Peroxiredoxin 6 (Prd x 6) is a novel peroxidase enzyme that is expressed at a high level in the lung. We tested the hypothesis that transgenic (Tg) mice overexpressing Prd x 6 would exhibit increased resistance to hyperoxia-induced lung injury. Wild-type and Tg mice were exposed to 100% O(2) and evaluated for survival, lung histopathology, total protein, and nucleated cells in bronchoalveolar lavage fluid (BALF), and oxidation of lung protein and lipids. Prd x 6 protein expression and enzyme activity were approximately 3-fold higher in Tg lungs compared with wild-type. Tg mice survived longer during exposure to 100% O(2) (LT(50) 104+/-2.8 h in Tg versus 88.9+/-1.1 h for wild-type). Lung wet/dry weight ratio and total protein and nucleated cell count in lung lavage fluid were significantly greater in wild-type mice at 72 and 96 h of hyperoxia compared with Tg mice. At 96 h of hyperoxia, Tg mice had less epithelial cell necrosis, perivascular edema, and inflammatory cell recruitment by light microscopy, and lower TBARS and protein carbonyls in lung homogenate (P<0.05). These results show that Tg mice have increased defense against lung injury in hyperoxia, providing evidence that Prd x 6 functions as a lung antioxidant enzyme.