TRP信号通路在大气细颗粒污染物诱导的急性肺损伤中的作用机制

Exposure to ambient fine particulate matters is a major non-infective factor for acute exacerbations of various respiratory diseases, increased mortality, and decreased lung function. Harmful gases could penetrate the body directly through the respiratory tract and lead to lung injury by inhalation. At present, the mechanism of PM2.5-induced acute lung injury is unclear, and most of the study focused on the animal model and in vitro experiments. This project will follow up healthy adults after long-term exposure to PM2.5 and real time monitor the concentration to obtain the continuous PM2.5 exposure data by combining the characteristics of time-activity pattern. The dose-response relationship between internal and external exposure to PM2.5 and declined in lung function or lung injury will be analyzed by time series and survival analysis. Then the role of TRP channel in PM2.5 exposed lung injury will be discussed through cell and animal model. Accordingly, this project will further elucidate TPRA1 / TPRV4 as a biomarker and intervention target for clinical diagnosis and treatment and thus to provide a scientific basis for PM2.5 related lung injury.

大气细颗粒物暴露是导致各种呼吸系统疾病急性发作、死亡率增加、肺功能下降的主要非感染性因素。有害气体可通过呼吸道直接侵入机体造成吸入性肺损伤。目前，对于PM2.5相关的肺损伤机制不明，且大多数研究仅停留在动物及体外实验阶段，很少有研究从人群出发探究PM2.5对呼吸系统的损伤。本项目拟通过随访长期暴露于PM2.5的健康成人，进行PM2.5实时个体暴露监测，结合调查对象的时间-活动模式特征，获得连续的PM2.5个体暴露监测数据。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肺损伤的暴露剂量-效应关系。并从细胞和动物水平分析PM2.5暴露与TRP信号通路的相关性。为进一步阐明TPRA1/TPRV4作为血清学标志物和临床干预靶点用于临床诊疗提供科学依据。

大气细颗粒物暴露是导致各种呼吸系统疾病急性发作、死亡率增加、肺功能下降的主要非感染性因素。有害气体可通过呼吸道直接侵入机体造成吸入性肺损伤。目前，对于PM2.5相关的肺损伤机制不明，本研究分别从细胞和动物水平分析PM2.5暴露与瞬时受体电位(TRP)信号通路的相关性。研究发现暴露于PM2.5与肺损伤和气道高反应性（AHR）相关。瞬时受体电位(TRP)香肽4(TRPV4)和锚蛋白1 (TRPA1)均在肺损伤和AHR中发挥重要作用。研究结果表面TRPV4和TRPA1通道在PM2.5诱导的肺损伤和AHR中均起重要作用。在PM2.5处理的大鼠中还发现血清炎症细胞因子的产生，诱导肺炎症基因表达(TNF-a、IL-1β、IL-6、IL-8)，以及肺氧化应激在暴露于PM2.5导致的急性肺损伤模型中发现有氧化应激的发生，表现为MDA升高，GSH和SOD降低，故初步研究表明TPRA1/TPRV4通过氧化应激启动NF-κB通路介导PM2.5诱导的大鼠急性肺损伤。从而为进一步阐明TPRA1/TPRV4作为血清学标志物和临床干预靶点用于临床诊疗提供科学依据。