GSTM1基因缺失对雾霾所致急性呼吸道炎症的影响及其机制

Haze air pollution, characterized by above-standard PM2.5 levels, takes place frequently in a large area of China, resulting in higher incidence of acute respiratory diseases. Thus, elucidation of the mechanisms for haze-related lung diseases and identification of susceptible population to haze toxicity is of practical significance. The glutathione S-transferase M1 (GSTM1) is a major antioxidant enzyme in human lung and about 53% of Chinese population presents GSTM1 null genotype. We have recently shown that the bronchial epithelial cells with GSTM1 null genotype responded more severely to air pollutant treatment than those with GSTM1 positive genotype. It is assumed that GSTM1 deficiency may act as a susceptibility factor to haze toxicity. This study will reveal whether GSTM1 deficiency aggravates haze-induced acute airway inflammation and underlying mechanisms by means of panel study and the in vitro model of primary human bronchial epithelial cells with GSTM1 null genotype. In the panel study, the subjects with GSTM1 positive and null genotypes will be examined 6 times using sputum induction for acute airway inflammatory responses under different haze conditions, followed by statistical analysis to specify whether GSTM1 deficiency could facilitate haze-induced airway inflammation. In addition to verifying the key results from the panel study the in vitro study will also elucidate which inflammatory signaling pathways can be modified by GSTM1 deficiency in the promotion of haze-induced airway inflammation.

以PM2.5浓度超标为特征的雾霾污染正在我国大面积频发，导致居民急性呼吸系统疾病发病率上升。研究雾霾致病机制、识别雾霾危害易感人群具有重要现实意义。GSTM1是肺脏中一个主要抗氧化酶，约53%中国人缺少GSTM1基因。课题组观察到GSTM1基因缺失可加重空气污染物对呼吸道上皮细胞的炎性作用，推测GSTM1基因缺失可能是雾霾危害的易感因素。为此，将利用人群定组研究和人呼吸道原代上皮细胞体外模型，揭示GSTM1基因缺失是否能加重雾霾对呼吸道的急性炎性作用及其机制。定组研究是在不同雾霾天气条件下，利用诱导痰技术分别对GSTM1阳性和阴性健康志愿者进行6次呼吸道急性炎性反应检测，再利用统计学模型分析GSTM1基因缺失是否可加重雾霾所致的呼吸道炎症。体外研究除了验证GSTM1基因缺失是否能增强雾霾的炎性作用外，重点阐明GSTM1基因缺失是通过影响哪些细胞内信号传导通路来增强雾霾的炎性作用。

以PM2.5浓度超标为特征的雾霾污染在我国大面积频发，导致居民急性呼吸系统疾病发病率上升。研究雾霾致病机制、识别雾霾危害易感人群具有重要现实意义。GSTM1是肺脏主要抗氧化酶，约53%中国人缺少GSTM1基因。本研究目的是阐明GSTM1基因缺失是否能加重雾霾对呼吸道的急性炎性作用及其可能机制。研究手段包括健康志愿者定组研究、体外细胞实验以及动物实验。健康志愿者定组研究结果显示，暴露雾霾主要成分（PM10、PM2.5和O3）可引起急性呼吸道炎症和氧化应激以及全身性健康效应，GSTM1(或GSTT1)基因缺失可不同程度加重雾霾诱发的呼吸道炎症和氧化应激，影响呼吸道微生态；体外研究结果表明GSTM1基因缺失可通过调节NFkB炎性信号通路增强PM2.5诱导的呼吸道原代上皮细胞炎性效应，氧化应激以及EGF受体活化在PM2.5诱发呼吸道上皮细胞炎性反应中发挥重要作用；大鼠PM2.5肺灌注实验结果表明，PM2.5可引起呼吸道炎症和肺损伤以及心血管系统功能紊乱，鱼油可明显拮抗PM2.5对大鼠的毒性作用。综上所述，雾霾主要成分可诱导人呼吸道炎症等多种有害健康效应，GSTM1基因缺失可通过炎性信号调节通路或干扰呼吸道微生态增强雾霾所致的呼吸道炎性效应。上述研究结果为进一步探索防治雾霾危害的有效干预措施、保护易感人群提供了重要实验依据。