Critical role of reactive nitrogen species in lung ischemia-reperfusion injury.
BACKGROUND
Peroxynitrite is a potent cytotoxic free radical produced by the reaction of nitric oxide with the superoxide ion produced in conditions of oxidative stress. The purpose of the study was to examine the role of this reactive nitrogen species in lung ischemia-reperfusion injury.


METHODS
Left lungs of male Long-Evans rats were rendered ischemic for 90 minutes and reperfused for up to 4 hours. Treated animals received FP-15 (a water-soluble iron containing metalloporphyrin that acts as a peroxynitrite decomposition catalyst). Injury was quantitated in terms of tissue neutrophil accumulation (myeloperoxidase content) and vascular permeability ((125)I bovine serum albumin [BSA] extravasation) and bronchoalveolar lavage cytokine, transcriptional factor and leukocyte content. Separate tissue samples were processed for immunohistology and nuclear protein analysis.


RESULTS
Lung vascular permeability was reduced in treated animals by 61% compared with control animals (p < 0.005). The protective effects of enhanced peroxynitrite decomposition correlated with a 72% reduction in tissue myeloperoxidase content (p < 0.001) and marked reductions in brochoalveolar lavage leukocyte accumulation. This correlated positively with the diminished expression of pro-inflammatory chemokines and nuclear transcription factors.


CONCLUSIONS
The deleterious effects of lung ischemia-reperfusion injury are in part mediated by the formation of peroxynitrite, as enhanced decomposition of this species is protective in this model. The development of potent water-soluble decomposition catalysts represents a potentially useful therapeutic tool in the prevention of lung ischemia-reperfusion injury after lung transplantation.
Naidu
Babu V
BV
Department of Surgery, University of Washington, Seattle, Washington 98195, USA.
Fraga
Charles
C
Salzman
Andrew L
AL
Szabo
Csaba
C
Verrier
Edward D
ED
Mulligan
Michael S
MS
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002199:Capillary Permeability / Q000187:drug effects; D018925:Chemokines / Q000378:metabolism; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008955:Models, Cardiovascular; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D026361:Reactive Nitrogen Species / Q000502:physiology*; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology*; D012128:Respiratory Distress Syndrome / Q000378:metabolism / Q000503:physiopathology*; D012720:Severity of Illness Index; D013223:Statistics as Topic; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000187:drug effects / Q000378:metabolism
D018925:Chemokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D026361:Reactive Nitrogen Species; D018808:Transcription Factor AP-1; D030421:Peroxynitrous Acid; C002744:3-nitrotyrosine; D014443:Tyrosine; D009195:Peroxidase