大气细颗粒物致肺功能下降及慢性阻塞性肺病的分子流行病学研究

Exposure to ambient particulate matter may lead to decline in lung function or development of chronic obstructive pulmonary diseases (COPD). The regular pattern and pathogenic mechanism of PM2.5 induced lung function decline and CODP remain unclear. This project will be conducted on established WHZH cohort through molecular epidemiological methods. The personal external exposure to PM2.5 and its components will be estimated through systemic measurements of indoor and outdoor ambient PM2.5. The personal internal exposure to the components of PM will be estimated through the levels of urinary metal and polycyclic aromatic hydrocarbon metabolites and exclude the amount from foods. We will follow the WHZH cohort, determine lung function for each participant and make diagnosis of COPD. The dose-response relationship between internal and external exposure to PM2.5 or its components and alter in lung function or incidence of COPD will be analyzed by time series and survival analysis. Attributable risk of lung function decline or COPD to PM2.5 or its components will be calculated. The association of PM2.5 exposure with changes of cytokines/proteins of inflammatory immune response or DNA methylation, and further association with lung function decline or COPD will be conducted. The role of mechanism of cytokines/proteins or DNA methylation during PM2.5 exposure and lung function decline or COPD will be discussed. The possible biomarkers for lung function decline or COPD will be selected through the analysis. This study will provide scientific basis for the mechanism of COPD development and prevention.

大气细颗粒物暴露可导致肺功能下降或者发展为慢性阻塞性肺病，其致病规律与机制仍不清楚，本项目拟采用分子流行病学研究方法，利用已经建立的武汉珠海社区队列，系统测定室内外空气PM2.5浓度计算队列成员PM2.5外暴露量，测定尿中金属、多环芳烃代谢产物，结合饮食分析推算PM组分内暴露量；随访武汉珠海队列，行肺功能测定和COPD诊断，采用时间序列和生存分析等方法分析空气PM2.5及其组分的内外暴露量、暴露时间与肺功能下降及COPD发病的暴露剂量-效应关系，计算肺功能下降及COPD发病归因于PM2.5的率；分析PM2.5暴露与免疫炎性反应等通路因子/蛋白变化、DNA甲基化改变的关联，以及与肺功能下降及COPD发病的关系，探讨免疫炎性反应等和DNA甲基化改变在PM2.5致肺功能下降及COPD发病中的作用，筛选肺功能下降及COPD的效应标志物。为进一步阐明COPD发生机制和制订预防对策提供科学依据。

本项目采用分子流行病学方法进行武汉珠海社区居民研究队列基线和2次随访研究。开展空气PM2.5及个体PM2.5及组分监测，基线和随访均问卷收集信息，进行肺功能测定等体检，并采集体检当日血尿样本。结果显示：武汉市PM2.5浓度是珠海市2.5倍左右。两市空气PM2.5中含39种金属和15种多环芳烃（PAHs），武汉市PM2.5中金属及类金属和多环芳烃水平明显高于珠海市。分析均校正了年龄、性别、吸烟、体质指数等混杂因素。个体PM2.5暴露与肺功能关联显示：2小时移动PM2.5暴露导致FEV1平均下降24ml，肺呼气速率指标PEF、MMF、FEF50％、FEF75％均显著下降（所有P<0.05）。个体PM2.5每升高10 μg/m3，肺功能FVC和FEV1分别降低2.94（95%CI：-5.10，-0.78）ml和2.02（-3.64，-0.39）ml，PEF降低1.35 (3.88，18.82)mL/s。长期PM2.5暴露引起肺功能下降，与持续低暴露组相比，PM2.5持续高暴露组肺功能指标FEV1/FVC3年后下降3.63%（0.02%～7.25%），6年后下降7.15%（0.03%～14.27%）。与持续低PM2.5暴露组相比，暴露波动和持续高暴露组慢阻肺发病危险度分别是3.50（95%CI：1.77，6.96）和5.78（2.78，12.05），提示长期持续PM2.5高暴露增加慢阻肺发病风险。PM2.5组分PAHs暴露与肺功能指标存在负向关联，PM2.5膜上萘、苊、荧蒽、芘浓度升高与FVC下降显著相关，荧蒽、芘升高与FEV1下降相关（所有P<0.05）。与持续低PAH暴露组相比，持续高暴露于苯并a笓、二苯并蒽和苯并苝3年后肺功能指标FVC分别下降214.7ml，226.1ml和265.0 ml。尿总PAHs和多种PAH代谢产物水平与肺功能指标FVC和FEV1呈负性关联。尿高分子量PAH可部分通过降低血浆CC16浓度和升高尿8-OHdG降低FVC，CC16和8-OHdG中介效应百分比为22.13%、14.42%。与PM2.5相关的肺功能下降及慢阻肺敏感标志物为炎性反应CC16和氧化损伤尿8-OHdG。本研究还观察到PM2.5其它组分对肺功能影响及表观遗传的作用。确认空气PM2.5及组分致肺功能下降及慢阻肺的暴露剂量-效应关系和初步探讨机制，有利于防控PM2.5呼吸危害。