PM2.5 aggravates NQO1-induced mucus hyper-secretion through release of neutrophil extracellular traps in an asthma model
PM2.5 aggravates NQO1-induced mucus hyper-secretion through release of neutrophil extracellular traps in an asthma model
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DOI：
10.1016/j.ecoenv.2021.112272
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发表时间：
2021-05-04
影响因子：
6.8
通讯作者：
Li, Guoping
中科院分区：
文献类型：
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作者：
He, Xiang;Zhang, Lei;Li, Guoping
背景：直径在2.5微米及以下的颗粒物(PM2.5)是大气环境中最复杂的污染物之一，对人类健康有害。流行病学证据表明，哮喘恶化与PM2.5暴露有关。然而，PM2.5在哮喘发生发展中的分子机制还没有完全阐明。方法：收集成都中国PM2.5样品，对其成分进行分析。在卵蛋白(OVA)诱导的小鼠哮喘模型中，研究了PM2.5暴露与哮喘严重程度的关系。对来自公共数据库的U-BIOPRED数据和我们自己的RNA-SEQ数据进行分析，以确定HUB基因。采用实时定量定量聚合酶链式反应、免疫荧光、免疫组织化学和病理染色等方法对PM2.5进行了体外和体内机理研究。结果：在PM2.5样品中，共鉴定出11种常量元素和微量元素，16种多环芳烃(PAHs)中有14种被检出，但菲和荧外均未检出。PM2.5暴露加重哮喘模型大鼠的肺部炎症、黏液分泌和中性粒细胞浸润。基于对轻度到重度哮喘数据集的转录组分析，显示粘液分泌和中性粒细胞脱颗粒与哮喘严重程度相关。此外，通过联合分析筛选出NAD(P)H：苯醌氧化还原酶1(NQO1)为中枢基因，其表达与哮喘患者MUC5AC的表达呈正相关。此外，在OVA诱导的哮喘模型和体外实验中，还发现PM2.5诱导的MU5AC的表达是由NQO1通过氧化应激引起的中性粒细胞外陷阱(NETs)来调节的。结论：综上所述，我们发现了哮喘严重程度与PM2.5暴露之间的潜在关系。此外，中性粒细胞去除、Nets抑制或抗NQO1可能是治疗PM2.5诱导的粘液高分泌的新的潜在治疗选择。
Background: Particulate matter of 2.5 & micro;m or less in diameter (PM2.5) is one of the most complex pollutants in the atmospheric environment and harmful to human health. Epidemiologic evidence suggests that asthma exacerbation is associated with PM2.5 exposure. However, the molecular mechanism of PM2.5 in the development of asthma is not fully addressed.Methods: PM2.5 was collected from Chengdu, China, and the components were analyzed. The relationship between PM2.5 exposure and asthma severity was investigated in an Ovalbumin (OVA)-induced murine model of asthma. U-BIOPRED data from public database and our own RNA-seq data were analyzed to identify the hub genes. Real-time qPCR, immunofluorescence, immunohistochemistry and pathological staining were applied for mechanism dissection in both in vitro and in vivo studies.Results: In PM2.5 samples, a total of 11 elements including major elements and trace elements were identified, 14 of the 16 Polycyclic aromatic hydrocarbons (PAHs) were detected except Acenaphthene and Fluorene. PM2.5 exposure aggravated pulmonary inflammation, mucus secretion, and neutrophils infiltration in asthma model. Based on transcriptome analysis of mild-to-severe asthma dataset, it showed that mucus secretion and neutrophil degranulation correlated with asthma severity. Moreover, NAD(P)H:quinone oxidoreductase 1 (NQO1) was screened out as a hub gene whose expression positively correlated with MUC5AC expression in patient with asthma by performing joint analysis. Furthermore, in OVA-induced asthma model and in vitro assay, it also revealed that PM2.5-induced MU5AC expression was regulated by NQO1 through neutrophil extracellular traps (NETs) caused by oxidative stress.Conclusion: Taken together, we discovered a potential relationship between asthma severity and PM2.5 exposure. In addition, neutrophil depletion, NETs inhibition or anti-NQO1 might be novel potential therapeutic options for treatment of PM2.5-induced mucus hyper-secretion.