ROS-ERS-EMT在PM2.5母源性暴露致子代肺间质病变中的作用机制

The situation of PM2.5 exposure is grim in recent years. Epidemiological investigation have related maternal exposure of PM2.5 to offspring lung disease.We found that reduced lung function in newborn rats associated with pulmonary interstitial fibrosis lesion induced by PM2.5 from Guangzhou maternal exposure. However, the mechanism is not clear. The mechanism of interstitial fibrosis lesion focuses on epithelial mesenchymal transformation (EMT) recently. ROS and endoplasmic reticulum stress (ERS) may induce EMT. We hypothesize that "PM2.5 maternal exposure increased ROS which trigger ERS in the lung, then caused phosphorylation of Smad2/3, Src and EMT in alveolar epithelial cells, resulting in offspring lung function decline caused by pulmonary interstitial disease" . This may be toxicity mechanism of PM2.5 from Guangzhou on lung development. Therefore, we intend to apply oriented induction of differentiation, immunohistochemistry, Western blot, and RNAi to to confirme our speculation in whole - cell - molecular three level. This project will reveal toxicity mechanisms of PM2.5 maternal exposure and provide important theoretical significance to deeply understand the relationship between maternal environment and offspring development.

近年PM2.5暴露现状严峻，流行病学发现PM2.5母源性暴露与子代肺部疾病相关，我们前期发现广州冬季PM2.5母源性暴露引起的仔鼠肺功能降低与子代肺间质纤维性病变有关，但机制不清。上皮间质转化（EMT）是间质纤维性病变发病机制的研究热点，而ROS、内质网应激（ERS)可引发EMT。 我们推测“PM2.5母源性暴露后通过使子代肺部ROS升高触发内质网应激，进而引起Smad2/3、Src磷酸化，导致肺泡上皮细胞发生EMT，从而导致肺间质纤维性病变引起子代肺功能下降”是广州冬季PM2.5母源性暴露肺发育毒性机制之一。本项目应用定向分化、免疫组织化学、western、RNAi等技术分析PM2.5母源性暴露后子代肺泡上皮的氧化应激、内质网应激、EMT等指标间关系，从整体-细胞-分子三个层面揭示PM2.5母源性暴露致子代肺功能下降的机制 ，对深入理解母体环境与子代发育间的关系具有重要的理论意义。

近年来空气颗粒污染物PM2.5暴露现状严峻，已成为危害人类健康的重要因素之一。流行病学发现PM2.5母源性暴露与子代肺部疾病相关，但机制不清。本项目侧重于母体环境暴露对子代肺发育的影响，利用PM2.5母源性暴露模型和体外细胞培养模型，发现母源性PM2.5暴露后大鼠子代出生体重降低，仔鼠肺功能下降，肺上皮细胞EMT异常改变，这种异常改变与PM2.5暴露母源性暴露引起的仔鼠肺组织氧化应激、TGFβ/SAMD通路改变相关，并且在体外利用细胞模型进行了验证。本项目从整体水平-体外细胞水平-分子水平三个层面研究了妊娠期 PM2.5 母源性暴露后子代肺泡上皮的氧化应激水平与肺上皮细胞间充质转化的关系，揭示了 PM2.5 诱发氧化应激调控肺间质纤维性病变的机制，有助于从动物到人类有层次系统地进一步理解 PM2.5 母源性暴露对子代肺组织发育影响的机制，为国家制定相关政策提供了理论依据。