Hydrogen gas reduces hyperoxic lung injury via the Nrf2 pathway in vivo

Am J Physiol Lung Cell Mol Physiol. 2013 May 15;304(10):L646-56. doi: 10.1152/ajplung.00164.2012. Epub 2013 Mar 8.


Hyperoxic lung injury is a major concern in critically ill patients who receive high concentrations of oxygen to treat lung diseases. Successful abrogation of hyperoxic lung injury would have a huge impact on respiratory and critical care medicine. Hydrogen can be administered as a therapeutic medical gas. We recently demonstrated that inhaled hydrogen reduced transplant-induced lung injury and induced heme oxygenase (HO)-1. To determine whether hydrogen could reduce hyperoxic lung injury and investigate the underlying mechanisms, we randomly assigned rats to four experimental groups and administered the following gas mixtures for 60 h: 98% oxygen (hyperoxia), 2% nitrogen; 98% oxygen (hyperoxia), 2% hydrogen; 98% balanced air (normoxia), 2% nitrogen; and 98% balanced air (normoxia), 2% hydrogen. We examined lung function by blood gas analysis, extent of lung injury, and expression of HO-1. We also investigated the role of NF-E2-related factor (Nrf) 2, which regulates HO-1 expression, by examining the expression of Nrf2-dependent genes and the ability of hydrogen to reduce hyperoxic lung injury in Nrf2-deficient mice. Hydrogen treatment during exposure to hyperoxia significantly improved blood oxygenation, reduced inflammatory events, and induced HO-1 expression. Hydrogen did not mitigate hyperoxic lung injury or induce HO-1 in Nrf2-deficient mice. These findings indicate that hydrogen gas can ameliorate hyperoxic lung injury through induction of Nrf2-dependent genes, such as HO-1. The findings suggest a potentially novel and applicable solution to hyperoxic lung injury and provide new insight into the molecular mechanisms and actions of hydrogen.

Keywords: NF-E2-related factor 2; heme oxygenase; hydrogen; inflammation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cytokines / metabolism
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Gases / administration & dosage
  • Gases / blood
  • Heme Oxygenase-1 / metabolism
  • Hydrogen / administration & dosage*
  • Hyperoxia / chemically induced
  • Hyperoxia / drug therapy*
  • Hyperoxia / metabolism
  • Hyperoxia / pathology
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Lung Injury / chemically induced
  • Lung Injury / drug therapy*
  • Lung Injury / metabolism
  • Lung Injury / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NF-E2-Related Factor 2 / metabolism*
  • Oxygen / administration & dosage
  • Oxygen / adverse effects
  • Permeability / drug effects
  • Rats
  • Rats, Inbred Lew
  • Signal Transduction / drug effects


  • Cytokines
  • Gases
  • NF-E2-Related Factor 2
  • Hydrogen
  • Heme Oxygenase-1
  • Oxygen