Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Life Sci. 2021 Feb 15;267:118941. doi: 10.1016/j.lfs.2020.118941. Epub 2020 Dec 24.
Acute lung injury (ALI) / acute respiratory distress syndrome (ARDS) is a critical clinical syndrome with complex pathology and pathogenesis. Since there is no specific treatment for ALI, it is important to study the mechanism of how ALI develop. Sestrin2 (Sesn2) plays a critical role in the regulation of cellular stress response and oxidant defense. However, the potential function of Sesn2 in ALI/ARDS and the associated mechanism remains unclear.
Lipopolysaccharide (LPS) induced ALI model was performed in the wild-type and Sesn2 knockout (Sesn2-/-) mice. The nod-like receptor protein 3 (NLRP3) inflammasome, cell pyroptosis and mitophagy were detected by western blots, immunofluorescent staining, flow cytometry. Lung injury were measured by histopathology and electron microscopy.
Knockout of Sesn2 enhanced LPS-induced ALI. As detailed in Sesn2 mice, NLRP3 inflammasome and cell pyroptosis were increased in lungs; IL-1β and IL-18 in serum and bronchoalveolar lavage fluid (BALF) were further promoted; In the isolated alveolar macrophages from Sesn2-/- mice, mitophagy induced by LPS was markedly inhibited, while reactive oxygen species (ROS), mitochondrial damage and cell pyroptosis were enhanced. Knocking down or overexpressing Sensn2 in J774.A1 cells demonstrated Sesn2 promoted Sequestosome1 (SQSTM1) expression and mitophagy by PTEN-induced putative kinase 1 (Pink1)/Parkin pathway.
Sesn2 protected ALI by promoting mitophagy that exerts protection of AMs pyroptosis and negative regulation of NLRP3 inflammasomes. These data indicated Sesn2 might be a potential target for ALI treatment.
急性肺损伤（ALI）/急性呼吸窘迫综合征（ARDS）是一种具有复杂病理生理学的严重临床综合征。由于目前尚无针对 ALI 的特效治疗方法，因此研究 ALI 发病机制具有重要意义。Sesn2（Sesn2）在细胞应激反应和氧化应激防御的调节中起着关键作用。然而，Sesn2 在 ALI/ARDS 中的潜在作用及其相关机制尚不清楚。
在野生型和 Sesn2 敲除（Sesn2-/-）小鼠中建立脂多糖（LPS）诱导的 ALI 模型。通过 Western blot、免疫荧光染色、流式细胞术检测 NOD 样受体蛋白 3（NLRP3）炎性体、细胞焦亡和线粒体自噬。通过组织病理学和电子显微镜测量肺损伤。
Sesn2 缺失增强了 LPS 诱导的 ALI。在 Sesn2 敲除小鼠中，肺部 NLRP3 炎性体和细胞焦亡增加；血清和支气管肺泡灌洗液（BALF）中的白细胞介素-1β（IL-1β）和白细胞介素-18（IL-18）进一步增加；在 Sesn2-/-小鼠分离的肺泡巨噬细胞中，LPS 诱导的线粒体自噬明显受到抑制，而活性氧（ROS）、线粒体损伤和细胞焦亡增强。在 J774.A1 细胞中敲低或过表达 Sensn2 表明，Sesn2 通过 PTEN 诱导的假定激酶 1（Pink1）/Parkin 通路促进自噬体相关蛋白 1（SQSTM1）表达和线粒体自噬。
Sesn2 通过促进线粒体自噬来保护 ALI，从而发挥对 AMs 焦亡的保护作用和对 NLRP3 炎性体的负调控作用。这些数据表明 Sesn2 可能是 ALI 治疗的潜在靶点。
