PM2.5致气道上皮细胞转分化的可能作用与机制研究

Chronic obstructive pulmonary disease ( COPD) is a common serious disease with an overall global prevalence of 9-10%, and is predicted to increase from sixth to third place in the international ranking of diseases causing mortality between 1990 and 2020. 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 heightened the focus on the role of ambient fine particulate matter air pollution <2.5 μm in diameter (PM2.5) on COPD. In COPD, remodeling process of smaller airways (<2 mm in diameter) may occur in response to smoking-induced damage to the airways. The previous studies show that the epithelial thickness of COPD is also increased and metaplasia of the epithelium is a more characteristic pathological change. Epithelial-mesenchymal transition (EMT) might play a key role in the development of airway remodeling of 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. This study will evaluate the effects of PM2.5 on airway remodeling, especially on EMT. The bronchial epithelial cells treated with PM2.5 will be examined by combining quantitative histology and gene expression studies of a series of biomarkers, such as E-cadherin (E-cad), smooth muscle actin (SMA), vimentin, zonula occluden-1(ZO-1), matrix metalloproteinases (MMPs), collagen type I (I-col), collagen type II(II-col), transforming growth factor beta (TGF-β). This study will elucidate the mechanisms of airway remodeling of COPD caused by air pollution, which would be beneficial to treat COPD patients.

PM2.5可通过呼吸道进入人体内导致慢性呼吸道疾病（如慢阻肺）的发生，但其机制尚不清楚。吸烟的慢阻肺患者肺内有EMT改变；PM可刺激人支气管上皮细胞发生氧化应激反应，而后者是启动EMT的重要因素。这些结果提示PM2.5可能会通过刺激上皮细胞的氧化应激而促进EMT。最近有研究发现慢阻肺与具有促进EMT功能的Snai1基因的多态性有关。Snail是Gli家族锌指蛋白在体外诱导转化的效应因子，而Gli介导Hh信号通路。研究显示慢阻肺与4q31基因座上的Hh诱导蛋白基因（HHIP)多态性有关，HHIP是Hh信号通路的调节物质，Hh信号通路是EMT的重要通路。据此推测，PM2.5可能通过Hh信号通路促进气道上皮细胞EMT而导致慢阻肺气道重塑。本课题将重点研究PM2.5对气道上皮细胞转化分的影响，阐述Hh信号通路在PM2.5引起的气道上皮细胞转分化中的作用与机制，为有针对性治疗慢阻肺寻找有效的新靶点。

PM2.5可通过呼吸道进入人体内导致慢性呼吸道疾病（如慢阻肺）的发生，但其机制尚不清楚。本研究发现，交通主干道旁大气PM2.5和木材烟雾PM2.5均可引起人支气管上皮细胞发生上皮-间充质细胞转分化改变。木材烟雾PM2.5诱导EMT的作用似乎更显著。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。WSPM2.5和TAPM2.5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，从而形成正反馈循环，在气道粘液高分泌状态的维持中起重要作用。木材烟雾PM2.5还通过不依赖EGFR的P38途径诱导MUC5AC增加。大气颗粒物暴露可以改变大鼠肺部菌群的组成，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。大气颗粒物暴露在致大鼠肺部慢阻肺样病理变化过程中改变了肠道菌群组成和引起肠道菌群位移，这种变化出现在肺组织结构发生变化之前，肠道菌群位移可通过肠-肺轴间接促进慢阻肺的发生。解析PM2.5在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。该研究对防治日益严重危害人类健康的慢阻肺具有十分重要的意义。