Developmental Lung Biology, Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatric Critical Care, Departments of Medicine and Pediatrics, University of Colorado, Aurora, CO, USA.
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, CO, USA.
FASEB J. 2021 Apr;35(4):e21468. doi: 10.1096/fj.202002778R.
Acute lung injury (ALI) is an inflammatory lung disease, which manifests itself in patients as acute respiratory distress syndrome (ARDS). Previous studies have implicated alveolar-epithelial succinate in ALI protection. Therefore, we hypothesized that targeting alveolar succinate dehydrogenase SDH A would result in elevated succinate levels and concomitant lung protection. Wild-type (WT) mice or transgenic mice with targeted alveolar-epithelial Sdha or hypoxia-inducible transcription factor Hif1a deletion were exposed to ALI induced by mechanical ventilation. Succinate metabolism was assessed in alveolar-epithelial via mass spectrometry as well as redox measurements and evaluation of lung injury. In WT mice, ALI induced by mechanical ventilation decreased SDHA activity and increased succinate in alveolar-epithelial. In vitro, cell-permeable succinate decreased epithelial inflammation during stretch injury. Mice with inducible alveolar-epithelial Sdha deletion (Sdha SPC-CreER mice) revealed reduced lung inflammation, improved alveolar barrier function, and attenuated histologic injury. Consistent with a functional role of succinate to stabilize HIF, Sdha SPC-CreER experienced enhanced Hif1a levels during hypoxia or ALI. Conversely, Hif1a SPC-CreER showed increased inflammation with ALI induced by mechanical ventilation. Finally, wild-type mice treated with intra-tracheal dimethlysuccinate were protected during ALI. These data suggest that targeting alveolar-epithelial SDHA dampens ALI via succinate-mediated stabilization of HIF1A. Translational extensions of our studies implicate succinate treatment in attenuating alveolar inflammation in patients suffering from ARDS.
急性肺损伤（ALI）是一种炎症性肺病，在患者中表现为急性呼吸窘迫综合征（ARDS）。先前的研究表明，肺泡上皮琥珀酸在 ALI 保护中起作用。因此，我们假设靶向肺泡琥珀酸脱氢酶 SDHA 将导致琥珀酸水平升高，并伴有肺保护作用。野生型（WT）小鼠或靶向肺泡上皮 Sdha 或缺氧诱导转录因子 Hif1a 缺失的转基因小鼠暴露于机械通气诱导的 ALI 中。通过质谱法以及氧化还原测量和肺损伤评估来评估肺泡上皮中的琥珀酸代谢。在 WT 小鼠中，机械通气诱导的 ALI 降低了 SDHA 活性并增加了肺泡上皮中的琥珀酸。在体外，细胞通透性琥珀酸可减少伸展损伤期间的上皮炎症。可诱导的肺泡上皮 Sdha 缺失（Sdha SPC-CreER 小鼠）的小鼠显示肺炎症减少，肺泡屏障功能改善，组织学损伤减轻。与琥珀酸稳定 HIF 的功能作用一致，Sdha SPC-CreER 在缺氧或 ALI 期间经历了增强的 Hif1a 水平。相反，机械通气诱导的 ALI 中 Hif1a SPC-CreER 表现出炎症增加。最后，用气管内二甲基琥珀酸处理的野生型小鼠在 ALI 期间得到了保护。这些数据表明，靶向肺泡上皮 SDHA 通过琥珀酸介导的 HIF1A 稳定作用减轻 ALI。我们研究的翻译扩展表明，琥珀酸盐治疗可减轻 ARDS 患者的肺泡炎症。
