Cheminant Jenna R, Deering-Rice Cassandra E, Massa Christopher B, Adhikari Ujjwal, Noll Jessica, Reilly Christopher A, Venosa Alessandro
Department of Pharmacology and Toxicology, University of Utah College of Pharmacy, Salt Lake City, Utah, United States.
Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States.
Am J Physiol Lung Cell Mol Physiol. 2025 Mar 1;328(3):L334-L349. doi: 10.1152/ajplung.00261.2024. Epub 2025 Jan 20.
Ozone (O) is a ubiquitous pollutant known to produce acute, transient inflammation through oxidative injury and inflammation. These effects are exacerbated in susceptible populations, such as the elderly and those exhibiting genetic mutations in central nodes of pulmonary function. To comprehend the impact of these predisposing factors, the present study examines structural, mechanical, and immunological responses to single acute O exposure (0.8 ppm, 3 h) in young (8-14-wk old), middle-aged (44-52-wk old), and old (>80-wk old) mice. Furthermore, this work compares the impact of a clinically relevant mutation in the gene encoding for the alveolar epithelial type 2 specific surfactant protein C. Aging was associated with reduced lung resistance and increases in respiratory elastic properties, the latter of which was exacerbated in SP-C mutant mice. Ozone exposure produced focal injury localized at the terminal bronchiole-to-alveolar junctions and enlarged alveoli in aged SP-C mutant lungs. Flow cytometric analysis revealed increases in mononuclear myeloid abundance in aged SP-C mutant lungs, paired with a contraction in CD8 expressing cells. Expansion of tertiary lymphoid tissues was also noted in aged groups, more evident in the mutant mice. Spatial transcriptomics of CD68 macrophages and CD45 nonimmune parenchymal cells highlighted age-dependent shifts in inflammatory and extracellular matrix organization signaling, and enrichment in senescence and chromatin remodeling pathways. These results illustrate the structural and immunological impact of O in the aging wild-type and mutant lung and emphasize the significance of modeling environmental exposure in at-risk populations. Environmental stress and genetic mutations in key functional nodes are linked to the pathogenesis and exacerbation of respiratory pathologies. These responses are exacerbated by aging, though the impact of these factors in combination is not clearly defined. Using a surfactant protein-C mutant line, our studies describe structural changes and phenotypic responses triggered by acute ozone exposure in the young/middle-aged/old lung. Spatial transcriptomics also found regionally distinct and enhanced activation in the aged lung.
臭氧（O）是一种普遍存在的污染物，已知其会通过氧化损伤和炎症产生急性、短暂性炎症。在易感人群中，如老年人以及那些在肺功能中心节点表现出基因突变的人群，这些影响会加剧。为了理解这些易感因素的影响，本研究检测了年轻（8 - 14周龄）、中年（44 - 52周龄）和老年（>80周龄）小鼠单次急性臭氧暴露（0.8 ppm，3小时）后的结构、力学和免疫反应。此外，这项工作比较了肺泡Ⅱ型特异性表面活性蛋白C编码基因中一种临床相关突变的影响。衰老与肺阻力降低和呼吸弹性特性增加有关，后者在SP - C突变小鼠中更为严重。臭氧暴露在老年SP - C突变小鼠的肺中产生了局限于终末细支气管到肺泡连接处的局灶性损伤以及肺泡增大。流式细胞术分析显示老年SP - C突变小鼠肺中单核髓系细胞丰度增加，同时表达CD8的细胞减少。在老年组中还观察到三级淋巴组织的扩张，在突变小鼠中更明显。对CD68巨噬细胞和CD45非免疫实质细胞进行空间转录组学分析，突出了炎症和细胞外基质组织信号传导中年龄依赖性的变化，以及衰老和染色质重塑途径的富集。这些结果说明了臭氧对衰老的野生型和突变型肺的结构和免疫影响，并强调了在高危人群中模拟环境暴露的重要性。环境应激和关键功能节点的基因突变与呼吸道疾病的发病机制和加重有关。这些反应会因衰老而加剧，尽管这些因素综合起来的影响尚不清楚。利用表面活性蛋白C突变系，我们的研究描述了急性臭氧暴露在年轻/中年/老年肺中引发的结构变化和表型反应。空间转录组学还发现老年肺中存在区域特异性且增强的激活。
