Linkage analysis of susceptibility to hyperoxia. Nrf2 is a candidate gene.
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.
Cho
Hye-Youn
HY
Department of Environmental Health Sciences, Johns Hopkins University, School of Public Health, Baltimore, Maryland, USA.
Jedlicka
Anne E
AE
Reddy
Sekhar P M
SP
Zhang
Liu-Yi
LY
Kensler
Thomas W
TW
Kleeberger
Steven R
SR
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D018893:Bronchoalveolar Lavage; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D016678:Genome; D005838:Genotype; D000860:Hypoxia; D008168:Lung / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009154:Mutation; D051267:NF-E2-Related Factor 2; D010100:Oxygen / Q000378:metabolism; D010641:Phenotype; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species; D013045:Species Specificity; D015534:Trans-Activators / Q000235:genetics*
D000975:Antioxidants; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D015534:Trans-Activators; D010100:Oxygen