REGULATION OF THE DUCTUS ARTERIOSUS

在早产儿中，动脉束在分娩后的许多天或数周内经常保持开放。在妊娠28周之前出生的新生儿中，多达70%需要某种形式的治疗来关闭他们的病人。如果不闭合，持续的动脉未闭与显著的发病率相关：支气管肺发育不良（长时间需要机械通气）和坏死性小肠结肠炎。大量研究表明，早期关闭动脉结节可降低支气管肺发育不良的严重程度，降低坏死性小肠结肠炎的发生率。尽管前列腺素合成抑制剂，如吲哚美辛，在85%的早产儿中会导致结节闭合，但在接受治疗的婴儿中，20-30%的婴儿会出现结节重新打开。最近的研究表明，出生后的切口壁缺氧是解剖重构（管腔内皮细胞增殖、迁移和平滑肌细胞死亡）的重要步骤，最终导致永久性闭合。在本应用程序中提出的研究将检查足月新生儿早期自发闭合的机制，以及早产儿延迟闭合的机制。他们还将研究吲哚美辛诱导闭合后高切口重开率的机制。他们将使用早产儿狒狒持续动脉结节未闭模型，这是唯一一个模仿早产儿动脉结节未闭周围长期事件的模型。他们将检验一种假设，即改变关节张力的血管活性因子（如前列腺素、一氧化氮）也与解除对解剖重构中涉及的生长因子和死亡因子的调节相互作用。他们将研究增加早产儿子宫壁缺氧的机制。他们将使用免疫组织化学、Western和Northern技术来研究mRNA和蛋白质表达的变化；他们将在分离的血管、内皮细胞和平滑肌细胞中进行细胞迁移、增殖和细胞死亡的测定。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启动和维持导管闭合过程的理解，以及为什么它不会发生在早产儿身上。

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.