全氟辛酸暴露与IL-13 R130Q多态性交互调控支气管平滑肌细胞引发儿童哮喘的研究

Asthma is caused by a complex interaction of genetic and environmental factors. Our previous research has found that IL-13 R130Q polymorphism is related to childhood asthma, and IL-13 variant (130Q) plays a stronger role in IgE synthesis and high affinity IgE receptor (FcεR1) expression on bronchial smooth muscle cells (BSMCs) than wild-type IL-13 (130R). Perfluorooctanoic acid (PFOA) is an environmental pollutant, to which children are often exposed in daily life. It has been demonstrated that PFOA exposure is a risk factor for asthma development in children. Interaction between IL-13 R130Q polymorphism and PFOA exposure on wheezing in children has been found in our cohort study. However, further research is needed to establish biological interaction between them in functional assays. Hypothesis is proposed that PFOA binds to IgE on BSMCs, and via FcεR1 and intracellular signal transduction, it causes contraction and secretion of BSMCs, resulting in airway inflammation and hyperresponsiveness, and that by increasing IgE synthesis and up-regulating FcεR1 on BSMCs, IL-13 variant amplifies the above pathway effects of PFOA, so that IL-13 variant and PFOA confer synergistic effects on BSMCs. This study will be carried out in vitro and in animal models, and aimed to investigate the interaction between PFOA exposure and IL-13 R130Q polymorphism on the functions of BSMCs and the pathological changes of airways, so as to establish the biological interaction and reveal the complex pathogenesis of childhood asthma.

哮喘由基因和环境因素共同作用引起。我们前期研究发现IL-13 R130Q多态性与儿童哮喘密切相关，变异型IL-13 130Q较野生型IL-13 130R致IgE合成及支气管平滑肌细胞表面受体 FcεR1表达增加。全氟辛酸是儿童生活中接触较多的一种环境污染物，可致儿童哮喘发生。我们在人群研究中发现变异型IL-13和全氟辛酸暴露在儿童喘息发生中存在协同作用，生物学功能水平上是否如此尚待探讨，故提出假设：全氟辛酸通过支气管平滑肌细胞表面IgE和受体 FcεR1及胞内信号转导，致细胞收缩和分泌，产生气道炎症和高反应；变异型IL-13通过促进IgE合成及上调受体FcεR1，使全氟辛酸上述通路效应放大，两者产生协同作用。本项目拟从体外和动物模型两个层面，探讨全氟辛酸暴露和IL-13 R130Q交互作用对支气管平滑肌细胞功能及气道病理的影响，从生物学功能角度证实两者存在协同作用，揭示儿童哮喘发病机制。

哮喘由基因和环境因素共同作用引起。我们前期研究发现IL-13 R130Q多态性与儿童哮喘密切相关，变异型IL-13 130Q较野生型IL-13 130R致IgE合成及支气管平滑肌细胞表面IgE高亲和力受体FcεRⅠ表达增加。全氟辛酸（PFOA）是儿童生活中接触较多的一种环境污染物，可致儿童哮喘发生。我们前期在人群研究中发现变异型IL-13和PFOA暴露在儿童喘息发生中存在协同作用，生物学功能水平上是否如此尚待探讨。因此本课题旨在探究PFOA暴露和IL-13 R130Q交互作用对支气管平滑肌细胞收缩和分泌功能的影响，从生物学功能角度证实两者存在协同作用，揭示儿童哮喘发病机制。本研究发现，PFOA与变异型IL-13 130Q协同促进支气管平滑肌细胞表面表达IgE高亲和力受体FcεRⅠ，PFOA诱导支气管平滑肌细胞表达肌动蛋白alpha SMA增加，PFOA与变异型IL-13 130Q共刺激促进支气管平滑肌细胞表达嗜酸细胞活化趋化因子Eotaxin。本研究初步证实了PFOA暴露与变异型IL-13对支气管平滑肌细胞功能产生协同作用，有助于进一步认识儿童哮喘复杂的发病机制，为哮喘防控提供了新的实验和理论依据。