上皮来源外泌体lncRNA MALAT1在PM2.5所致COPD气道重塑中的作用及机制研究

PM2.5 was found to promote the airway remodeling development of chronic obstructive pulmonary disease (COPD), but its pathogenesis remains unclear. It has been shown that exosome (transfering information between cells) and long chain non-coding RNA (lncRNA), play very important regulatory roles in a variety of diseases. However, there are few studies reported that the roles and mechanisms of exosome and lncRNA in the pulmonary damages induced by PM2.5. Based on the previous research, we are going to investigate the roles and mechinasms of epithelial-derived exosome lncRNA MALAT1 in PM2.5-induced airway remodeling of COPD by using the following two models. (i) Cell model, fibroblasts were treated by exosome derived from epithelial cells with PM2.5 treatment, or were co-cultured with epithelial cells; and after up-regulating or down-regulating lncRNA MALAT1 in lung epithelial cells, to observe the effect of epithelial-derived exosome lncRNA MALAT1 on the activation of lung fibroblasts via regulating miR-143-3p/CTGF; (ii) the animal model of airway remodeling in COPD induced by PM2.5. Our results will be helpful to understand the molecular mechanisms underlying PM2.5-induced airway remodeling in COPD, which will provide scientific basis to find early biomarkers and novel measures.

PM2.5引起慢性阻塞性肺病(COPD)气道重塑的发生发展，但致病机制仍不清楚。细胞之间传递信息的外泌体及其所包含的长链非编码RNA（lncRNA）在多种疾病的发生发展中具有重要调控作用，而其在PM2.5所致肺损害中作用机制研究甚少。本项目在前期研究基础上，拟利用PM2.5刺激肺上皮细胞分泌的外泌体处理肺成纤维细胞，或以上两种细胞共培养等方式，探究上皮来源外泌体对肺成纤维细胞活化的影响；进一步上调或下调lncRNA MALAT1后，观察外泌体lncRNA MALAT1调控miR-143-3p/CTGF对肺成纤维细胞活化的影响；最后构建PM2.5所致大鼠COPD模型，在细胞和动物水平上探讨上皮来源外泌体lncRNA MALAT1在PM2.5所致COPD气道重塑中的作用，以揭示PM2.5所致COPD气道重塑的分子机制，为寻找PM2.5所致肺损伤的早期生物标志和发现新的防治措施提供科学依据。

PM2.5引起慢性阻塞性肺病(COPD)气道重塑的发生发展，但致病机制仍不清楚。细胞之间传递信息的外泌体及其所包含的长链非编码RNA（lncRNA）在多种疾病的发生发展中具有重要调控作用，而其在PM2.5所致肺损害中作用机制研究甚少。通过本项目的研究，取得如下研究成果：1）发现PM2.5能够促进肺上皮细胞增殖加快（Toxicol Appl Pharmacol，2019），并分泌大量细胞外泌体，且通过对上皮来源外泌体进行lncRNAs高通量筛选发现，除MALAT1外，HOTAIRM1等10种lncRNAs表达上调显著，经验证筛选选取HOTAIRM1进行深入探究；发现外泌体HOTAIRM1通过调控TGF-β/SAMD3通路促进肺成纤维细胞活化而分泌大量胶原蛋白参与COPD气道重塑。2）本项目通过高通量测序另发现PM2.5的有机组分能够通过上调lncRNA loc107985872上调而激活Notch1信号通路介导肿瘤干细胞表型的形成进而促进肺腺癌进展（Environ Pollut，2020）；3）以及PM2.5有机组分亦能激活ERβ通路介导炎症发生促进肺癌进展（Chemosphere，2021），进而均能刺激肺上皮细胞恶性转化增殖加快，参与PM2.5所致肺上皮支气管损伤等。总之，本项目在原申请计划的基础上，通过高通量测序等技术创新性的发现多种lncRNAs参与PM2.5诱导肺损伤及COPD气道重塑的过程，丰富了PM2.5促进肺损伤及COPD气道重塑发生发展的分子机制，为寻找控制大气细颗粒物暴露所致危害的早期生物标志及发现新的防控措施提供科学依据。