Genome Center, University of California Davis, Davis, California 95616, USA.
Center for Health and the Environment, School of Veterinary Medicine, University of California Davis, Davis, California 95616, USA.
Toxicol Sci. 2023 Jan 31;191(1):79-89. doi: 10.1093/toxsci/kfac117.
Asthma is a common chronic respiratory disease exacerbated by multiple environmental factors. Acute ozone exposure has previously been implicated in airway inflammation, airway hyperreactivity, and other characteristics of asthma, which may be attributable to altered sphingolipid metabolism. This study tested the hypothesis that acute ozone exposure alters sphingolipid metabolism within the lung, which contributes to exacerbations in characteristics of asthma in allergen-sensitized mice. Adult male and female BALB/c mice were sensitized intranasally to house dust mite (HDM) allergen on days 1, 3, and 5 and challenged on days 12-14. Mice were exposed to ozone following each HDM challenge for 6 h/day. Bronchoalveolar lavage, lung lobes, and microdissected lung airways were collected for metabolomics analysis (N = 8/sex/group). Another subset of mice underwent methacholine challenge using a forced oscillation technique to measure airway resistance (N = 6/sex/group). Combined HDM and ozone exposure in male mice synergistically increased airway hyperreactivity that was not observed in females and was accompanied by increased airway inflammation and eosinophilia relative to control mice. Importantly, glycosphingolipids were significantly increased following combined HDM and ozone exposure relative to controls in both male and female airways, which was also associated with both airway resistance and eosinophilia. However, 15 glycosphingolipid species were increased in females compared with only 6 in males, which was concomitant with significant associations between glycosphingolipids and airway resistance that ranged from R2 = 0.33-0.51 for females and R2 = 0.20-0.34 in male mice. These observed sex differences demonstrate that glycosphingolipids potentially serve to mitigate exacerbations in characteristics of allergic asthma.
哮喘是一种常见的慢性呼吸道疾病，由多种环境因素加重。急性臭氧暴露以前与气道炎症、气道高反应性和哮喘的其他特征有关，这可能归因于鞘脂代谢的改变。本研究检验了以下假设：急性臭氧暴露改变了肺部的鞘脂代谢，这导致了变应原致敏小鼠哮喘特征的加重。成年雄性和雌性 BALB/c 小鼠在第 1、3 和 5 天经鼻腔接受屋尘螨（HDM）过敏原致敏，并在第 12-14 天进行挑战。在每次 HDM 挑战后，小鼠暴露于臭氧中 6 小时/天。收集支气管肺泡灌洗液、肺叶和微解剖肺气道进行代谢组学分析（N = 8/性别/组）。另一组小鼠使用强迫振荡技术进行乙酰甲胆碱挑战，以测量气道阻力（N = 6/性别/组）。雄性小鼠联合 HDM 和臭氧暴露协同增加了气道高反应性，而在雌性小鼠中未观察到这种情况，并且与对照小鼠相比，气道炎症和嗜酸性粒细胞增多增加。重要的是，与对照相比，雄性和雌性气道中联合 HDM 和臭氧暴露后糖脂显着增加，这也与气道阻力和嗜酸性粒细胞增多相关。然而，与雄性相比，雌性有 15 种糖脂增加，而雄性只有 6 种，这与糖脂与气道阻力之间存在显著相关性，女性的 R2 范围为 0.33-0.51，而男性的 R2 范围为 0.20-0.34。这些观察到的性别差异表明，糖脂可能有助于减轻变应性哮喘特征的加重。
