大气细颗粒物引起线粒体损伤介导的炎症反应及与儿童喘息、哮喘发病关系的研究

The occurrence of acute asthma attacks increases due to aerobic fine particulate exposure. However, it still remains controversial whether it is able to increase the risk of asthma incidence in children, The present project intends to adopt a perspective birth cohort study design, focus on the 2–3 years old children from the constructed birth cohort, to follow-up the initiation, promotion and the clinical subtype of children wheeze, and to diagnose the asthma at 6 years old; the fine particulate matter and its components at different life stages after birth will be evaluated based on the environmental monitoring data of and the analyses of the components of the sampled fine particulate matter, and to study the correlation between exposure to fine particulate matter and the incidence of wheeze and/or asthma in children, as well as to identify the sensitive window; based upon above mentioned, case-control method will be adopted to elucidate the relationship between the incidence of wheeze and/or asthma and the mitochondrial impairment and relative inflammation caused by exposure to fine particulate matter, and to screen biomarkers that can predict the development of asthma, by matching asthma cases with controls and assessing mitochondrial impairment and inflammatory parameters in cord blood, 3-year and 6-year old children peripheral blood respectively, as well as the pulmonary function at 6 years old. The present project will provide direct evidence for clarifying the correlation between exposure to aerobic fine particulate matter and the development of children asthma, and elucidate the effects of mitochondrial impairment and relative inflammation reaction caused by exposure to fine particulate matter in this process.

大气细颗粒物暴露可使哮喘患者急性发作增加，但是否会增加儿童哮喘发病的风险目前仍有争议。本项目拟采用前瞻性出生队列研究设计，以已建立的出生队列中2-3岁儿童为研究对象，随访儿童喘息发生、发展与临床分型，在6岁时进行哮喘诊断；利用细颗粒物环境监测数据，并对细颗粒物进行组分分析，评估队列儿童出生后不同时间段细颗粒物及组分暴露水平，研究细颗粒物暴露与儿童喘息、哮喘发病的关联，确定作用敏感期；在此基础上采用病例对照方法，检测队列新发哮喘病例和对照儿童脐带血、3岁和6岁外周血中线粒体损伤和炎症反应指标及6岁时肺功能，阐明细颗粒物暴露引起的线粒体损伤和相应炎症反应与喘息、哮喘发病的关系，并筛选能早期预警哮喘发生的生物标志物。本项目研究将为明确大气细颗粒物暴露与儿童哮喘发病的关联提供直接证据，并阐明细颗粒物引起的线粒体损伤和相应的炎症反应在其中的作用。

大气细颗粒物暴露可使哮喘患者急性发作增加，但是否会增加儿童喘息发病的风险目前仍有争议。本项目采用前瞻性出生队列研究设计，发现孕期和儿童期细颗粒物暴露会导致儿童喘息发病风险升高，且出生后第一年可能是细颗粒物导致儿童喘息的暴露敏感窗口期。阐明了线粒体介导的炎症反应在细颗粒物暴露导致儿童喘息发生中的作用，发现长期暴露于高浓度的细颗粒物会导致持续的氧化应激，引起线粒体DNA损伤和拷贝数降低，反映了细颗粒物引起的线粒体氧化损伤；同时通过炎性损伤引起炎症相关细胞因子浓度升高，从而介导儿童喘息发病。主要研究成果包括：（1）利用土地利用回归模型对研究对象孕期和儿童期细颗粒物暴露水平进行评估，发现从出生到1岁期间细颗粒物暴露导致儿童喘息风险升高，出生后第一年可能是细颗粒物导致儿童喘息的暴露敏感窗口期。（2）发现长期暴露于高浓度的细颗粒物会引起脐血线粒体DNA损伤和拷贝数降低，可能是细颗粒物导致儿童喘息的潜在生物学机制。（3）发现细颗粒物暴露水平升高与脐血端粒长度降低有关，端粒长度可能是生命早期细颗粒物引起儿童喘息的潜在生物学机制。（4）研究发现细颗粒物暴露引起儿童血中γ干扰素（IFN-γ）、白介素-4（IL-4）、白介素-6（IL-6）等细胞因子浓度升高，这些细胞因子作为反映机体早期炎性反应的敏感指标，提示细颗粒物可能通过炎性损伤导致炎症因子水平升高从而介导儿童喘息的发生，因此炎症因子可能是细颗粒物导致儿童喘息的潜在生物标志物。（5）研究发现孕晚期和出生后前两年细颗粒物暴露与T淋巴细胞亚群增加有关，而孕早期细颗粒物暴露与T淋巴细胞亚群降低有关，说明细颗粒物暴露与免疫功能之间存在非线性关系。T淋巴细胞亚群也可作为细颗粒物导致儿童喘息的潜在生物标志物。本研究基于出生队列，为明确生命早期大气细颗粒物暴露与儿童喘息发病的关联提供了直接证据，并阐明了细颗粒物引起的线粒体损伤和相应的炎症反应在其中的作用。