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.