Closure of the Primate Ductus Arteriosus

描述(由申请人提供)： 对于早产儿，动脉导管在出生后经常保持开放许多天。多达70%的新生儿在怀孕28周前出生，需要某种形式的治疗来闭合他们的未闭导管。如果不关闭，持续的动脉导管未闭(PDA)与显著的发病率有关：支气管肺发育不良的严重程度增加，需要长时间的机械通气，以及坏死性小肠结肠炎的发生率增加。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85%会导致导管关闭，但在接受治疗的婴儿中，有20%-30%的婴儿会发生导管重新开放。最近的研究表明，出生后导管壁缺氧的发育引发了解剖学上的变化，阻止了导管在出生后重新开放。在早产导管永久关闭期间，管腔内皮细胞增殖，互相粘连，并堵塞狭窄的管腔间隙。导致内皮细胞发生这些变化的机制目前尚不清楚。最近观察到，出生后管腔内皮细胞的变化与管壁的炎性变化密切相关。本申请中提出的研究将通过检测动脉导管未闭对肺水肿、肺形态和肺表面活性物质的影响，确定动脉导管持续未闭如何改变早产儿的肺功能。他们将确定炎症在导管重塑和永久性导管关闭中的作用。他们将确定内皮细胞黏附分子(如VE-钙粘附素)在内皮细胞堵塞形成中的作用。他们将确定血管内皮生长因子(VEGF)在导管重塑过程中发生的炎症变化和VE钙粘素重组中的作用。他们将使用实时定量聚合酶链式反应、原位杂交和免疫组织化学来研究体内和体外的mRNA和蛋白质表达的变化。他们将在器官培养中使用分离的动脉导管，以研究缺氧对组织中促炎因子表达的影响。他们将使用管腔内皮细胞和细胞黏附试验来研究内皮黏附分子在体外内皮栓形成中的作用。这些研究应该会增加我们对动脉导管未闭如何改变早产儿肺功能以及是什么导致其永久闭合的理解。

DESCRIPTION (provided by applicant): In the premature infant, the ductus arteriosus frequently remains open for many days after birth. As many as 70% of newborns delivered prior to 28 weeks gestation will require some form of therapy to close their patent ductus. If left unclosed, a persistent patent ductus arteriosus (PDA) is associated with significant morbidity: increased severity of bronchopulmonary dysplasia, a prolonged need for mechanical ventilation, and an increased incidence of necrotizing enterocolitis. Although inhibitors of prostaglandin synthesis, like indomethacin, induce ductus closure in 85% of preterm infants in whom they are used, ductus reopening occurs in 20-30% of treated infants. Recent studies demonstrate that the postnatal development of ductus wall hypoxia initiates the anatomic changes that prevent the ductus from reopening after birth. During permanent closure of the preterm ductus, luminal endothelial cells proliferate, adhere to each other, and plug up the constricted luminal space. The mechanisms that induce these changes in the endothelium are currently unknown. Recently it has been observed that the postnatal changes in the luminal endothelium are closely associated with inflammatory changes in the ductus wall. The studies proposed in this application will determine how a persistent patent ductus arteriosus alters lung function in the preterm newborn by examining its effects on lung edema, lung morphology and lung surfactant. They will determine the role of inflammation in ductus remodeling and permanent ductus closure. They will determine the role of endothelial adhesion molecules (like VE-cadherin) in endothelial plug formation. And they will determine the role of Vascular Endothelial Growth Factor (VEGF) on the inflammatory changes and the reorganization of VE cadherin that occur during ductus remodeling. They will use Real Time PCR, in situ hybridization, and immunohistochemistry to study changes in mRNA and protein expression in vivo and in vitro. They will use isolated ductus arteriosus in organ culture to study the role of hypoxia on the expression of proinflammatory factors in the tissue. They will use ductus luminal endothelial cells and assays of cell adhesion to study the role of endothelial adhesion molecules on endothelial plug formation in vitro. These studies should increase our understanding of how the patent ductus arteriosus alters pulmonary function in the preterm infant and what produces its permanent closure.