Linkage analysis of susceptibility to hyperoxia Nrf2 is a candidate gene

H. Y. Cho, A. E. Jedlicka, S. P.M. Reddy, L. Y. Zhang, T. W. Kensler, S. R. Kleeberger

Research output: Contribution to journalArticlepeer-review

Abstract

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, Nfe212 (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.

Original languageEnglish (US)
Pages (from-to)42-51
Number of pages10
JournalAmerican journal of respiratory cell and molecular biology
Volume26
Issue number1
DOIs
StatePublished - 2002

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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