AhR在环境颗粒暴露致中性粒细胞性哮喘中的作用机制研究

项目名称： AhR在环境颗粒暴露致中性粒细胞性哮喘中的作用机制研究

项目编号： No.81200021

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学一处

项目作者： 王苹莉

作者单位： 浙江大学

项目金额： 23万元

中文摘要： 哮喘发病率增加与污染大气中颗粒物暴露相关，其机制尚不清楚。我们最近发现环境超细颗粒物（UFP）暴露选择性地增加了哮喘小鼠肺部Th17免疫应答及中性粒细胞炎症，对Th2与嗜酸粒细胞却无明显影响（AJRCMB 2011）。本课题在此基础上进一步探讨UFP致中性粒细胞性哮喘的作用及分子机制。芳香烃受体（AhR）是环境污染物的一个重要受体，在树突状细胞（DC）中高表达。我们发现UFP与AhR有很强的结合能力，并据此推测DC表面的AhR可能介导了UFP暴露所致的DC功能改变及下游Th免疫应答。本研究将利用AhR-/-小鼠，通过整体动物模型，DC细胞过继，T细胞分化等方法，观察AhR对UFP诱导的DC成熟，功能变化，以及免疫微环境改变的影响，并进一步研究其对下游Th细胞分化的作用，从而为UFP暴露致哮喘气道中性粒细胞炎症阐明一种新的机制，也为AhR作为干预环境污染物对哮喘影响的可能靶点提供理论依据。

中文关键词： 芳香烃受体；超细颗粒；树突状细胞；中性粒细胞；哮喘

英文摘要： Numerous studies have suggested a strong link between exposure to ambient particulate matters and the increased incidence of asthma, whereas the mechanisms underlying this phenomenon remain incomplete understood. Our previous study demonstrated that a combustion-generated ultrafine particulate (UFP) selectively enhanced the Th17 immune response and neutrophilic inflammation in an animal model of allergic asthma, while exerted little effects on Th2 immune response and eosinophilic inflammation (AJRCMB 2011). In the current project, we will further investigate the role and underlying molecular mechanisms of UFP-induced neutrophilic airway inflammation. The aryl hydrocarbon receptor (AhR), a well-characterized receptor for environmental contaminants, is highly expressed on dendritic cells (DCs). We have observed a strong binding ability of UFP to AhR, and hence hypothesize that AhR on DCs might play a pivotal role in the induction of DCs maturation and downstream Th responses following UFP exposure. We will use AhR knockout mice (AhR-/-) and methods such as animal model of neutrophilic asthma, adoptive transfer of DCs, and T cell differentiation, to characterize the role of AHR in DC maturation and function, as well as the DC-induced cytokine microenvironment and Th cell polarization. This study will clarify the mo

英文关键词： aryl hydrocarbon receptor(AhR)；ultrafine particulates；dendritic cell；neutrophil；asthma