N-acetylcysteine attenuates phosgene-induced acute lung injury via up-regulation of Nrf2 expression.
Previous studies indicated that oxidative stress was involved in phosgene-induced acute lung injury (ALI) and many antioxidants had been used to prevent ALI. N-acetylcysteine (NAC) had been used to protect ALI induced by various types of oxidative stress. Considering the limited information of NAC on phosgene-induced ALI, the purpose of this study was to elucidate the molecular mechanisms of phosgene-induced ALI and the protective effects of NAC. This study discovered that intraperitoneal administration of NAC significantly alleviated phosgene-induced pulmonary edema, as confirmed by decreased lung wet to dry weight ratio and oxidative stress markers. The content of l-gamma-glutamyl-l-cysteinyl-glycine (glutathione; GSH) and the ratio of the reduced and disulfide forms (GSH/GSSG), significant indicators of the antioxidative ability, were apparently inhibited by phosgene exposure. However, both indicators could be reversed by NAC administration, indicating that dysregulation of redox status of glutathione might be the cause of phosgene-induced ALI. The nuclear factor (NF)-E2-related factor 2 (Nrf2), which has been proven to up-regulate the expression of glutathione reductase (GR), was obviously decreased by phosgene exposure. However, NAC administration elevated Nrf2 expression significantly. In conclusion, these data provided the first evidences showing that it was the transcriptional factor Nrf2 that connected phosgene-induced ALI with GSH metabolism. NAC protected against oxidative stress through acting on this newly disclosed Nrf2/GR/GSH pathway, by which NAC elevated the biosynthesis of protective GSH to repair and reconstitute the defense system destroyed by phosgene.
Ji
Lin
L
Department of Toxicology, The Fourth Military Medical University, 17 Changle West Road, Xi'an, China.
Liu
Rui
R
Zhang
Xiao Di
XD
Chen
Hong Li
HL
Bai
Hua
H
Wang
Xin
X
Zhao
Hai Long
HL
Liang
Xin
X
Hai
Chun Xu
CX
D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use*; D055371:Acute Lung Injury / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*; D000818:Animals; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000502:physiology; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors / Q000502:physiology; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis* / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010705:Phosgene / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D051267:NF-E2-Related Factor 2; D010705:Phosgene; D005980:Glutathione Reductase; D005978:Glutathione; D000111:Acetylcysteine