title: Hydrogen gas reduces hyperoxic lung injury via the Nrf2 pathway in vivo.
abstract: 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.
authors.affiliation: Division of Cardiothoracic Transplantation, Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kawamura
authors.forename: Nobunao
authors.initials: N
authors.lastname: Wakabayashi
authors.forename: Norihisa
authors.initials: N
authors.lastname: Shigemura
authors.forename: Chien-Sheng
authors.initials: CS
authors.lastname: Huang
authors.forename: Kosuke
authors.initials: K
authors.lastname: Masutani
authors.forename: Yugo
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Kentaro
authors.initials: K
authors.lastname: Noda
authors.forename: Ximei
authors.initials: X
authors.lastname: Peng
authors.forename: Toru
authors.initials: T
authors.lastname: Takahashi
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.forename: Meinoshin
authors.initials: M
authors.lastname: Okumura
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Toyoda
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Kensler
authors.forename: Atsunori
authors.initials: A
authors.lastname: Nakao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005740:Gases / Q000008:administration & dosage / Q000097:blood; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006859:Hydrogen / Q000008:administration & dosage*; D018496:Hyperoxia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D055370:Lung Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010100:Oxygen / Q000008:administration & dosage / Q000009:adverse effects; D010539:Permeability / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016207:Cytokines; D005740:Gases; D051267:NF-E2-Related Factor 2; D006859:Hydrogen; D051547:Heme Oxygenase-1; D010100:Oxygen
keywords: NF-E2-related factor 2; heme oxygenase; hydrogen; inflammation