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American Journal of Respiratory and Critical Care Medicine Vol 166. pp. S51-S56, (2002)
© 2002 American Thoracic Society

Article

Transgenic and Knockout Models for Studying the Role of Lung Antioxidant Enzymes in Defense against Hyperoxia

Ye-Shih Ho

Institute of Environmental Health Sciences and Department of Biochemistry and Molecular Biology, Wayne State University, Detroit, Michigan

Correspondence and requests for reprints should be addressed to Ye-Shih Ho, Ph.D., Institute of Environmental Health Sciences, Wayne State University, 2727 Second Avenue, Detroit, MI 48201. E-mail: yho{at}wayne.edu

ABSTRACT

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 ß-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.

Key Words: reactive oxygen species • superoxide dismutase • glutathione peroxidase • oxidant-mediated tissue injury




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