Linkage Analysis of Susceptibility to Hyperoxia: Nrf2 Is a Candidate Gene
HY Cho, AE Jedlicka, SPM Reddy… - American journal of …, 2002 - atsjournals.org
HY Cho, AE Jedlicka, SPM Reddy, LY Zhang, TW Kensler, SR Kleeberger
American journal of respiratory cell and molecular biology, 2002•atsjournals.orgA 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 …
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 …
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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