Transgenic Mice Overexpressing Peroxiredoxin 6 Show Increased Resistance to Lung Injury in Hyperoxia

Abstract

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.

Reactive Oxygen Species in Inflammation and Tissue Injury

“…All subtypes of Peroxiredoxins are expressed in lung tissue (190). The Prx6 knockout mice exhibit enhanced hypersensitivity to hyperoxia-induced lung injury (439), whereas Prx6 overexpressed mice were resistant to such damage (441). Prx1 knockout mice were also reported to be prone to bleomycin-induced lung inflammation (214) and allergic airway inflammation (187).…”

Targeted disruption of the glutaredoxin 1 gene does not sensitize adult mice to tissue injury induced by ischemia/reperfusion and hyperoxia

“…Previous studies have shown that overexpression of manganese superoxide dismutase, extracellular superoxide dismutase (ECSOD), or 1-Cys peroxiredoxin (Prdx6) in the lungs of transgenic mice greatly attenuates lung damage resulting from exposure to hyperoxia [47][48][49]. Conversely, knockout mice deficient in ECSOD or Prdx6 are particularly vulnerable to the same model of lung injury [50,51].…”

A novel lysophosphatidylcholine acyl transferase activity is expressed by peroxiredoxin 6

“…These activities require the binding of Prdx6 to phospholipids in a specifi c orientation in relation to cys47, the active site for GPx activity, and to S32-H26-D140, the catalytic triad for PLA 2 activity ( 2, 3 ). The GPx activity of Prdx6 plays a key role in the antioxidant defense of the lung, as well as other organs (4)(5)(6)(7)(8), and has been shown recently to participate in the repair of peroxidized cell membranes by reduction of phospholipid hydroperoxides ( 3,9 ). The PLA 2 activity of Prdx6 also participates in the repair of peroxidized cell membranes by liberating the sn -2 oxidized fatty acid to generate lysophosphatidylcholine (LPC) ( 9,10 ).…”