Cho Hye-Youn, Wang Xuting, Li Jianying, Bell Douglas A, Kleeberger Steven R
Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709.
Genomic Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709.
Curr Opin Toxicol. 2016 Dec;1:125-133. doi: 10.1016/j.cotox.2016.10.006. Epub 2016 Oct 29.
Hyperoxia exposure of newborn rodents has served as a model for bronchopulmonary dysplasia (BPD) phenotypes found in a sub-population of human premature infants. We previously demonstrated that Nrf2 modulates molecular events during saccular-to-alveolar lung maturation and also has a protective role in the pathogenesis of hyperoxia-induced acute lung injury, mortality, arrest of saccular-to-alveolar transition, and lung injury, using -deficient and wild-type neonate mice. In this review, we describe how whole-genome transcriptome analyses can identify the means through which Nrf2 transcriptionally modulates organ injury and morphology, cellular growth/proliferation, vasculature development, and immune response during BPD-like pathogenesis. We illustrate how recently developed bioinformatics tools can be used to identify sets of Nrf2-dependently modulated genes in the BPD model, and elucidate direct Nrf2 downstream targets and chemicals/drugs that may act on them. These approaches will provide significant insights into promising therapeutic agents for Nrf2-dependent treatments of complications of preterm birth like BPD.
新生啮齿动物暴露于高氧环境已成为人类早产婴儿亚群中出现的支气管肺发育不良（BPD）表型的模型。我们之前利用Nrf2基因敲除和野生型新生小鼠证明，Nrf2在肺泡囊到肺泡的肺成熟过程中调节分子事件，并且在高氧诱导的急性肺损伤、死亡率、肺泡囊到肺泡转变停滞以及肺损伤的发病机制中具有保护作用。在这篇综述中，我们描述了全基因组转录组分析如何能够确定Nrf2在BPD样发病机制中对器官损伤和形态、细胞生长/增殖、血管发育以及免疫反应进行转录调节的方式。我们说明了如何利用最近开发的生物信息学工具来识别BPD模型中Nrf2依赖性调节的基因集，并阐明Nrf2的直接下游靶点以及可能作用于这些靶点的化学物质/药物。这些方法将为有前景的治疗药物提供重要见解，用于Nrf2依赖性治疗早产并发症如BPD。
