大气细颗粒物诱发呼吸系统自噬功能紊乱的机制研究

Fine particulate matters are the primary pollutants of urban atmosphere in China. In recent years, increasing concentration of fine particles is closely related to the rapid growth of the incidence of respiratory disease in big cities. However, detailed mechanism of respiratory system damage induced by fine particles remains unclear. In this project, based on markedly different physical-chemical properties of fine particles and coarse particles as well as the complexity of their sources and causes, different-sized carbon blacks are used as simplified model of particles and heavy metals are chosen as representative of other atmospheric pollutants. Combing radio-labeling techniques, synchrotron-based X-ray microscopy with conventional toxicological evaluation methods, we will investigate the interaction of different-sized carbon blacks and various metals as well as their respiratory toxicity. On this basis, we will focus on exploring the effect of carbon black-heavy metal interactions on autophagy in target cells and tissues of respiratory system, obtaining particle size and concentration threshold which induced autophagy dysfunction, revealing detailed mechanism of respiratory system damage induced by fine particles. Our results will provide a new insight into understanding the toxicological and health effects of atmospheric fine particles, which have potential to aid in developing pharmaceutical agents that target autophagy to decrease fine particle related respiratory infections and inflammation.

细颗粒物是我国城市大气的首要污染物，不断增加的细颗粒物浓度与近年来大城市呼吸系统疾病发病率高速增长密切相关。但是，迄今细颗粒物诱发呼吸系统损伤的深层次毒性机制仍不清楚。基于大气细颗粒物和粗颗粒物不同的物理化学性质以及它们的来源和成因复杂等特点，本项目提出以不同粒径碳黑作为简化的大气颗粒物模型，选择重金属为其它污染物的代表，应用放射性核素标记和同步辐射X射线显微成像技术结合常规的毒理学评估方法，研究不同粒径碳黑和各种重金属的相互作用及呼吸毒性。重点探索碳黑-重金属相互作用对呼吸系统靶细胞及靶器官自噬功能的影响，得出诱导自噬紊乱的颗粒物粒径及浓度的阈值，揭示大气细颗粒物诱发呼吸系统损伤的深层次毒性机制。研究结果为理解大气细颗粒物的毒理和健康效应提供全新的视角，也为进一步开发以自噬信号通路为靶点的药物，降低大气细颗粒物诱发的呼吸系统感染及炎症提供基础研究的支撑。

细颗粒物是我国城市大气的首要污染物，不断增加的细颗粒物浓度与近年来大城市呼吸系统疾病发病率高速增长密切相关。但是，迄今细颗粒物诱发呼吸系统损伤的深层次毒性机制仍不清楚。基于大气细颗粒物和粗颗粒物不同的物理化学性质以及它们的来源和成因复杂等特点，本项目提出了以不同粒径碳黑作为简化的大气颗粒物模型，选择重金属为其它污染物的代表，研究不同粒径碳黑和各种重金属的相互作用及呼吸毒性。重点应用同步辐射X射线显微成像技术，证明碳黑颗粒载带大量金属污染物进入生命体系，导致了呼吸毒性的显著加强。并且，结合多种分子生物学研究方法，揭示了导致呼吸毒性加强的深层次生物学机制－呼吸系统的自噬和溶酶体功能紊乱。研究结果为理解大气细颗粒物的毒理和健康效应提供全新的视角，也为进一步开发以自噬信号通路为靶点的药物，降低大气细颗粒物诱发的呼吸系统感染及炎症提供基础研究的支撑。