| First Author | Vohwinkel CU | Year | 2021 |
| Journal | FASEB J | Volume | 35 |
| Issue | 4 | Pages | e21468 |
| PubMed ID | 33687752 | Mgi Jnum | J:308347 |
| Mgi Id | MGI:6725246 | Doi | 10.1096/fj.202002778R |
| Citation | Vohwinkel CU, et al. (2021) Targeting alveolar-specific succinate dehydrogenase A attenuates pulmonary inflammation during acute lung injury. FASEB J 35(4):e21468 |
| abstractText | 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(loxp/loxp) 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(loxp/loxp) SPC-CreER experienced enhanced Hif1a levels during hypoxia or ALI. Conversely, Hif1a(loxp/loxp) 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. |
