Antenatal betamethasone for persistent pulmonary hypertension of newborn

描述（由申请人提供）：新生儿持续性肺动脉高压（PPHN）发生在出生时肺血管阻力未能降低时。受影响的婴儿是低氧血症，发病率和死亡率的风险增加。新生儿重症监护的进步极大地提高了PPHN患儿的生存率。然而，PPHN的幸存者继续增加长期残疾。目前的治疗策略侧重于已经患有低氧血症和心肺不稳定的婴儿的抢救治疗。理想的干预措施是在产前纠正肺动脉血管功能障碍，以恢复对肺部的正常适应。对患有产前导管收缩（一种模仿PPHN的模型）的胎儿羔羊的研究表明，肺血管功能障碍与氧化应激的增加有关。在该模型中，抗氧化信号如超氧化物歧化酶（SOD）和一氧化氮（NO）减少，促氧化剂内皮素肽（ET-1）增加。我们之前对PPHN羔羊的研究表明，产前糖皮质激素倍他米松可以降低氧化应激，恢复SOD和NO水平，并降低ET-1的表达。产前倍他米松被广泛用于早产，作为一种有针对性的干预措施，以促进肺成熟。本研究探讨了产前倍他米松会改善PPHN出生后肺循环和氧合适应的新假设。研究将在羔羊中进行产前动脉导管结扎以诱导PPHN。怀孕母羊将被随机分配接受倍他米松或生理盐水。胎羊羔将在接近足月妊娠时通过剖腹产娩出，并通气12小时。通气研究完成后，将从安乐死羔羊身上采集肺部进行进一步研究。这些研究的具体目的是研究产前倍他米松对以下方面的影响：(1)肺和全身血管压力的转变和出生后氧合；(2)离体肺动脉对血管舒张剂和血管收缩剂刺激的反应；(3)肺动脉中氧化应激标志物，如超氧化物、8-异前列腺素和过氧亚硝酸盐；(4)通过测量eNOS的表达来平衡促氧化和抗氧化信号。PAs中SOD异构体和ET-1。这些研究将是调查这种产前干预对有PPHN风险的婴儿的重要前奏。这种有针对性的干预有可能改善患有PPHN的婴儿的预后。

DESCRIPTION (provided by applicant): 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.