Critical role of reactive nitrogen species in lung ischemia–reperfusion injury

Abstract

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 ( 125I 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.