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

Tomohiro Kawamura, Nobunao Wakabayashi, Norihisa Shigemura, Chien Sheng Huang, Kosuke Masutani, Yugo Tanaka, Kentaro Noda, Ximei Peng, Toru Takahashi, Timothy R. Billiar, Meinoshin Okumura, Yoshiya Toyoda, Thomas W. Kensler, Atsunori Nakao*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

132 Scopus citations


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.

Original languageEnglish
Pages (from-to)L646-L656
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Issue number10
StatePublished - 2013
Externally publishedYes


  • Heme oxygenase
  • Hydrogen
  • Inflammation
  • NF-E2-related factor 2


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