Hydrogen protects against hyperoxia-induced apoptosis in type II alveolar epithelial cells via activation of PI3K/Akt/Foxo3a signaling pathway

Biochem Biophys Res Commun. 2018 Jan 8;495(2):1620-1627. doi: 10.1016/j.bbrc.2017.11.193. Epub 2017 Dec 2.

Abstract

Oxidative stress is regarded as a key regulator in the pathogenesis of prolonged hyperoxia-induced lung injury, which causes injury to alveolar epithelial cells and eventually leads to development of bronchopulmonary dysplasia (BPD). Many studies have shown that hydrogen has a protective effect in a variety of cells. However, the mechanisms by which hydrogen rescues cells from damage due to oxidative stress in BPD remains to be fully elucidated. This study sought to evaluate the effects of hydrogen on hyperoxia-induced lung injury and to investigate the underlying mechanism. Primary type II alveolar epithelial cells (AECIIs) were divided into four groups: control (21% oxygen), hyperoxia (95% oxygen), hyperoxia + hydrogen, and hyperoxia + hydrogen + LY294002 (a PI3K/Akt inhibitor). Proliferation and apoptosis of AECIIs were assessed using MTS assay and flow cytometry (FCM), respectively. Gene and protein expression were detected by quantitative polymerase chain reaction (q-PCR) and western blot analysis. Stimulation with hyperoxia decreased the expression of P-Akt, P- FoxO3a, cyclinD1 and Bcl-2. Hyperoxic conditions increased levels of Bim, Bax, and Foxo3a, which induced proliferation restriction and apoptosis of AECIIs. These effects of hyperoxia were reversed with hydrogen pretreatment. Furthermore, the protective effects of hydrogen were abrogated by PI3K/Akt inhibitor LY294002. The results indicate that hydrogen protects AECIIs from hyperoxia-induced apoptosis by inhibiting apoptosis factors and promoting the expression of anti-apoptosis factors. These effects were associated with activation of the PI3K/Akt/FoxO3a pathway.

Keywords: AECIIs; Hydrogen; Hyperoxia; LY294002; PI3K/Akt/FoxO3a pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / drug therapy
  • Acute Lung Injury / metabolism
  • Acute Lung Injury / pathology
  • Alveolar Epithelial Cells / drug effects*
  • Alveolar Epithelial Cells / metabolism*
  • Alveolar Epithelial Cells / pathology
  • Animals
  • Apoptosis / drug effects
  • Bcl-2-Like Protein 11 / genetics
  • Cells, Cultured
  • Cyclin D1 / genetics
  • Female
  • Forkhead Box Protein O3 / genetics
  • Forkhead Box Protein O3 / metabolism
  • Gene Expression / drug effects
  • Genes, bcl-2 / drug effects
  • Hydrogen / metabolism
  • Hydrogen / pharmacology*
  • Hyperoxia / drug therapy*
  • Hyperoxia / metabolism*
  • Hyperoxia / pathology
  • Oxidative Stress / drug effects
  • Phosphatidylinositol 3-Kinases / metabolism
  • Pregnancy
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • bcl-2-Associated X Protein / genetics

Substances

  • Bax protein, rat
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, rat
  • Ccnd1 protein, rat
  • FOXO3 protein, rat
  • Forkhead Box Protein O3
  • RNA, Messenger
  • bcl-2-Associated X Protein
  • Cyclin D1
  • Hydrogen
  • Proto-Oncogene Proteins c-akt