Linkage analysis of susceptibility to hyperoxia -: Nrf2 is a candidate gene

被引:154
作者
Cho, HY [1 ]
Jedlicka, AE [1 ]
Reddy, SPM [1 ]
Zhang, LY [1 ]
Kensler, TW [1 ]
Kleeberger, SR [1 ]
机构
[1] Johns Hopkins Univ, Sch Publ Hlth, Dept Environm Hlth Sci, Div Physiol, Baltimore, MD 21205 USA
关键词
D O I
10.1165/ajrcmb.26.1.4536
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 (F-2) 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, Nfe2/2 (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 F-2 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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页码:42 / 51
页数:10
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