The therapeutic effect of controlled reoxygenation on chronic hypoxia-associated brain injury

Cardiopulmonary bypass (CPB) is the most general technique applied in congenital heart disease (CHD). However, standard CPB poses a specific pathologic condition for patients during surgery: exposure to reoxygenation. When surgery is performed on cyanotic infants, standard CPB is usually initiated at a high concentration of oxygen without consideration of cytotoxic effects. Controlled reoxygenation is defined as using normoxic CPB with a pump prime the PO2 (oxygen tension in the blood) of which is matched to the patient's preoperative saturation. The aim of this study is to determine whether controlled reoxygenation could avoid standard reoxygenation injury and to clarify the molecular signaling pathways during hypoxia. We successfully established the reproducing abnormal brain observed in mice, of chronic hypoxia during the period of early postnatal development, which is equivalent to the third trimester in humans. Mice were treated with standard reoxygenation and controlled reoxygenation after hypoxia for 24 h. We then assessed the brain tissue of these mice. In standard reoxygenation treated hypoxia mice, the caspase-3-dependent neuronal apoptosis was enhanced by increasing concentration of oxygen. Interestingly, controlled reoxygenation inhibited neurons and glial cells apoptosis through suppressing cleavage of caspase-3 and PARP. We also found that controlled reoxygenation suppressed LCN2 expression and inflammatory cytokines (including TNF-α, IL-6, and CXCL10) production, in which JAK2/STAT3 signaling pathway might participate. In conclusion, our findings propose a novel therapeutic potential of controlled reoxygenation on cardiopulmonary bypass during congenital heart disease.