Carbon monoxide reduces pulmonary ischemia–reperfusion injury in miniature swine

Objectives

Carbon monoxide is produced endogenously as a by-product of heme catalysis and has been shown to reduce ischemia–reperfusion injury in a variety of organs in murine models. The aims of this translational research were to establish an in situ porcine lung model of warm ischemia–reperfusion injury and to evaluate the cytoprotective effects of low-dose inhaled carbon monoxide in this model.

Methods

Warm ischemia was induced for 90 minutes by clamping the left pulmonary artery and veins in 8 Clawn miniature swine (Japan Farm CLAWN Institute, Kagoshima, Japan). The left main bronchus was also dissected and reanastomosed just before reperfusion. Four animals were treated with inhaled carbon monoxide at a concentration of approximately 250 ppm throughout the procedure. Lung function and structure were serially accessed via lung biopsy, chest x-ray films, and blood gas analysis.

Results

Carbon monoxide inhalation dramatically decreased the lung injury associated with ischemia and reperfusion. Two hours after reperfusion, the arterial oxygen tension of the carbon monoxide–treated group was 454 ± 34 mm Hg, almost double the arterial oxygen tension of the control group (227 ± 57 mm Hg). There were fewer pathologic changes seen on chest x-ray films and in biopsy samples from animals in the carbon monoxide–treated group. Animals in the carbon monoxide–treated group also had fewer inflammatory cell infiltrates and a markedly smaller increase in serum concentrations of the proinflammatory cytokines interleukin 1β, interleukin 6, and high-mobility group box 1 after ischemia–reperfusion injury.

Conclusions

The perioperative administration of low-dose inhaled carbon monoxide decreases warm ischemia–reperfusion injury in lungs in miniature swine. This protective effect is mediated in part by the downregulation of proinflammatory mediators.

CTSNet classification: 9, 12, 38.1

Abbreviations and Acronyms: CO, carbon monoxide, COHb, carboxyhemoglobin, CXR, chest x-ray, HMGB1, high-mobility group box 1, IRI, ischemia–reperfusion injury, Pao₂, arterial oxygen tension