Pharmacologic Contributors to Patent Ductus Arteriosus

项目摘要 出生后的血管适应依赖于动脉导管（DA）的闭合，这是一种胎儿血管分流 连接肺动脉和主动脉DA闭合失败导致DA（PDA）持续通畅， 这是一种常见的疾病，与最脆弱婴儿的发病率和死亡率增加有关。电流 PDA的药物治疗是有限的，并且仅集中于单一治疗途径- 环加氧酶介导的前列腺素（PG）合成。然而，最近的数据显示， 基因和药物途径参与了驱动出生后DA的血管舒张到血管收缩的转变 结束努力确定新的DA选择性血管收缩剂忽略了正在进行的血管舒张的可能性， 刺激使DA松弛永久化并抑制其闭合。因为重症早产儿会接触到 在DA关闭期间使用多种药物，我们假设使用的药物 在新生儿重症监护室预防DA关闭并导致PDA。 早产儿的DA在发育过程中会对血管舒张信号做出反应。我们事先 使用小鼠模型和人类数据的研究表明，经常用于早产儿的药物 对DA的意外血管舒张作用，包括特定抗生素、抗酸剂和利尿剂。这些数据 提示药物引起DA松弛是PDA的一个可改变的因素，但这还没有被系统地 评估。因此，我们假设NICU中常用的药物对 关闭过早的DA和特定的药物组合协同作用，损害产后 地方检察官结案小鼠和人体组织将用于在三个目的中测试该假设：1）确定是否 新生儿药典中的药物可以预防DA闭合的初始阶段-平滑肌收缩， 导致DA管腔的生理性闭合; 2）确定新生儿药典中的药物是否损害 DA闭合的第二阶段-纤维肌重塑-导致收缩的 3）确定相互作用对DA关闭的任一阶段产生不利影响的药物组合。药物作用将 使用早产小鼠DA平滑肌的初级（体外）高通量筛选（HTS）进行检查 细胞一系列的二次筛选试验将优先考虑单一和协同组合的命中， 对效价/有效性、DA选择性和毒性的影响，以进一步研究其离体和体内血管活性作用， 一种新的离体小鼠DA-再开放测定将用于筛选感兴趣的药物。打击的效果 DA-血管舒张化合物将在离体人新生儿DA节段和大型国家实验中进行检查。 早产儿数据库这些研究具有很高的转化潜力，将明确确定 药物或药物组合增加了早产儿PDA的风险，提供了一种创新的方法， 加强NICU中PDA的保守治疗。

Project Summary Vascular adaptation after birth is dependent on closure of the ductus arteriosus (DA), a fetal vascular shunt connecting the pulmonary artery and aorta. Failure of DA closure results in persistent patency of the DA (PDA), a common disorder associated with increased morbidity and mortality in the most vulnerable infants. Current pharmacological treatments for PDA are limited and only focus on a single therapeutic pathway – cyclooxygenase-mediated prostaglandin (PG) synthesis. However, recent data reveal complex networks of genes and druggable pathways involved in the vasodilatory-to-vasoconstrictive shift that drives postnatal DA closure. Efforts to identify new DA-selective vasoconstrictors overlook the possibility that ongoing vasodilatory stimuli perpetuate DA relaxation and inhibit its closure. Because critically ill preterm newborns are exposed to multiple medications during the time that DA closure takes place, we postulate that pharmacologic agents used in the neonatal ICU prevent DA closure and contribute to PDA. The DA of prematurely-born infants is developmentally primed to respond to vasodilatory signals. Our prior studies using mouse models and human data show that drugs frequently used in preterm infants have unexpected vasodilatory effects on the DA, including specific antibiotics, antacids, and diuretics. These data suggest that drug-induced DA relaxation is a modifiable contributor to PDA, but this has not been systematically evaluated. We therefore hypothesize that drugs commonly used in the NICU have an adverse effect on closure of the premature DA and that specific drug combinations act synergistically to impair postnatal DA closure. Mouse and human tissues will be used to test this hypothesis in three Aims: 1) Determine whether drugs in the neonatal pharmacopeia prevent the initial phase of DA closure - smooth muscle constriction - that leads to physiologic closure of the DA lumen; 2) Determine whether drugs in the neonatal pharmacopeia impair the second phase of DA closure - fibromuscular remodeling - that leads to permanent sealing of the constricted DA; 3) Identify drug combinations that interact to adversely affect either phase of DA closure. Drug effects will be examined using primary (in vitro) high throughput screening (HTS) of preterm mouse DA smooth muscle cells. A series of secondary screening assays will prioritize single- and synergistic combinations of hits based on potency/efficacy, DA-selectivity, and toxicity for further study of their ex vivo and in vivo vasoactive effects on the DA. A novel ex vivo mouse DA-reopening assay will be used to screen for drugs of interest. The effect of hit DA-vasodilatory compounds will be examined on ex vivo human neonatal DA segments and in a large national database of preterm infants. These studies have high translational potential and will definitively identify which drugs or drug combinations pose increased risks for PDA in preterm infants, providing an innovative approach to enhance conservative PDA management efforts in the NICU.