title: Hydrogen inhalation ameliorates ventilator-induced lung injury.
abstract: BACKGROUND
  Mechanical ventilation (MV) can provoke oxidative stress and an inflammatory response, and subsequently cause ventilator-induced lung injury (VILI), a major cause of mortality and morbidity of patients in the intensive care unit. Inhaled hydrogen can act as an antioxidant and may be useful as a novel therapeutic gas. We hypothesized that, owing to its antioxidant and anti-inflammatory properties, inhaled hydrogen therapy could ameliorate VILI.
  
  
  METHODS
  VILI was generated in male C57BL6 mice by performing a tracheostomy and placing the mice on a mechanical ventilator (tidal volume of 30 ml/kg without positive end-expiratory pressure, FiO(2) 0.21). The mice were randomly assigned to treatment groups and subjected to VILI with delivery of either 2% nitrogen or 2% hydrogen in air. Sham animals were given same gas treatments for two hours (n = 8 for each group). The effects of VILI induced by less invasive and longer exposure to MV (tidal volume of 10 ml/kg, 5 hours, FiO(2) 0.21) were also investigated (n = 6 for each group). Lung injury score, wet/dry ratio, arterial oxygen tension, oxidative injury, and expression of pro-inflammatory mediators and apoptotic genes were assessed at the endpoint of two hours using the high-tidal volume protocol. Gas exchange and apoptosis were assessed at the endpoint of five hours using the low-tidal volume protocol.
  
  
  RESULTS
  Ventilation (30 ml/kg) with 2% nitrogen in air for 2 hours resulted in deterioration of lung function, increased lung edema, and infiltration of inflammatory cells. In contrast, ventilation with 2% hydrogen in air significantly ameliorated these acute lung injuries. Hydrogen treatment significantly inhibited upregulation of the mRNAs for pro-inflammatory mediators and induced antiapoptotic genes. In the lungs treated with hydrogen, there was less malondialdehyde compared with lungs treated with nitrogen. Similarly, longer exposure to mechanical ventilation within lower tidal volume (10 mg/kg, five hours) caused lung injury including bronchial epithelial apoptosis. Hydrogen improved gas exchange and reduced VILI-induced apoptosis.
  
  
  CONCLUSIONS
  Inhaled hydrogen gas effectively reduced VILI-associated inflammatory responses, at both a local and systemic level, via its antioxidant, anti-inflammatory and antiapoptotic effects.
authors.affiliation: Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
authors.forename: Chien-Sheng
authors.initials: CS
authors.lastname: Huang
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kawamura
authors.forename: Sungsoo
authors.initials: S
authors.lastname: Lee
authors.forename: Naobumi
authors.initials: N
authors.lastname: Tochigi
authors.forename: Norihisa
authors.initials: N
authors.lastname: Shigemura
authors.forename: Bettina M
authors.initials: BM
authors.lastname: Buchholz
authors.forename: John D
authors.initials: JD
authors.lastname: Kloke
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Toyoda
authors.forename: Atsunori
authors.initials: A
authors.lastname: Nakao
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001784:Blood Gas Analysis / Q000379:methods; D006859:Hydrogen / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011897:Random Allocation; D012121:Respiration, Artificial / Q000009:adverse effects*; D055397:Ventilator-Induced Lung Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*
chemical_list: D006859:Hydrogen