Transgenic and knockout models for studying the role of lung antioxidant enzymes in defense against hyperoxia.
Although a role for antioxidant enzymes in preventing lung injury from hyperoxic exposure has been implicated in a number of early studies, a direct test for the hypothesis was not available. We intended to address this question using genetically modified mice in which the expression of a single antioxidant enzyme was either enhanced or diminished. We reasoned that if an antioxidant enzyme functions in protecting lung cells against oxidant-mediated injury, the level of its gene expression would correlate with the degree of tolerance to hyperoxia. Overexpression of functional human manganese superoxide dismutase (MnSOD) in lung alveolar type I and type II cells, fibroblasts, and capillary endothelial cells in strain B6C3 mice was achieved by incorporating a human beta-actin promoter-based MnSOD transgene into the mouse genome. However, MnSOD overexpression failed to prolong the survival of transgenic mice on exposure to greater than 99% oxygen compared with wild-type mice. In addition, mice deficient in copper-zinc superoxide dismutase or cellular glutathione peroxidase exhibited a marked sensitivity to numerous models of oxidant tissue injury but were not hypersensitive to hyperoxia. These data suggest that the role of these three antioxidant enzymes in preventing oxidant-mediated lung injury from hyperoxic exposure is negligible, and other cellular antioxidant enzymes and systems may be primarily used by the lungs in defense against hyperoxia.
Ho
Ye-Shih
YS
Institute of Environmental Health Sciences and Department of Biochemistry and Molecular Biology, Wayne State University, Detroit, Michigan 48201, USA. yho@wayne.edu
D000818:Animals; D005979:Glutathione Peroxidase / Q000378:metabolism / Q000502:physiology*; D018496:Hyperoxia / Q000201:enzymology / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D017382:Reactive Oxygen Species / Q000009:adverse effects*; D013482:Superoxide Dismutase / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*
D017382:Reactive Oxygen Species; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase