Am. J. Respir. Cell Mol. Biol., Volume 26, Number 1, January, 2002 42-51

Linkage Analysis of Susceptibility to Hyperoxia
Nrf2 Is a Candidate Gene

Hye-Youn Cho, Anne E. Jedlicka, Sekhar P. M. Reddy, Liu-Yi Zhang, Thomas W. Kensler, and Steven R. Kleeberger

Department of Environmental Health Sciences, Johns Hopkins University, School of Public Health, Baltimore, Maryland

A strong role for reactive oxygen species (ROS) has been proposed in the pathogenesis of a number of lung diseases. Hyperoxia (> 95% oxygen) generates ROS and extensive lung damage, and has been used as a model of oxidant injury. However, the precise mechanisms of hyperoxia-induced toxicity have not been completely clarified. This study was designed to identify hyperoxia susceptibility genes in C57BL/6J (susceptible) and C3H/HeJ (resistant) mice. The quantitative phenotypes used for this analysis were pulmonary inflammatory cell influx, epithelial cell sloughing, and hyperpermeability. Genome-wide linkage analyses of intercross (F₂) and recombinant inbred cohorts identified significant and suggestive quantitative trait loci on chromosomes 2 (hyperoxia susceptibility locus 1 [Hsl1]) and 3 (Hsl2), respectively. Comparative mapping of Hsl1 identified a strong candidate gene, Nfe2l2 (nuclear factor, erythroid derived 2, like 2 or Nrf2) that encodes a transcription factor NRF2 which regulates antioxidant and phase 2 gene expression. Strain-specific variation in lung Nrf2 messenger RNA expression and a T  C substitution in the B6 Nrf2 promoter that cosegregated with susceptibility phenotypes in F₂ animals supported Nrf2 as a candidate gene. Results from this study have important implications for understanding the mechanisms through which oxidants mediate the pathogenesis of lung disease.

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