Carbon monoxide inhalation ameliorates conditions of lung grafts from rat brain death donors

Background Successful lung transplantation has been limited by the scarcity of donors. Brain death （BD） donors are major source of lung transplantation. Whereas BD process induces acute lung injury and aggravates lung ischemia reperfusion injury. Carbon monoxide （CO） inhalation at 50-500 parts per million （ppm） can ameliorate lung injury in several models. We examined in rats whether CO inhalation in BD donor would show favorable effects on lung grafts. Methods Rats were randomly divided into 4 groups. In sham group, donor rats received insertion of a balloon catheter into the cranial cavity, but the balloon was not inflated. In BD-only group, donor rats were ventilated with 40% oxygen after BD confirmation. In BD＋CO250 and BD＋CO500 groups, donor rats inhaled, after BD confirmation, 250 ppm or 500 ppm CO for 120 minutes prior to lung procurement, and orthotopic lung transplantation was performed. The rats were sacrificed 120 minutes after the lung transplantation by exsanguination, and their blood and lung graft samples were obtained. A total of 8 rats fulfilling the criteria were included in each group. Results The inhalation decreased the severity of lung injury in grafts from BD donors checked by histological examination. CO pretreatment reversed the aggravation of PaO2/FiO2 in recipients from BD donors. The CO inhalation down-regulated pro-inflammatory cytokines （TNF-α, IL-6） along with the increase of anti-inflammatory cytokine （IL-10） in recipient serum, and inhibited the activity of myeloperoxidase in grafts tissue. The inhalation significantly decreased cell apoptosis in lung grafts, inhibiting mRNA and protein expression of intercellular adhesion molecule-1 （ICAM-1） and caspase-3 in lung grafts. Further, the inhalation activated phosphorylation of p38 expression and inhibited phosphorylation of anti-extracellular signal-regulated kinase （ERK） expression in lung grafts. The effects of CO at 500 ppm were greater than those at 250 ppm. Conclusions CO exerts potent protective effects on lung grafts from BD donor, exhibiting anti-inflammatory and anti-apoptosis functions by modulating the mitogen-activated protein kinase （MAPK） signal transduction.