Transcriptional profiling of the murine airway response to acute ozone exposure

Ambient ozone (O3) exposure has serious consequences on respiratory health, including airway inflammation and injury. Decades of research have yielded thorough descriptions of these outcomes; however, less is known about the molecular processes that drive them. The aim of this study was to further describe the cellular and molecular responses to O3 exposure in murine airways, with a particular focus on transcriptional responses in two critical compartments: conducting airways (CA) and airway macrophages (AM). After exposing adult, female C57BL/6J mice to filtered air, 1 or 2 ppm O3, we assessed hallmark responses including airway inflammation (cell counts and cytokine secretion) and injury (epithelial permeability), followed by gene expression profiling of CA and AM by RNA-seq. As expected, we observed concentration-dependent increases in airway inflammation and injury. CA and AM both exhibited changes in gene expression to both 1 and 2 ppm O3 that were largely compartment-specific. In CA, genes associated with epithelial barrier function, detoxification processes, and cellular proliferation were altered, while O3 affected genes involved in innate immune signaling, cytokine production, and extracellular matrix remodeling in AM. Further, CA and AM also exhibited notable differences in concentration-response expression patterns for large numbers of genes. Overall, our study has described transcriptional responses to acute O3 exposure, revealing both shared and unique gene expression patterns across multiple concentrations of O3 and in two important O3-responsive tissues. These profiles provide broad mechanistic insight into pulmonary O3 toxicity, and reveal a variety of targets for focused follow-up studies.

环境臭氧（O3）暴露可对呼吸系统健康造成严重危害，包括引发气道炎症与气道损伤。数十年来的研究已对上述结局进行了详尽阐述，但针对其背后的分子驱动机制，目前仍缺乏足够了解。本研究旨在进一步阐明小鼠气道在O3暴露后的细胞与分子应答反应，重点关注两个关键功能分区：传导气道（conducting airways, CA）与气道巨噬细胞（airway macrophages, AM）的转录应答特征。本研究将成年雌性C57BL/6J小鼠分别暴露于过滤空气、1 ppm或2 ppm的O3环境中，随后评估了标志性应答指标：包括气道炎症（细胞计数与细胞因子分泌水平）与气道损伤（上皮通透性），并通过RNA测序（RNA-seq）对传导气道与气道巨噬细胞进行基因表达谱分析。正如预期，我们观察到气道炎症与损伤程度随O3暴露浓度升高呈浓度依赖性增强。传导气道与气道巨噬细胞在1 ppm和2 ppm O3暴露后均出现基因表达改变，且此类改变大多具有分区特异性。在传导气道中，与上皮屏障功能、解毒过程及细胞增殖相关的基因表达发生显著改变；而在气道巨噬细胞中，O3暴露则影响了固有免疫信号传导、细胞因子产生及细胞外基质重塑相关基因的表达。此外，大量基因的浓度依赖性表达模式在传导气道与气道巨噬细胞之间也存在显著差异。综上，本研究阐明了急性O3暴露后的转录应答特征，揭示了不同O3暴露浓度下，以及两种重要的O3应答组织中，既存在共有也存在独特的基因表达模式。上述基因表达谱为肺部O3毒性的机制研究提供了全面视角，并为后续针对性验证研究提供了多个潜在靶点。