MitoQ对急性肺损伤血管内皮细胞的保护作用及机制研究

Acute lung injury (ALI) is one of common severe disorders in clinic. Its mortality was up to 70% due to lack of effective treatment. The uncontrolled lung inflammation and increased pulmonary microvascular permeability are the key pathogenesis of ALI. MitoQ is one of typical mitochondrial antioxidants which can mitigate cellular oxidative stress by means of clearing reactive oxygen species, inhibiting peroxidation reaction and protecting the mitochondria. In this study, we will establish the LPS-induced ALI mouse model to investigate the protective role of MitoQ and its related mechanisms. Using a cellular injury model of pulmonary vascular endothelial cells, we will explore the effect of MitoQ on mitochondrial resuscitation, cellular inflammation and oxidative stress. Furthermore, the relationship between inflammation-related toll-like receptors (TLR) and the metabolism-related peroxisome proliferator-activated receptor γ (PPARγ) will be revealed in the vascular endothelial cells. The present project will provide potentially novel therapy for ALI.

急性肺损伤（ALI）是临床常见危重症，目前缺乏有效治疗手段，病死率可高达70%。肺部炎症失控和微血管通透性增加是ALI发病的重要机制。米托蒽醌甲磺酸盐（MitoQ）是一类靶向线粒体的抗氧化剂，可清除活性氧，抑制过氧化反应，保护线粒体，从而减轻细胞氧化应激。本课题利用脂多糖LPS建立的ALI小鼠模型，研究MitoQ对ALI的保护作用和相关机制。体外建立肺血管内皮细胞损伤模型，进一步探讨MitoQ对线粒体功能的修复作用，对细胞炎症和氧化应激的影响。同时深入阐明肺血管内皮细胞炎症相关的Toll样受体和代谢相关的PPARγ受体在内皮损伤中相互调节关系。本研究将有助于为治疗急性肺损伤提供新的手段。

急性肺损伤(ALI)是临床常见的危重症，肺部炎症失控和微血管通透性增加是ALI发病的重要机制。最近研究表明活性氧(ROS)过度产生和线粒体损伤会加剧ALI炎症过程。MitoQ是一类靶向线粒体的抗氧化剂，但其对ALI的作用仍不清楚。我们的研究表明，脂多糖(LPS)诱导的ALI过程中发生过氧化，而该氧化还原的失调可以被MitoQ部分逆转。腹腔内注射MitoQ后，ALI小鼠内皮细胞凋亡伴随的肺血管高通透性和肺功能受损也被部分纠正。在体外研究中，MitoQ能纠正LPS诱导人肺微血管内皮细胞(HPMEC)产生的过度ROS，线粒体功能障碍和细胞凋亡。细胞RNA转录组测序发现在MitoQ治疗组中MafF基因表达明显上调。此外，MitoQ能抑制Nrf2蛋白酶途径的降解并增加其核易位，从而上调其下游抗氧化反应元件信号通路相关基因如HO-1和NQO-1的表达。转染Nrf2或Maff小干扰RNA后可以消除 MitoQ对HPMEC的保护作用。分子对接模型表明MitoQ能够在适当的结合位点与Nrf2形成空间互补。Nrf2缺陷小鼠能部分消除MitoQ对ALI小鼠肺组织损伤的保护作用。因此，MitoQ能通过维持线粒体稳态，抑制内皮细胞凋亡，保护肺气血屏障和调节肺部炎症在ALI中发挥有益作用。本研究为ALI防治提供了新的手段。