Ventilation with gases containing enhanced fractions of oxygen is the cornerstone of therapy for patients with hypoxia and acute respiratory distress syndrome. Yet, hyperoxia treatment increases free reactive oxygen species (ROS)-induced lung injury, which is reported to disrupt autophagy/mitophagy. Altered extranuclear activity of the catalytic subunit of telomerase, TERT, plays a protective role in ROS injury and autophagy in the systemic and coronary endothelium. We investigated interactions between autophagy/mitophagy and TERT that contribute to mitochondrial dysfunction and pulmonary injury in cultured rat lung microvascular endothelial cells (RLMVECs) exposed in vitro, and rat lungs exposed in vivo to hyperoxia for 48 hours. Hyperoxia induced mitochondrial damage in rat lungs (TOMM20, MTT), which was paralleled by increased markers of inflammation (MPO, IL-1β, TLR9), impaired autophagy signaling (Beclin-1, LC3B-II/1, p62), and decreased the expression of TERT. Mitochondrial specific autophagy (mitophagy) was not altered as hyperoxia increased expression of Pink1 but not Parkin. Hyperoxia-induced mitochondrial damage (TOMM20) was more pronounced in rats that lack the catalytic subunit of TERT, and resulted in a reduction in cellular proliferation rather than cell death in RLMVECs. Activation of TERT or autophagy individually offset mitochondrial damage (MTT). Combined activation/inhibition failed to alleviate hyperoxic-induced mitochondrial damage in vitro, while activation of autophagy in vivo decreased mitochondrial damage (MTT) in both WT and rats lacking TERT. Functionally, activation of either TERT or autophagy preserved transendothelial membrane resistance. Altogether, these observations show that activation of autophagy/mitophagy and/or TERT mitigate loss of mitochondrial function and barrier integrity in hyperoxia.

中文翻译：

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高氧条件下的自噬、TERT 和线粒体功能障碍

使用含氧量更高的气体进行通气是缺氧和急性呼吸窘迫综合征患者治疗的基石。然而，高氧治疗会增加游离活性氧 (ROS) 诱导的肺损伤，据报道这会破坏自噬/线粒体自噬。端粒酶催化亚基 TERT 的核外活性改变，在全身和冠状动脉内皮中的 ROS 损伤和自噬中起保护作用。我们研究了自噬/线粒体自噬和 TERT 之间的相互作用，这些相互作用导致体外暴露的培养大鼠肺微血管内皮细胞 (RLMVEC) 和体内暴露于高氧 48 小时的大鼠肺中的线粒体功能障碍和肺损伤。高氧诱导大鼠肺线粒体损伤（TOMM20，MTT），与此同时，炎症标志物（MPO、IL-1β、TLR9）增加、自噬信号受损（Beclin-1、LC3B-II/1、p62）和 TERT 表达降低。线粒体特异性自噬（mitophagy）没有改变，因为高氧增加了 Pink1 的表达，但没有增加 Parkin。高氧诱导的线粒体损伤（TOMM20）在缺乏 TERT 催化亚基的大鼠中更为明显，并导致 RLMVEC 中细胞增殖减少而不是细胞死亡。TERT 或自噬的激活单独抵消线粒体损伤 (MTT)。联合激活/抑制未能减轻体外高氧诱导的线粒体损伤，而体内自噬的激活减少了 WT 和缺乏 TERT 的大鼠的线粒体损伤 (MTT)。在功能上，TERT 或自噬的激活保留了跨内皮膜阻力。总之，这些观察结果表明，自噬/线粒体自噬和/或 TERT 的激活减轻了高氧条件下线粒体功能和屏障完整性的丧失。