RT Journal Article SR Electronic T1 High-dose oral N-acetylcysteine, a glutathione prodrug, modulates inflammation in cystic fibrosis JF Proceedings of the National Academy of Sciences of the United States of America JO Proc Natl Acad Sci U S A FD National Academy of Sciences SP 4628 OP 4633 DO 10.1073/pnas.0511304103 VO 103 IS 12 A1 Tirouvanziam, Rabindra A1 Conrad, Carol K. A1 Bottiglieri, Teodoro A1 Herzenberg, Leonore A. A1 Moss, Richard B. A1 Herzenberg, Leonard A. YR 2006 UL http://www.pnas.org/content/103/12/4628.abstract AB Neutrophilic airway inflammation is a hallmark of cystic fibrosis (CF). As high oxidant producers, airway neutrophils contribute largely to the systemic redox imbalance seen in CF. In turn, this chronic and profound imbalance can impact circulating neutrophils before their migration into airways. Indeed, in 18 CF patients with stable disease, blood neutrophils were readily deficient in the pivotal antioxidant glutathione (P = 0.003, compared with 9 healthy controls). In a phase 1 study, this deficiency was improved (P = 0.025) by the glutathione prodrug N-acetylcysteine, given orally in high doses (0.6 to 1.0 g three times daily, for 4 weeks). This treatment was safe and markedly decreased sputum elastase activity (P = 0.006), the strongest predictor of CF pulmonary function. Consistently, neutrophil burden in CF airways was decreased upon treatment (P = 0.003), as was the number of airway neutrophils actively releasing elastase-rich granules (P = 0.005), as measured by flow cytometry. Pulmonary function measures were not improved, as expected with short-term treatment. After excluding data from subjects without baseline airway inflammation, positive treatment effects were more pronounced and included decreased sputum IL-8 levels (P = 0.032). Thus, high-dose oral N-acetylcysteine has the potential to counter the intertwined redox and inflammatory imbalances in CF.