N-ACETYLCYSTEINE DOES NOT PROTECT AGAINST TYPE-II CELL INJURY AFTER PROLONGED EXPOSURE TO HYPEROXIA IN RATS

Although the antioxidant properties of N-acetylcysteine (NAC) in vitro are widely accepted, the efficacy of NAC in the prevention of O-2 tox icity in vivo is poorly documented. The aim of our study was to invest igate the presumed protective effect of NAC on hyperoxic lung injury, focusing on gamma-glutamyltransferase (gamma-CT) activity and glutathi one (GSH) levels in lung tissue, epithelial lining fluid (ELF), and is olated rat type II cells immediately after their isolation and 48 h la ter when kept in culture in normoxia. Thirty-four male Wistar rats wer e divided in three groups (n = 10-14) and were exposed to air or to 60 or 85% O-2 for 7 days. One-half of the rats in each group received 20 0 mg/kg NAC intraperitoneally one time per day from 3 days before expo sure until the end of the experiment, and the other one-half received the vehicle. In the 85% O-2-exposed animals, NAC led to more respirato ry distress and weight loss. NAC did not prevent the rise in bronchoal veolar lavage lactate dehydrogenase and alkaline phosphatase, but it d id prevent the rise in calculated ELF volume. NAC decreased GSH levels (1.4-fold) and gamma-GT activity (1.8-fold) in the air-exposed type I I cells. In the 60% O-2-exposed group, no effects of NAC were seen (ex cept for a decrease in gamma-GT mRNA expression), but, in the 85% O-2- exposed group, NAC gave rise to higher GSH (2.6-fold) and higher gamma -GT activity (2.9-fold) in the ELF and lower GSH (6.9-fold) and higher gamma-GT activity (3.6-fold) in the type II cells. Even in culture, G SH levels remained 1.5-fold lower than in the cells from the air-expos ed animals and 2-fold lower than in the cells from the 85% O-2-exposed animals. There was increased DNA damage (as assessed by thymidine inc orporation) and apoptosis after hyperoxia, especially after 60% O-2, a nd this effect was amplified after NAC treatment. Although protective at the endothelial side, NAC treatment led to adverse effects at the e pithelial side, despite, or probably because of, restoration of the EL F GSH levels in the presence of high O-2 levels. Because NAC is rapidl y metabolized to cysteine, it is plausible that the effects of NAC are manifested through the toxic effects of cysteine.