title: Nitrite reduces acute lung injury and improves survival in a rat lung transplantation model.
abstract: Ischemia/reperfusion injury (IRI) is the most common cause of early mortality following lung transplantation (LTx). We hypothesized that nitrite, an endogenous source of nitric oxide (NO), may protect lung grafts from IRI. Rat lung grafts were stored in preservation solution at 4°C for 6 hours. Both grafts and recipients were treated with nitrite. Nitrite treatment was associated with significantly higher levels of tissue oxygenation, lower levels of cytokines and neutrophil/macrophage infiltration, lower myeloperoxidase activity, reduced oxidative injury and increased cGMP levels in grafts than in the controls. Treatment with either a nitric oxide scavenger or a soluble guanylyl cyclase (sGC) inhibitor diminished the beneficial effects of nitrite and decreased cGMP concentrations. These results suggest that nitric oxide, generated from nitrite, is the molecule responsible for the effects of nitrite via the nitric oxide/sGC/cGMP pathway. Allopurinol, a xanthine oxidoreductase (XOR) inhibitor, abrogated the protective effects of nitrite, suggesting that XOR is a key enzyme in the conversion of nitrite to nitric oxide. In vitro experiments demonstrated that nitrite prevented apoptosis in pulmonary endothelial cells. Nitrite also exhibits longer survival rate in recipients than control. In conclusion, nitrite inhibits lung IRI following cold preservation and had higher survival rate in LTx model.
authors.affiliation: Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Sugimoto
authors.forename: T
authors.initials: T
authors.lastname: Okamoto
authors.forename: A
authors.initials: A
authors.lastname: Nakao
authors.forename: J
authors.initials: J
authors.lastname: Zhan
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: J
authors.initials: J
authors.lastname: Kohmoto
authors.forename: D
authors.initials: D
authors.lastname: Tokita
authors.forename: C F
authors.initials: CF
authors.lastname: Farver
authors.forename: M M
authors.initials: MM
authors.lastname: Tarpey
authors.forename: T R
authors.initials: TR
authors.lastname: Billiar
authors.forename: M T
authors.initials: MT
authors.lastname: Gladwin
authors.forename: K R
authors.initials: KR
authors.lastname: McCurry
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology / Q000517:prevention & control*; D000818:Animals; D004195:Disease Models, Animal; D006084:Graft Rejection; D006085:Graft Survival / Q000187:drug effects; D016040:Lung Transplantation / Q000009:adverse effects* / Q000379:methods; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D009573:Nitrites / Q000494:pharmacology*; D018384:Oxidative Stress / Q000502:physiology*; D009195:Peroxidase / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D015427:Reperfusion Injury / Q000517:prevention & control*
chemical_list: D009573:Nitrites; D009569:Nitric Oxide; D009195:Peroxidase