Comparison of peroxiredoxin 6 and GSH peroxidase 1 null mice on sensitivity to oxidative stress

Cytosolic GSH peroxidase (GPx1) is a classical antioxidant enzyme while peroxiredoxin 6 (Prdx6) is a recently described GSH peroxidase that has been increasingly recognized for its role in defense against oxidative lung injury. This study compared the effect of deletion of these enzymes by gene targeting on lung injury during exposure to 100% O 2 at 1 ata. Expression levels of SOD 1 and 2, GPx1, and catalase were similar in Prdx6 null and C57 Bl/6 wild type (WT) lung homogenate. The time to 50% mortality (96 h in WT mice) was 84 h in GPx1 null and 60 h in Prdx6 null. With O 2 exposure for 72h, Prdx6 null mice showed, compared to WT, significantly (P< 0.05) increased wet/dry lung weight (7.96 vs. 6.32), protein (404 vs. 190 μg/g body wt) and nucleated cells (3.1 x 10 5 vs. 2.3 x 10 5 ) in the bronchoalveolar lavage fluid, and lung TBARS (126 vs. 50 pmol/mg prot). By contrast, values for these parameters in GPx1 null mice were close to the WT and significantly less than Prdx6 null. Histologic examination confirmed greater injury in the Prdx6 null compared to both GPx1 null and WT. Peroxidase activity measured in Prdx6 null lung homogenate compared to WT showed 95% loss of phosphatidylcholine hydroperoxide (PCOOH) reduction but no difference with H 2 O 2 as substrate; GPx1 null lung showed the inverse (no change with PCOOH and 90% loss with H 2 O 2 ). These results indicate that the anti‐oxidant protection provided by Prdx6 in hyperoxia exceeds that of GPx1 and suggest that the mechanism is due to its ability to directly reduce peroxidized membrane lipids [HL79063].