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  3. Hydrogen alleviates impaired lung epithelial barrier in acute respiratory distress syndrome via inhibiting Drp1-mediated mitochondrial fission through the Trx1 pathway

Hydrogen alleviates impaired lung epithelial barrier in acute respiratory distress syndrome via inhibiting Drp1-mediated mitochondrial fission through the Trx1 pathway

  • Free Radic Biol Med. 2024 Jun:218:132-148. doi: 10.1016/j.freeradbiomed.2024.03.022.
Yun Long 1,  Yang Ang 2,  Wei Chen 3,  Yujie Wang 3,  Min Shi 4,  Fan Hu 5,  Qingqing Zhou 1,  Yadan Shi 1,  Baokui Ge 1,  Yigen Peng 1,  Wanyou Yu 1,  Hongguang Bao 6,  Qian Li 7,  Manlin Duan 8,  Ju Gao 9
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Jiangning Hospital Affiliated to Nanjing Medical University, Nanjing, 211100, China.
  • 2 Department of Anesthesiology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210002, China.
  • 3 Department of Otolaryngology, Jinling College Affiliated to Nanjing Medical University, Nanjing, 211100, China.
  • 4 Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China.
  • 5 State Key Labortory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, 211166, China.
  • 6 Department of Anesthesiology, Nanjing First Hospital, Nanjing Medical University, Jiangsu, 210000, China.
  • 7 Department of Anesthesiology, Jiangning Hospital Affiliated to Nanjing Medical University, Nanjing, 211100, China; Department of Anesthesiology, Nanjing First Hospital, Nanjing Medical University, Jiangsu, 210000, China. Electronic address: a162033973@163.com.
  • 8 Department of Anesthesiology, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, 210019, China. Electronic address: dml1200@126.com.
  • 9 Department of Anesthesiology, Yangzhou Clinical Medical College, Nanjing Medical University, Yangzhou, 225001, China; Department of Anesthesiology, Northern Jiangsu People's Hospital, Yangzhou, 225001, China. Electronic address: gaoju_003@163.com.
PMID: 38554812 DOI: 10.1016/j.freeradbiomed.2024.03.022
Abstract

Acute respiratory distress syndrome (ARDS) is an acute and severe clinical complication lacking effective therapeutic interventions. The disruption of the lung epithelial barrier plays a crucial role in ARDS pathogenesis. Recent studies have proposed the involvement of abnormal mitochondrial dynamics mediated by dynamin-related protein 1 (Drp1) in the mechanism of impaired epithelial barrier in ARDS. Hydrogen is an anti-oxidative stress molecule that regulates mitochondrial function via multiple signaling pathways. Our previous study confirmed that hydrogen modulated oxidative stress and attenuated acute pulmonary edema in ARDS by upregulating thioredoxin 1 (Trx1) expression, but the exact mechanism remains unclear. This study aimed to investigate the effects of hydrogen on mitochondrial dynamics both in vivo and in vitro. Our study revealed that hydrogen inhibited lipopolysaccharide (LPS)-induced phosphorylation of Drp1 (at Ser616), suppressed Drp1-mediated mitochondrial fission, alleviated epithelial tight junction damage and cell Apoptosis, and improved the integrity of the epithelial barrier. This process was associated with the upregulation of Trx1 in lung epithelial tissues of ARDS mice by hydrogen. In addition, hydrogen treatment reduced the production of Reactive Oxygen Species in LPS-induced airway epithelial cells (AECs) and increased the mitochondrial membrane potential, indicating that the mitochondrial dysfunction was restored. Then, the expression of tight junction proteins occludin and zonula occludens 1 was upregulated, and Apoptosis in AECs was alleviated. Remarkably, the protective effects of hydrogen on the mitochondrial and epithelial barrier were eliminated after applying the Trx1 inhibitor PX-12. The results showed that hydrogen significantly inhibited the cell Apoptosis and the disruption of epithelial tight junctions, maintaining the integrity of the epithelial barrier in mice of ARDS. This might be related to the inhibition of Drp1-mediated mitochondrial fission through the Trx1 pathway. The findings of this study provided a new theoretical basis for the application of hydrogen in the clinical treatment of ARDS.

Keywords

Acute respiratory distress syndrome; Dynamin-related protein 1; Hydrogen; Mitochondrial fission; Thioredoxin 1.

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