REGULATION OF THE DUCTUS ARTERIOSUS

在早产儿中，动脉口在分娩后经常保持开放数天或数周。多达70%在怀孕28周前分娩的新生儿将需要某种形式的治疗来关闭他们的患者Doctus。如果不闭合，持续的动脉导管未闭与严重的发病率有关：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，早期闭合动脉导管可减轻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。尽管前列腺素合成的抑制剂，如消炎痛，在使用它们的早产儿中会导致85%的早产儿关闭，但在接受治疗的婴儿中，有20%-30%的早产儿会重新开放。最近的研究表明，出生后室壁缺氧的发展是导致永久闭合的解剖重建(管腔内皮细胞增殖、迁移和平滑肌细胞死亡)的关键步骤。这项申请中提出的研究将检查足月新生儿早期自发关闭Doctus的机制，以及涉及早产儿延迟关闭的机制。他们还将研究消炎痛诱导关闭后文件重新开通率高的机制。他们将使用持续动脉导管未闭的早产狒狒模型，这是唯一一个模拟早产人类动脉导管未闭周围长期事件的模型。他们将检验这样一种假设，即改变Doctus张力的血管活性因子(例如，前列腺素、一氧化氮)也与血管活性物质相互作用，并对参与解剖重构的生长因子和死亡因子进行放松调控。他们将研究早产儿Doctus Wall缺氧增加的机制。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；他们将使用细胞迁移、增殖和细胞死亡的分析方法，在培养中的分离血管、内皮细胞和平滑肌细胞。他们将描述受体种群的变化，并在体内测试他们的发现。这些研究应该会增加我们对出生后导管关闭的启动和维持过程以及为什么早产儿不会发生这一过程的理解。

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.