REGULATION OF THE DUCTUS ARTERIOSUS

在早产儿中，动脉膜在分娩后经常保持开放许多天或数周。在妊娠28周之前分娩的新生儿中，多达70%需要某种形式的治疗来关闭他们的患者文档。如果不关闭，持续性动脉膜未闭与严重的发病率相关：支气管肺发育不良（长期需要机械通气）和坏死性小肠结肠炎。大量研究表明，动脉膜早期闭合可降低支气管肺发育不良的严重程度，并降低坏死性小肠结肠炎的发生率。虽然前列腺素合成抑制剂，如吲哚美辛，在使用它们的早产儿中诱导85%的牙本质闭合，但在20-30%的治疗婴儿中牙本质重新打开。最近的研究表明，出生后发育的间质壁缺氧是导致永久性闭合的解剖重构（管腔内皮细胞增殖、迁移和平滑肌细胞死亡）的重要步骤。本申请中提出的研究将检查足月新生儿中早期自发性脐带闭合所涉及的机制以及早产新生儿延迟闭合所涉及的机制。他们还将研究吲哚美辛诱导关闭后高比率的Doctus重新开放的机制。他们将使用持续性动脉导管未闭的早产狒狒模型，这是唯一模拟早产人类动脉导管未闭周围长期事件的模型。他们将研究改变医生张力的血管活性因子（例如，肾上腺素，一氧化氮）也与解剖重塑中涉及的生长因子和死亡因子的失调相互作用。他们将研究早产新生儿中增加膜壁缺氧的机制。他们将使用免疫组织化学，Western和北方技术来研究mRNA和蛋白质表达的变化;他们将使用细胞迁移，增殖和细胞死亡的测定在离体血管，内皮细胞和平滑肌细胞培养。他们将描述受体群体的变化，并在体内测试他们的发现。这些研究应该增加我们对出生后是什么启动和维持导管闭合过程以及为什么它不会发生在早产儿中的理解。

In the premature infant, the doctus arteriosus frequently remains open for many days or weeks after delivery. As many as 70% of newborns delivered prior to 28 weeks gestation will require some form of therapy to close their patient doctus. If left unclosed, a persistent patent doctus arteriosus is associated with significant morbidity: bronchopulmonary dysplasia (with its prolonged need for mechanical ventilation) and necrotizing enterocolitis. Numerous studies have shown that early closure of the doctus arteriosus decreases the severity of bronchopulmonary dysplasia and decreases the incidence of necrotizing enterocolitis. Although inhibitors of prostaglandin synthesis, like indomethacin,, induce doctus closure in 85% of preterm infants in whom they are used, doctus reopening occurs in 20-30% of treated infants. Recent studies demonstrate that the postnatal development of doctus wall hypoxia is an essential step in the anatomic remodeling (luminal endothelial proliferation, migration, and smooth muscle cell death) that leads to permanent closure. The studies proposed in this application will examine the mechanisms involved in early, spontaneous doctus closure in the full-term newborn and those involved in the delayed closure of the premature newborn. They will also examine the mechanisms involved in the high rate of doctus reopening after indomethacin-induced closure. They will use the premature baboon model of persistent patent doctus arteriosus, which is the only model that mimics the long-term events surrounding doctus patency in the preterm human. They will examine the hypothesis that vasoactive factors that alter doctus tone (e.g., prostaglandins, nitric oxide) also interact with an deregulate the growth factors and death factors involved in anatomic remodeling. They will examine mechanisms to increase doctus wall hypoxia in the preterm newborn. They will use immunohistochemical, Western, and Northern techniques to study changes in mRNA and protein expression; they will use assays of cell migration, proliferation, and cell death in isolated vessels, endothelial and smooth muscle cells in culture. They will characterize changes in receptor populations and test their findings in vivo. These studies should increase our understanding of what initiates and sustains the process of ductus closure after birth and why it does not occur in the preterm infant.