Comparison of glutathione peroxidase 1 and peroxiredoxin 6 in protection against oxidative stress in the mouse lung.

Peroxiredoxin 6 (Prdx6) and cytosolic GSH peroxidase (GPx1), both GSH-dependent peroxidases, were compared for the effects of their knockout on injury and lipid peroxidation in: (a) lungs of mice exposed to 0.85 or 1.0atm O(2), (b) isolated perfused mouse lungs exposed to 5mM tert-butylhydroperoxide (t-BOOH) or 1mM paraquat, and (c) primary mouse pulmonary microvascular endothelial cells exposed to 50muM t-BOOH. Derangements in GPx1 null were similar or slightly greater than in wild type for all parameters in the various models of oxidant stress, whereas Prdx6 null showed markedly increased effects. GSH peroxidase activity with phosphatidylcholine hydroperoxide as substrate in GPx1-null lung homogenate was decreased only slightly vs wild type, whereas activity in Prdx6-null lungs was decreased by ~95%, indicating that Prdx6 is the major enzyme for reduction of oxidized lung phospholipids. Expression levels of oxidant-related genes measured with a PCR-based gene array indicated no significant differences between the Prdx6 and the GPx1 null except for the target genes and IL-19. Thus, Prdx6-null mice are significantly more sensitive to oxidant stress compared to GPx1 null, suggesting that scavenging of phospholipid hydroperoxides by Prdx6 plays a major role in lung antioxidant defense.