title: Hydrogen preconditioning during ex vivo lung perfusion improves the quality of lung grafts in rats.
abstract: BACKGROUND
  Although the benefits of ex vivo lung perfusion (EVLP) have been globally advocated, the potentially deleterious effects of applying EVLP, in particular activation of proinflammatory cascades and alteration of metabolic profiles, are rarely discussed. This study examined proinflammatory events and metabolic profiles in lung grafts on EVLP and tested whether preconditioning lung grafts with inhaled hydrogen, a potent, cytoprotective gaseous signaling molecule, would alter the lungs' response to EVLP.
  
  
  METHODS
  Rat heart-lung blocks were mounted on an acellular normothermic EVLP system for 4 hr and ventilated with air or air supplemented with 2% hydrogen. Arterial and airway pressures were monitored continuously; perfusate was sampled hourly to examine oxygenation. After EVLP, the lung grafts were transplanted orthotopically into syngeneic rats, and lung function was examined.
  
  
  RESULTS
  Placing lung grafts on EVLP resulted in significant upregulation of the messenger RNAs for several proinflammatory cytokines, higher glucose consumption, and increased lactate production. Hydrogen administration attenuated proinflammatory changes during EVLP through upregulation of the heme oxygenase-1. Hydrogen administration also promoted mitochondrial biogenesis and significantly decreased lactate production. Additionally, in the hydrogen-treated lungs, the expression of hypoxia-inducible factor-1 was significantly attenuated during EVLP. These effects were maintained throughout EVLP and led to better posttransplant lung graft function in the recipients of hydrogen-treated lungs.
  
  
  CONCLUSIONS
  Lung grafts on EVLP exhibited prominent proinflammatory changes and compromised metabolic profiles. Preconditioning lung grafts using inhaled hydrogen attenuated these proinflammatory changes, promoted mitochondrial biogenesis in the lungs throughout the procedure, and resulted in better posttransplant graft function.
authors.affiliation: 1 Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, PA. 2 Department of Medical Engineering, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa, Japan. 3 Address correspondence to: Norihisa Shigemura, M.D., Ph.D., 200 Lothrop Street Suite C-900, Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Noda
authors.forename: Norihisa
authors.initials: N
authors.lastname: Shigemura
authors.forename: Yugo
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Jay
authors.initials: J
authors.lastname: Bhama
authors.forename: Jonathan
authors.initials: J
authors.lastname: D'Cunha
authors.forename: Hirosuke
authors.initials: H
authors.lastname: Kobayashi
authors.forename: James D
authors.initials: JD
authors.lastname: Luketich
authors.forename: Christian A
authors.initials: CA
authors.lastname: Bermudez
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006859:Hydrogen / Q000494:pharmacology / Q000627:therapeutic use*; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D019344:Lactic Acid / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D016040:Lung Transplantation / Q000379:methods*; D008297:Male; D008928:Mitochondria / Q000187:drug effects; D010477:Perfusion / Q000009:adverse effects* / Q000379:methods; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D060888:Real-Time Polymerase Chain Reaction; D014185:Transplantation, Isogeneic / Q000379:methods; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D015415:Biomarkers; D016207:Cytokines; D020011:Protective Agents; D019344:Lactic Acid; D006859:Hydrogen; D051547:Heme Oxygenase-1