Center for Genes, Environment, and Health, and.
RTI International, Research Triangle Park, North Carolina.
Am J Respir Cell Mol Biol. 2020 Aug;63(2):172-184. doi: 10.1165/rcmb.2019-0454OC.
Air pollution particulate matter <2.5 μm (PM) exposure is associated with poor respiratory outcomes. Mechanisms underlying PM-induced lung pathobiology are poorly understood but likely involve cellular and molecular changes to the airway epithelium. We extracted and chemically characterized the organic and water-soluble components of air pollution PM samples, then determined the whole transcriptome response of human nasal mucociliary airway epithelial cultures to a dose series of PM extracts. We found that PM organic extract (OE), but not water-soluble extract, elicited a potent, dose-dependent transcriptomic response from the mucociliary epithelium. Exposure to a moderate OE dose modified the expression of 424 genes, including activation of aryl hydrocarbon receptor signaling and an IL-1 inflammatory program. We generated an OE-response gene network defined by eight functional enrichment groups, which exhibited high connectivity through , , and . This OE exposure also robustly activated a mucus secretory expression program (>100 genes), which included transcriptional drivers of mucus metaplasia ( and ). Exposure to a higher OE dose modified the expression of 1,240 genes and further exacerbated expression responses observed at the moderate dose, including the mucus secretory program. Moreover, the higher OE dose significantly increased the / gel-forming mucin expression ratio and strongly downregulated ciliated cell expression programs, including key ciliating cell transcription factors (e.g., and ). Chronic OE stimulation induced mucus metaplasia-like remodeling characterized by increases in MUC5AC secretory cells and MUC5AC mucus secretions. This epithelial remodeling may underlie poor respiratory outcomes associated with high PM exposure.
空气污染细颗粒物（PM）<2.5μm 的暴露与呼吸道不良结局有关。PM 引起的肺部病理生物学机制尚不清楚，但可能涉及气道上皮细胞和分子的变化。我们提取并化学表征了空气污染 PM 样本的有机和水溶性成分，然后确定了人鼻黏液纤毛气道上皮培养物对 PM 提取物剂量系列的全转录组反应。我们发现 PM 有机提取物（OE），而不是水溶性提取物，能从黏液纤毛上皮引发强烈的、剂量依赖性的转录组反应。暴露于中等 OE 剂量会改变 424 个基因的表达，包括芳基烃受体信号和 IL-1 炎症程序的激活。我们生成了一个由八个功能富集组定义的 OE 反应基因网络，通过 、 和 表现出高度的连通性。这种 OE 暴露还强烈激活了粘液分泌表达程序（超过 100 个基因），其中包括粘液化生的转录驱动因子（ 和 ）。暴露于更高的 OE 剂量会改变 1240 个基因的表达，并进一步加剧在中等剂量下观察到的表达反应，包括粘液分泌程序。此外，更高的 OE 剂量显著增加了 /凝胶形成粘蛋白的表达比率，并强烈下调了纤毛细胞表达程序，包括关键的纤毛细胞转录因子（例如 和 ）。慢性 OE 刺激诱导了粘液化生样重塑，其特征是 MUC5AC 分泌细胞和 MUC5AC 粘液分泌的增加。这种上皮重塑可能是与高 PM 暴露相关的不良呼吸结局的基础。
