目前认为氧化应激反应几乎是所有支气管肺发育不良（BPD）早产儿发病的必经之路，然而DNA损伤作为氧化应激最严重的损伤形式，是否参与该病发生尚不清楚。本项目在前期发现并证实DNA损伤贯穿于氧化应激全程的基础上，率先提出了肺上皮细胞（AT-Ⅱ）DNA修复障碍是影响BPD肺泡发育的最早期环节。首先建立BPD动物模型及氧化应激细胞模型，应用基因转染、Western blot及透射电镜等检测方法：1）证实经OGG1基因的经典DNA修复途径虽表达上调，但不足以维持BPD早期肺上皮细胞DNA稳定性；2）验证自噬系统的过度激活，削弱了OGG1特异性识别并切除DNA链中8-oxoG作用，干扰了DNA损伤修复过程；3）阐明抗氧化应激通路Nrf2表达抑制，“屏蔽”自噬蛋白p62，引发自噬事件的分子机制。最终在动物整体水平，通过靶向调节Nrf2--自噬--DNA损伤，提供改善BPD肺泡发育不良结局的早期干预途径。

There is no doubt oxidative stress is involved in the pathology of bronchopulmonary dysplasia (BPD) in preterm infants, and it is even considered as the only way which participates in all the form of BPD development. However, it is not clear whether DNA damage takes part in the pathogenesis and development. Our early research has proved that DNA damage occurs throughout the whole process of the oxidative stress response. Based on that, we first propose epithelial cell repair disability is the initial step affecting BPD lung development. Taking the autophagy activation as the starting point, we elucidate that althouth the classic DNA repair pathway is activated by the 8-oxoguanine DNA glycosylase (OGG1), but it is not enough to maintain the stability of lung epithelial cells in the early stage of BPD; we also verify the excessive activation of autophagy impairs the effect of OGG1 in the specific recognition and resection of 8-oxoG in the DNA chain, in consequence interferes with damaged DNA repair process in the early stage of BPD. The molecular mechanism of autophagy triggered by Nrf2/Keap1 Signaling Pathway and "shielding" of autophagy protein p62 is explored. Finally the protective effect of Nrf2 activation is confirmed in both vivo and vitro that it improves late lung development outcomes in BPD.