Antenatal betamethasone for persistent pulmonary hypertension of newborn

描述(申请人提供)：新生儿持续性肺动脉高压(PPHN)是指出生时肺血管阻力未能降低。受影响的婴儿患有低氧血症，发病率和死亡率增加。新生儿重症监护的进步极大地提高了患有PPHN的婴儿的存活率。然而，PPHN的幸存者继续增加了长期残疾。目前的治疗策略侧重于对已经患有低氧血症和心肺不稳定的婴儿进行抢救治疗。对这些婴儿的理想干预将纠正产前肺动脉的血管功能障碍，恢复对肺的正常适应。对患有产前导管狭窄的胎羊的研究表明，肺血管功能障碍与氧化应激增加有关。在该模型中，肺动脉超氧化物歧化酶(SOD)和一氧化氮(NO)等抗氧化信号减少，而促氧化剂内皮素-1(ET-1)升高。我们以前对患有PPHN的羔羊的研究表明，产前糖皮质激素倍他米松可以减少氧化应激，恢复SOD和NO水平，并减少ET-1的表达。倍他米松被广泛用于早产，作为一种促进肺成熟的针对性干预措施。这项建议中的研究调查了一项新的假设，即产前倍他米松将改善PPHN患者出生后肺循环和氧合的适应。研究将在产前结扎动脉导管的羔羊身上进行，以诱导PPHN。怀孕的母羊将被随机分配接受倍他米松或生理盐水治疗。胎儿羔羊将通过剖腹产在接近足月妊娠时分娩，并将进行12小时的呼吸机。在通风研究完成后，将从安乐死的羔羊身上采集肺进行进一步研究。本研究的具体目的是探讨出生前倍他米松对(1)肺和全身血管压力的转换和出生后氧合的影响(2)离体肺动脉对血管扩张剂和血管收缩刺激的反应(3)氧化应激的标志物，如肺动脉中的超氧化物歧化酶、8-异前列腺素和过氧亚硝酸盐；(4)通过检测PAS中eNOS、SOD亚型和ET-1的表达，来研究促氧化和抗氧化信号的平衡。这些研究将是对PPHN高危婴儿进行产前干预研究的重要前奏。这种有针对性的干预有可能改善患有PPHN的婴儿的结局。 公共卫生相关性：项目叙述出生时肺血管扩张失败会导致新生儿持续的肺动脉高压。这种情况与受影响婴儿的低氧血症和死亡或残疾风险增加有关。这项拟议的研究将调查产前应用倍他米松在婴儿出生前恢复正常肺血管功能以避免低氧血症的作用。

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.