can be useful in the treatment of systemic sclerosis (SSc) patients. N-Acetylcysteine (NAC) is able to expand natural antioxidant defenses by increasing intracellular gluthatione concentration and it has been proposed as an antioxidant therapy in respiratory distress syndromes. The aim of our study was to determine whether lung macrophages obtained from SSc patient bronchoalveolar lavage (BAL) express the inducible form of nitric oxide synthase (iNOS) and whether NAC can reduce the peroxynitrite ðONOO À Þ and O À 2 production of these cells. Alveolar macrophages were isolated from BAL of 32 patients and used for the immunocytochemical determination of iNOS, and the production of ONOO À and O À 2 was measured by fluorimetric or spectrophotometric methods, respectively. Lung macrophages obtained from SSc patients expressed a higher level of iNOS compared to healthy subject cells. NAC preincubation (5 Â 10 À5 M, 24 h) significantly reduced ()21%) the ONOO À production in formyl Met-Leu-Phe (fMLP)-activated cells and slightly reduced it under resting conditions, whereas NAC preincubation was unable to modify the release of O À 2 both in basal condition and in fMLP-stimulated cells. We conclude that since SSc lung macrophages express high levels of iNOS and produce a significant quantity of ONOO À , NAC administration reduces ONOO À production and can be an useful treatment to alleviate SSc symptoms. Ó 2002 Elsevier Science (USA). All rights reserved.Keywords: Systemic sclerosis; Inducible nitric oxide synthase; N-acetylcysteine; Peroxynitrite; Superoxide anion; Alveolar macrophages Nitric oxide (NO) 1 is physiologically produced by constitutive nitric oxide synthase isoforms (cNOS) and in several pathophysiological conditions by an inducible nitric oxide synthase isoform (iNOS). In systemic sclerosis (SSc) patients, NO is increased in exhaled air [1,2] while it is decreased in those patients with pulmonary hypertension [2,3]. Moreover, serum NO levels are enhanced [4], iNOS is highly expressed in mononuclear cells infiltrating the skin [4] and peripheral blood mononuclear cells produce increased NO levels when stimulated with IL-1 [5]. NO can be synthesized by different kinds of cells. Among these cells, macrophages play a pivotal role in the inflammatory infiltrate and, in patients with tubercolosis, iNOS is expressed in alveolar macrophages [6]. Inflammatory cells produce reactive oxygen species (ROS) that, reacting with NO, form tissue-damaging NO-derived inflammatory oxidants. ROS