Persistent pulmonary hypertension of the newborn (PPHN) occurs when the pulmonary vascular resistance fails to decrease at birth. The affected infants are hypoxemic and have an increased risk of morbidity and mortality. Advances in newborn intensive care have dramatically improved the survival of infants with PPHN. However, survivors of PPHN continue to have increased long-term disabilities. Current treatment strategies focus on rescue therapies for infants that are already ill with hypoxemia and cardio-pulmonary instability. Ideal intervention for these babies will correct the vascular dysfunction in pulmonary arteries antenatally to restore normal adaptation to the lungs. Studies in fetal lambs with prenatal ductal constriction, a model that mimics PPHN, have shown that pulmonary vascular dysfunction is associated with an increase in oxidative stress. A decrease in anti-oxidant signals such as superoxide dismutase (SOD) and nitric oxide (NO) and an increase in pro-oxidant, endothelin peptide (ET-1) occur in pulmonary arteries in this model. Our previous studies in lambs with PPHN demonstrated that antenatal betamethasone, a glucocorticoid, reduces the oxidative stress, restores SOD and NO levels and decreases ET-1 expression. Antenatal betamethasone is extensively used in premature labor as a targeted intervention to promote lung maturity. Studies in this proposal investigate the novel hypothesis that antenatal betamethasone will improve the postnatal adaptation of pulmonary circulation and oxygenation in PPHN. Studies will be done in lambs with prenatal ligation of ductus arteriosus to induce PPHN. Pregnant ewes will be randomly assigned to receive betamethasone or saline. Fetal lambs will be delivered close to term gestation by C-section and will be ventilated for a period of 12 hours. After the ventilation studies are completed, lungs will be harvested from euthanized lambs for additional studies. The specific aims of the proposed studies are to investigate the effect of antenatal betamethasone on (1) Transition of pulmonary and systemic vascular pressures and postnatal oxygenation (2) Response of isolated pulmonary arteries from the lungs to vasodilator and vasoconstrictor stimuli (3) Markers of oxidative stress, such as, superoxide, 8-isoprostanes and peroxynitrite in pulmonary arteries and (4) Balance of pro- and anti-oxidant signaling by measuring expression of eNOS, SOD isoforms and ET-1 in PAs. These studies will be an important prelude to investigation of this antenatal intervention in babies at risk for PPHN. This targeted intervention has the potential to improve the outcome of babies with PPHN. PUBLIC HEALTH RELEVANCE: Project Narrative Failure of pulmonary vasodilation to occur at birth results in persistent pulmonary hypertension of newborn. This condition is associated with hypoxemia and increased risk of death or disability in the affected infants. The proposed studies will investigate the role of antenatal betamethasone to restore normal vascular function to the infant's lungs before birth to avoid periods of hypoxemia.
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