Ozone is known to cause lung injury and resident cells of the respiratory tract, i.e., epithelial cells and macrophages, respond to inhaled ozone in a variety of ways that affect their survival, morphology, and functioning. However, a complete understanding of the sex-associated and the cell type-specific gene expression changes in response to ozone exposure is still limited. Through transcriptomics, we aimed to analyze gene expression alterations and associated enrichment of biological pathways enrichment in three distinct cell type-enriched compartments of ozone-exposed murine lungs. We sub-chronically exposed adult males and females to 0.8ppm ozone or filtered air. RNA-Seq was performed on airway epithelium-enriched airways, parenchyma, and purified airspace macrophages. Differential gene expression and biological pathway analyses were performed and supported by cellular and immunohistochemical analyses. While a majority of differentially expressed genes (DEGs) in ozone-exposed versus air-exposed groups were common between both sexes, sex-specific DEGs were also identified in all the three tissue compartments. As compared to ozone-exposed males, ozone-exposed females had significant alterations in gene expression in three compartments. Pathways relevant to cell division and DNA repair were enriched in the ozone-exposed airways indicating ozone-induced airway injury and repair which was further supported by immunohistochemical analyses. In addition to cell division and DNA repair pathways, inflammatory pathways were also enriched within the parenchyma supporting contribution by both epithelial and immune cells. Finally, immune response and cytokine-cytokine receptor interactions were enriched in macrophages, indicating ozone-induced macrophage activation. Lastly, our analyses also revealed ozone-induced upregulation of mucoinflammation- and mucous cell metaplasia-associated pathways.

中文翻译：

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臭氧暴露鼠肺的隔室特异性转录组学揭示了与粘膜炎性肺病相关的性别和细胞类型相关的扰动

众所周知，臭氧会导致肺损伤，呼吸道的常驻细胞，即上皮细胞和巨噬细胞，会以多种方式对吸入的臭氧做出反应，从而影响它们的存活、形态和功能。然而，对臭氧暴露响应的性别相关和细胞类型特异性基因表达变化的完整理解仍然有限。通过转录组学，我们旨在分析暴露于臭氧的鼠肺的三个不同细胞类型富集区室中的基因表达改变和相关的生物通路富集。我们将成年男性和女性亚慢性暴露于 0.8ppm 臭氧或过滤空气中。对富含气道上皮的气道、实质和纯化的空腔巨噬细胞进行 RNA-Seq。通过细胞和免疫组织化学分析进行差异基因表达和生物途径分析并提供支持。虽然臭氧暴露组和空气暴露组中的大多数差异表达基因 (DEGs) 在两性之间都很常见，但在所有三个组织隔室中也发现了性别特异性 DEGs。与暴露于臭氧的雄性相比，暴露于臭氧的雌性在三个区室中的基因表达发生了显着变化。与细胞分裂和 DNA 修复相关的通路在臭氧暴露的气道中富集，表明臭氧引起的气道损伤和修复，这得到了免疫组织化学分析的进一步支持。除了细胞分裂和 DNA 修复途径外，炎症途径也在实质内丰富，支持上皮细胞和免疫细胞的贡献。最后，巨噬细胞富含免疫反应和细胞因子-细胞因子受体相互作用，表明臭氧诱导的巨噬细胞活化。最后，我们的分析还揭示了臭氧诱导的粘液炎症和粘液细胞化生相关通路的上调。