Closure of the Primate Ductus Arteriosus

描述（由申请人提供）： 在早产儿中，动脉导管在出生后经常保持开放许多天。多达70%的新生儿在妊娠28周之前分娩，需要某种形式的治疗来关闭其未闭的导管。如果不闭合，持续性动脉导管未闭（PDA）与显著的发病率相关：支气管肺发育不良的严重程度增加，机械通气的需要延长，坏死性小肠结肠炎的发病率增加。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%的导管闭合，但在20-30%的治疗婴儿中导管重新开放。最近的研究表明，出生后发育的导管壁缺氧引发的解剖学变化，防止出生后导管重新开放。在早产儿导管的永久性关闭过程中，管腔内皮细胞增殖，相互粘附，并堵塞狭窄的管腔空间。诱导内皮细胞发生这些变化的机制目前尚不清楚。最近，它已被观察到，在管腔内皮细胞的出生后的变化密切相关的导管壁的炎症变化。本申请中提出的研究将通过检查其对肺水肿、肺形态和肺表面活性物质的影响来确定持续性动脉导管未闭如何改变早产新生儿的肺功能。他们将确定炎症在导管重塑和永久性导管关闭中的作用。他们将确定内皮粘附分子（如VE-钙粘蛋白）在内皮栓形成中的作用。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钙粘蛋白重组中的作用。他们将使用真实的时间PCR、原位杂交和免疫组织化学来研究体内和体外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来研究缺氧对组织中促炎因子表达的作用。他们将使用导管腔内皮细胞和细胞粘附测定来研究内皮粘附分子在体外内皮栓形成中的作用。这些研究应该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关闭的理解。

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.