Department of Critical Care Medicine, People's Hospital of Longhua, Shenzhen 518109, China.
Department of Anesthesiology, Shenzhen Hospital, Southern Medical University, Shenzhen 518110, China.
Biomed Res Int. 2019 May 8;2019:2193706. doi: 10.1155/2019/2193706. eCollection 2019.
The regulation of intracellular mitochondria degradation is mediated by mitophagy. While studies have shown that mitophagy can lead to mitochondrial dysfunction and cell damage, the role of Mdivi-1 and mitophagy remains unclear in acute lung injury (ALI) pathogenesis. In this study, we demonstrated that Mdivi-1, which is widely used as an inhibitor of mitophagy, ameliorated acute lung injury assessed by HE staining, pulmonary microvascular permeability assay, measurement of wet/dry weight (W/D) ratio, and oxygenation index (PaO2/FiO2) analysis. Then, the mitophagy related proteins were evaluated by western blot. The results indicated that LPS-induced activation of mitophagy was inhibited by Mdivi-1 treatment. In addition, we found that Mdivi-1 protected A549 cells against LPS-induced mitochondrial dysfunction. We also found that Mdivi-1 reduced pulmonary cell apoptosis in the LPS-challenged rats and protected pulmonary tissues from oxidative stress (represented by the content of superoxide dismutase, malondialdehyde and lipid peroxides in lung). Moreover, Mdivi-1 treatment ameliorated LPS-induced lung inflammatory response and cells recruitment. These findings indicate that Mdivi-1 mitigates LPS-induced apoptosis, oxidative stress, and inflammation in ALI, which may be associated with mitophagy inhibition. Thus, the inhibition of mitophagy may represent a potential therapy for treating ALI.
细胞内线粒体降解的调节是通过自噬来介导的。虽然研究表明自噬会导致线粒体功能障碍和细胞损伤，但 Mdivi-1 和自噬在急性肺损伤（ALI）发病机制中的作用尚不清楚。在这项研究中，我们证明了 Mdivi-1（广泛用作自噬抑制剂）可通过 HE 染色、肺微血管通透性测定、湿/干重比（W/D）测量和氧合指数（PaO2/FiO2）分析改善急性肺损伤。然后，通过 Western blot 评估自噬相关蛋白。结果表明，Mdivi-1 处理抑制了 LPS 诱导的自噬激活。此外，我们发现 Mdivi-1 可保护 A549 细胞免受 LPS 诱导的线粒体功能障碍。我们还发现，Mdivi-1 减少了 LPS 刺激的大鼠肺细胞凋亡，并保护肺组织免受氧化应激（以肺中超氧化物歧化酶、丙二醛和脂质过氧化物的含量来表示）。此外，Mdivi-1 治疗可改善 LPS 诱导的肺炎症反应和细胞募集。这些发现表明，Mdivi-1 减轻了 LPS 诱导的 ALI 中的细胞凋亡、氧化应激和炎症，这可能与自噬抑制有关。因此，自噬的抑制可能代表了治疗 ALI 的一种潜在疗法。
