Hossain Tanvir, Secor Jackson T, Eckmann David M
Department of Anesthesiology, The Ohio State University, Columbus 43210, Ohio, USA.
Center for Medical and Engineering Innovation, The Ohio State University, Columbus 43210, Ohio, USA.
Oxid Med Cell Longev. 2025 Sep 22;2025:5589475. doi: 10.1155/omcl/5589475. eCollection 2025.
Exposure to hyperoxia lasting either a few days at normobaria or a few hours at hyperbaria induces pulmonary oxygen toxicity. Cellular functional changes resulting from oxygen toxicity include alterations in both mitochondrial dynamics and bioenergetics. The primary goal of this study was to quantify the prophylactic effects of three compounds, caffeine, MitoQ, and γ-aminobutyric acid (GABA), to protect human pulmonary cells in vitro from mitochondrial alterations induced by normobaric- and hyperbaric-hyperoxic conditions. Using cultured lung microvascular and pulmonary artery endothelial cells as well as A549 cells, we examined mitochondrial dynamic and bioenergetics function following exposure to normobaric-hyperoxic (5% CO and 95% O for 72 h) and hyperbaric-hyperoxic (~5% CO equivalent and remainder O at pressure of 4.8 atmosphere absolute (ATA) for 4 h) conditions in the presence of the drugs. Mitochondrial respiration parameters, inner membrane potential, motility, intracellular distribution, and size were measured, along with quantitation of respiration complex levels. Redistribution of intracellular ATP-linked respiration was determined. Comparisons of results were made to controls under normobaric-normoxic conditions. Effects of the drugs under control conditions were also measured. Presence of the drugs resulted in differential effects on hyperoxia-induced alterations in cellular respiration function, stability of mitochondrial potential, and distribution of ATP-linked respiration within the cell. Inclusion of these drugs also produced unique signatures for respiration complex protein levels. Moreso for caffeine than for MitoQ and GABA, its inclusion in the face of hyperoxic exposure served to preserve mitochondrial bioenergetics function, primarily by promoting intracellular redistribution of mitochondrial volume to the perinuclear space. These results indicate a potential role for pharmacologic prophylaxis via therapeutics targeted to support mitochondrial function as a means of protecting the lung from hyperoxia-induced pulmonary cellular oxygen toxicity.
在常压下暴露于高氧环境数天或在高压下暴露数小时会引发肺部氧中毒。氧中毒导致的细胞功能变化包括线粒体动力学和生物能量学的改变。本研究的主要目的是量化三种化合物，即咖啡因、MitoQ和γ-氨基丁酸（GABA）的预防作用，以保护体外培养的人肺细胞免受常压和高压高氧条件诱导的线粒体改变。我们使用培养的肺微血管和肺动脉内皮细胞以及A549细胞，在药物存在的情况下，检测了暴露于常压高氧（5%二氧化碳和95%氧气，持续72小时）和高压高氧（约5%二氧化碳当量，其余为氧气，压力为4.8绝对大气压（ATA），持续4小时）条件后的线粒体动态和生物能量学功能。测量了线粒体呼吸参数、内膜电位、运动性、细胞内分布和大小，以及呼吸复合体水平的定量分析。确定了细胞内ATP相关呼吸的重新分布。将结果与常压常氧条件下的对照组进行比较。还测量了药物在对照条件下的作用。药物的存在对高氧诱导的细胞呼吸功能改变、线粒体电位稳定性以及细胞内ATP相关呼吸的分布产生了不同的影响。加入这些药物还产生了呼吸复合体蛋白水平的独特特征。与MitoQ和GABA相比，咖啡因在高氧暴露情况下的加入更有助于维持线粒体生物能量学功能，主要是通过促进线粒体体积向核周空间的细胞内重新分布。这些结果表明，通过靶向支持线粒体功能的治疗方法进行药物预防可能具有保护肺部免受高氧诱导的肺细胞氧中毒的作用。
