BACKGROUND Administration of inhaled carbon monoxide before organ ischemic injury exerts protective effects in animal models. Because there are no data showing that this also works after an ischemic insult, our objective in this study was to investigate whether inhaled carbon monoxide attenuates cardiopulmonary bypass (CPB)-induced lung injury in a pig model. METHODS Animals were randomized to a SHAM group (n = 5), a SHAM group plus inhaled carbon monoxide (n = 5), standard CPB (n = 10), and to CPB plus inhaled carbon monoxide (n = 10). Carbon monoxide (250 ppm) was given for 1 hour after termination of CPB. Lung biopsies were obtained before CPB, immediately after separation from CPB, and for 5 hours after termination of CPB to determine expression of pulmonary heat shock proteins 70 and 90, cytokines, alveolar macrophage infiltration, and fluorogenic caspase-3 activity. RESULTS At 5 hours after CPB, administration of inhaled carbon monoxide was associated with reduced pulmonary expression of the inflammatory cytokines tumor necrosis factor (CPB + CO 521 ± 77 vs CPB 821 ± 97 pg · mL(-1), P < 0.001) and interleukin-6 (304 ± 81 vs 860 ± 153 pg · mL(-1), P < 0.001), increased pulmonary expression of the cytoprotective heat shock protein 70 (CPB + CO 79 ± 14 vs CPB 36 ± 9 ng · mL(-1), P < 0.001) and the antiinflammatory cytokine interleukin-10 (CPB + CO 278 ± 40 vs CPB 63 ± 20 pg · mL(-1), P < 0.001), and with reduced pulmonary apoptotic protein caspase-3 activity (CPB + CO 0.73 ± 0.11 vs CPB 0.99 ± 0.1 RFU, P < 0.05). Carbon monoxide administration was associated with reduced histological evidence of lung injury and alveolar macrophage infiltration (78 ± 39 vs 145 ± 34 counts per field of vision, P < 0.001). CONCLUSIONS These results suggest that administration of low concentrations of carbon monoxide after CPB ("postconditioning") protects the lung from CPB-related lung injury.