title: Nebulized nitrite protects rat lung grafts from ischemia reperfusion injury.
abstract: OBJECTIVE
  Nebulization is a potential method for delivering therapeutic agents to lung grafts. Recent evidence suggests that nitrite may mitigate ischemia-reperfusion injury via a nitric oxide-dependent pathway.
  
  
  METHODS
  Syngeneic orthotopic left lung transplantation was performed in rats after 7 hours of cold ischemia. Sodium nitrite (3 mg) or phosphate-buffered saline (controls) was delivered before procurement via nebulization.
  
  
  RESULTS
  Nitrite treatment was associated with better oxygenation, lower peak airway pressure, lower wet/dry ratio, reduced myeloperoxidase level and macrophage infiltration, increased cyclic guanosine monophosphate (cGMP) levels, and decreased levels of interleukin 6, interleukin 1-β, inducible nitric oxide synthase, and intercellular adhesion molecule-1 at 2 hours after reperfusion. Treatment with 2-(4-carboxypheny)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, a nitric oxide scavenger, reversed the beneficial effects of nitrite and decreased cGMP concentration in grafts. A dose-response curve of nitrite was performed at the following doses: 0.3 mg (N0.1), 3.0 mg (N1.0), 5.25 mg (N1.75), 7.5 mg (N2.5), and 15.0 mg (N5.0). All treatments, excluding N1.0, resulted in poorer oxygenation, higher peak airway pressures, and higher wet/dry ratio. Higher dosage groups (N1.75, N2.5, and N5.0) exhibited positive immunostaining of nitrotyrosine and increased the intensity of nitrotyrosine in immunoblotting.
  
  
  CONCLUSIONS
  These data suggest that nebulized nitrite limits lung ischemia-reperfusion injury and may prove a clinically useful strategy but requires appropriate dosing to limit oxidative injury at high doses.
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Okamoto
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Allison
authors.initials: A
authors.lastname: Janocha
authors.affiliation: Department of Anatomic Pathology, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Caral F
authors.initials: CF
authors.lastname: Farver
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine and the Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pa.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio; Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic, Cleveland, Ohio. Electronic address: mccurrk@ccf.org.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: McCurry
mesh_terms: D000818:Animals; D008168:Lung / Q000098:blood supply* / Q000601:surgery*; D016040:Lung Transplantation; D008297:Male; D009330:Nebulizers and Vaporizers; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*; D012977:Sodium Nitrite / Q000008:administration & dosage*
chemical_list: D012977:Sodium Nitrite