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，并有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婴儿的存活率。然而，PPHN幸存者的长期残疾继续增加。目前的治疗策略集中在对已经患有低氧血症和心肺不稳定的婴儿进行抢救治疗。对这些婴儿理想的干预措施是在出生前纠正肺动脉的血管功能障碍，以恢复对肺部的正常适应。对具有产前导管收缩的胎羊（一种模拟PPHN的模型）的研究表明，肺血管功能障碍与氧化应激增加相关。肺动脉超氧化物歧化酶（SOD）和一氧化氮（NO）等抗氧化信号降低，促氧化剂内皮素（ET-1）升高。我们以前在患有PPHN的羔羊中的研究表明，产前的糖皮质激素betlethanol可降低氧化应激，恢复SOD和NO水平，降低ET-1表达。早产时广泛使用肺促成熟剂，作为促进肺成熟的靶向干预措施。本研究提出了一个新的假说，即产前的β-肾上腺素能改善产后PPHN肺循环和氧合的适应性。将在羔羊中进行产前结扎动脉导管以诱导PPHN的研究。将妊娠母羊随机分配接受倍他米松或生理盐水。胎羊将在接近足月妊娠时通过剖腹产分娩，并通气12小时。通气研究完成后，将从人道处死的羔羊中收获肺用于其他研究。所提出的研究的具体目的是调查产前betteron对（1）肺和全身血管压力和出生后氧合的转变（2）从肺分离的肺动脉对血管舒张剂和血管收缩剂刺激的反应（3）氧化应激的标志物，如超氧化物，8-异前列腺素和过氧亚硝基阴离子;（4）肺动脉内皮型一氧化氮合酶（eNOS）、超氧化物歧化酶（SOD）亚型和内皮素-1（ET-1）的表达。这些研究将是一个重要的前奏调查产前干预婴儿的风险PPHN。这种有针对性的干预有可能改善PPHN婴儿的结局。 公共卫生相关性：出生时肺血管扩张失败导致新生儿持续性肺动脉高压。这种情况与低氧血症和受影响婴儿的死亡或残疾风险增加有关。拟议的研究将调查产前betterfly的作用，以恢复正常的血管功能，婴儿的肺部出生前，以避免低氧血症的时期。

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.