Linkage analysis of susceptibility to hyperoxia -: Nrf2 is a candidate gene
Linkage analysis of susceptibility to hyperoxia -: Nrf2 is a candidate gene
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DOI：
10.1165/ajrcmb.26.1.4536
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发表时间：
2002-01-01
影响因子：
6.4
通讯作者：
Kleeberger, SR
中科院分区：
文献类型：
--
作者：
Cho, HY;Jedlicka, AE;Kleeberger, SR
活性氧（ROS）在许多肺部疾病的发病机制中起着重要作用。高氧（> 95%氧）产生ROS和广泛的肺损伤，并已被用作氧化损伤的模型。然而，高氧诱导的毒性的确切机制尚未完全阐明。本研究旨在鉴定C57 BL/6 J（易感）和C3 H/HeJ（耐药）小鼠的高氧易感基因。用于该分析的定量表型为肺部炎性细胞流入、上皮细胞脱落和高通透性。全基因组连锁分析的intercross（F-2）和重组近交群体确定显着的和暗示的数量性状基因座上的染色体2（高氧敏感性基因座1 [Hsl 1]）和3（Hsl 2），分别。Hsl 1的比较作图鉴定了一个强候选基因，Nfe 2/2（核因子，红细胞衍生2，like 2或Nrf 2），其编码调节抗氧化剂和2相基因表达的转录因子NRF 2。肺Nrf 2信使RNA表达的菌株特异性变化和B6 Nrf 2启动子中的T -> C取代与F-2动物中的易感性表型共分离，支持Nrf 2作为候选基因。这项研究的结果对于理解氧化剂介导肺部疾病发病机制具有重要意义。
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.