van Klaveren R J, Dinsdale D, Pype J L, Demedts M, Nemery B
Laboratory of Pneumology, Katholieke Universiteit Leuven, Belgium.
Am J Physiol. 1997 Sep;273(3 Pt 1):L548-55. doi: 10.1152/ajplung.1997.273.3.L548.
Although the antioxidant properties of N-acetylcysteine (NAC) in vitro are widely accepted, the efficacy of NAC in the prevention of O2 toxicity in vivo is poorly documented. The aim of our study was to investigate the presumed protective effect of NAC on hyperoxic lung injury, focusing on gamma-glutamyltransferase (gamma-GT) activity and glutathione (GSH) levels in lung tissue, epithelial lining fluid (ELF), and isolated rat type II cells immediately after their isolation and 48 h later when kept in culture in normoxia. Thirty-four male Wistar rats were divided in three groups (n = 10-14) and were exposed to air or to 60 or 85% O2 for 7 days. One-half of the rats in each group received 200 mg/kg NAC intraperitoneally one time per day from 3 days before exposure until the end of the experiment, and the other one-half received the vehicle. In the 85% O2-exposed animals, NAC led to more respiratory distress and weight loss. NAC did not prevent the rise in bronchoalveolar lavage lactate dehydrogenase and alkaline phosphatase, but it did 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 II cells. In the 60% O2-exposed group, no effects of NAC were seen (except for a decrease in gamma-GT mRNA expression), but, in the 85% O2-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, GSH levels remained 1.5-fold lower than in the cells from the air-exposed animals and 2-fold lower than in the cells from the 85% O2-exposed animals. There was increased DNA damage (as assessed by thymidine incorporation) and apoptosis after hyperoxia, especially after 60% O2, and this effect was amplified after NAC treatment. Although protective at the endothelial side, NAC treatment led to adverse effects at the epithelial side, despite, or probably because of, restoration of the ELF GSH levels in the presence of high O2 levels. Because NAC is rapidly metabolized to cysteine, it is plausible that the effects of NAC are manifested through the toxic effects of cysteine.
尽管N-乙酰半胱氨酸（NAC）在体外的抗氧化特性已被广泛认可，但其在体内预防氧中毒的功效却鲜有文献记载。我们研究的目的是调查NAC对高氧性肺损伤的假定保护作用，重点关注肺组织、上皮衬液（ELF）以及分离的大鼠II型细胞在刚分离后以及在常氧条件下培养48小时后的γ-谷氨酰转移酶（γ-GT）活性和谷胱甘肽（GSH）水平。34只雄性Wistar大鼠被分为三组（每组n = 10 - 14），分别暴露于空气、60%或85%的氧气中7天。每组中有一半的大鼠从暴露前3天开始每天腹腔注射200mg/kg NAC，直至实验结束，另一半则注射赋形剂。在暴露于85%氧气的动物中，NAC导致更多的呼吸窘迫和体重减轻。NAC未能阻止支气管肺泡灌洗乳酸脱氢酶和碱性磷酸酶的升高，但确实阻止了计算得出的ELF体积的增加。NAC降低了暴露于空气中的II型细胞中的GSH水平（1.4倍）和γ-GT活性（1.8倍）。在暴露于60%氧气的组中，未观察到NAC的作用（γ-GT mRNA表达降低除外），但在暴露于85%氧气的组中，NAC使ELF中的GSH升高（2.6倍）和γ-GT活性升高（2.9倍），而使II型细胞中的GSH降低（6.9倍）和γ-GT活性升高（3.6倍）。即使在培养过程中，GSH水平仍比暴露于空气中的动物的细胞低1.5倍，比暴露于85%氧气的动物的细胞低2倍。高氧后，尤其是在暴露于60%氧气后，DNA损伤（通过胸苷掺入评估）和细胞凋亡增加，而NAC处理后这种效应被放大。尽管NAC在内皮方面具有保护作用，但尽管或可能由于在高氧水平下ELF中GSH水平的恢复，NAC处理在上皮方面却导致了不良影响。由于NAC迅速代谢为半胱氨酸，NAC的作用可能是通过半胱氨酸的毒性作用表现出来的。
