Edaravone protects rats and human pulmonary alveolar epithelial cells against hyperoxia injury: heme oxygenase-1 and PI3K/Akt pathway may be involved

Exp Lung Res. 2015;41(7):404-14. doi: 10.3109/01902148.2015.1054053.

Abstract

Purpose/aim: Hyperoxic acute lung injury (HALI) is a clinical syndrome as a result of prolonged supplement of high concentrations of oxygen. As yet, no specific treatment is available for HALI. The present study aims to investigate the effects of edaravone on hyperoxia-induced oxidative injury and the underlying mechanism.

Materials and methods: We treated rats and human pulmonary alveolar epithelial cells with hyperoxia and different concentration of edaravone, then examined the effects of edaravone on cell viability, cell injury and two oxidative products. The roles of heme oxygenase-1 (HO-1) and PI3K/Akt pathway were explored using Western blot and corresponding inhibitors.

Results: The results showed that edaravone reduced lung biochemical alterations induced by hyperoxia and mortality of rats, dose-dependently alleviated cell mortality, cell injury, and peroxidation of cellular lipid and DNA oxidative damage. It upregulated cellular HO-1 expression and activity, which was reversed by PI3K/Akt pathway inhibition. The administration of zinc protoporphyrin-IX, a HO-1 inhibitor, and LY249002, a PI3K/Akt pathway inhibitor, abolished the protective effects of edaravone in cells.

Conclusions: This study indicates that edaravone protects rats and human pulmonary alveolar epithelial cells against hyperoxia-induced injury and the antioxidant effect may be related to upregulation of HO-1, which is regulated by PI3K/Akt pathway.

Keywords: HO-1; PI3K/Akt pathway; edaravone; hyperoxia; oxidative injury.

MeSH terms

  • Acute Lung Injury / drug therapy
  • Acute Lung Injury / metabolism
  • Alveolar Epithelial Cells / drug effects*
  • Alveolar Epithelial Cells / metabolism
  • Animals
  • Antioxidants / metabolism
  • Antipyrine / analogs & derivatives*
  • Antipyrine / pharmacology
  • Cell Survival / drug effects
  • Cells, Cultured
  • Edaravone
  • Epithelial Cells / drug effects*
  • Epithelial Cells / metabolism
  • Heme Oxygenase-1 / metabolism*
  • Humans
  • Hyperoxia / drug therapy*
  • Hyperoxia / metabolism
  • Male
  • Oxidation-Reduction / drug effects
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Protoporphyrins / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Up-Regulation / drug effects

Substances

  • Antioxidants
  • Protoporphyrins
  • zinc protoporphyrin
  • Heme Oxygenase-1
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Edaravone
  • Antipyrine