长链非编码核酸在大气细颗粒物所致气道重塑中的作用研究

Chronic obstructive pulmonary disease ( COPD) is a common serious disease with an overall global prevalence of 9–10%. A predominant pathological feature of COPD is airway remodeling which causes irreversible airflow limitation. The remodeling process of smaller airways (<2 mm in diameter) in COPD may occur in response to smoking-induced damage to the airways. Although tobacco smoking is the primary cause of COPD, many other environmental and occupational exposures contribute to the pathology of COPD. The recent research has focused on the role of ambient fine particulate matter air pollution <2.5 μm in diameter (PM2.5) on COPD. But the mechanism(s) that allow small airways to thicken in close proximity to lung tissue undergoing emphysematous destruction remains a puzzle that needs to be solved. Many research showed that long non-coding RNAs (lncRNAs) play an important role in the process of cell differentiation, proliferation and apoptosis, which were reportedly involved in regulation of gene expression and associated with diseases. To explore the role of lncRNAs in Epithelial-mesenchymal transition (EMT) and smooth muscle cells proliferation of COPD may be helpful to elaborate the pathogenesis of airway remodeling. This study will evaluate the lncRNAs and its characteristics from cells exposed to PM2.5, COPD animal models caused by particulate matter air pollution and COPD patients. The non-coding RNA regulatory network and its mechanism in EMT caused by PM2.5 will be further investigated. This research might provide the scientific basis for selection of molecular targets for pharmacological intervention on COPD.

大气颗粒物（PM）在慢阻肺发病中的作用日益受到关注，气道结构重塑是慢阻肺的一个特征性病变，是不可逆气流受限的重要病理学基础。气道重塑的过程涉及多种细胞的病理改变和众多的基因表达异常，如平滑肌增殖和表型改变，间质细胞表型向肌纤维化转化，上皮细胞分泌粘蛋白数量和种类的改变等。研究PM导致慢阻肺气道重塑的发生机制对于有效防治慢阻肺意义重大。非编码RNA（ncRNA）具有基因表达调控功能，在细胞分化、增殖和凋亡等过程中具有重要作用，它的异常表达与许多疾病有关，以在生物体内数量巨大的长链非编码RNA（lncRNA）为切入点，可能将为阐述气道重塑机制带来新的希望。本研究将围绕PM对慢阻肺气道重塑的作用及机制这一关键科学问题，从细胞、动物模型、慢阻肺患者几个层面，研究交通和生物燃料来源颗粒物暴露致机体健康危害特征及作用机制，进一步探讨lncRNA调控网络及机理，为遴选慢阻肺药物干预分子靶点提供科学依据。

长链非编码RNA为切入点研究COPD的发病机制有可能成为阐述慢阻肺气道重塑机理的一条新途径。本研究发现，生物燃料烟雾和机动车尾气两种不同来源的PM2.5长期暴露均可导致大鼠出现COPD样病理特征性改变和气流受限的肺功能损害，且两种不同来源PM引起的肺组织病理和病理生理学改变存在差异。通过对COPD患者筛查研究发现lncRNA COPDA1通过MS4A1介导上调SOCE促进HBSMC增殖，证实了COPDA1在HBSMCs中的可能作用；lncRNA LINC00926可促进气道平滑肌增殖，并调控人T淋巴细胞PDCD1蛋白的表达和气道平滑肌细胞PDCD-L1蛋白的表达；提示有效降低lncRNA COPDA1和LINC00926在慢阻肺患者体内表达，或许可以改善气道平滑肌异常增殖。lncRNA RP11-86H7.1结合miRNA-9-5p发挥ceRNA作用，阻碍miRNA在支气管上皮细胞中对NFKB1的抑制作用，从而上调交通相关PM2.5刺激引起NF-κB持续激活导致的炎症反应。lncRNA LNC_DAPK1可结合凋亡抑制蛋白Survivin/Birc5，通过结合Survivin/XIAP复合体，使Birc3蛋白高表达而起到抗凋亡的功能，抑制了木材烟雾PM2.5引起的气道上皮细胞凋亡。木材烟雾PM2.5和交通相关PM2.5均能通过Shh通路促进人支气管平滑肌迁移和分泌。木材烟雾PM2.5暴露可诱导大鼠气道酸性粘液及粘蛋白MUC5AC增加和人气道上皮细胞粘蛋白MUC5AC合成，其机制涉及TACE/AR/EGFR/ERK途径，EGFR/ERK信号通路通过正反馈机制促使AR水平增加，形成正反馈循环，在气道粘液高分泌状态的维持中起重要作用。大气颗粒物暴露可以改变大鼠肺部和肠道菌群的组成，这种改变出现在肺组织结构发生变化之前，而肺部菌群的失衡与肺部固有免疫和适应性免疫功能的变化有关，肠道菌群位移可通过肠-肺轴间接促进慢阻肺的发生。烟草烟雾中尼古丁诱导的α7nAChR激活可通过磷酸化Akt的Ser473位点提高TRPC6的表达，导致钙内流增加，促进HBSMCs增殖和收缩。解析lncRNA在PM2.5引起的慢阻肺气道重塑发生中的作用与机制，为有针对性的治疗慢阻肺寻找有效的新靶点。