Lung Vascular Disease in Infants and Children: Mechanisms and Treatment

与肺分支形态发生相反，对肺血管发育的调节机制以及毛细血管生长与肺泡化之间的联系的研究相对较新，范围有限。缺乏关于肺血管生长及其与肺泡生长的联系的信息是不幸的，因为肺循环的发育异常有助于几种重要的新生儿心肺疾病的发病机制，包括新生儿肺动脉高压。此外，越来越多的人认识到，在人类疾病背景下，理解肺血管生长的基本机制的重要性，可能在支气管肺发育不良（BPD）的背景下得到最好的强调。BPD是一个与急性和长期肺部后果相关的重要卫生保健问题。最近的动物和临床研究数据表明，血管生长受损可能导致肺结构异常，特别是肺泡化减少，因此在BPD的发病机制中起关键作用。然而，对于未成熟肺血管损伤的机制、这种损伤对肺生长发育的影响，以及它在BPD和肺动脉高压发病机制中的作用，我们知之甚少。该提案的总体目标是提供临床和基础信息，以深入了解BPD特征肺血管异常的机制，评估目前可用的旨在减少肺损伤和恢复血管和肺生长的治疗方法，并在动物模型中研究旨在改善围产期肺损伤和恢复血管和肺生长的新方法。提出3个临床项目和2个基础项目。临床项目将评估吸入一氧化氮（iNO）对BPD的影响，特定遗传因素在婴儿BPD易感性中的作用，以及发展改进的技术来评估肺动脉高压的存在和对肺动脉高压婴儿治疗的反应。两个基础项目将剖析小鼠、啮齿动物和绵羊肺血管重塑的机制，并评估新型药物对这些模型中肺血管疾病的影响。长期目标是利用从这些模型中获得的信息来开发新的和改进的BPD婴儿治疗方法。

In contrast to lung branching morphogenesis, studies of the mechanisms that regulate lung vascular development and that link capillary growth with alveolarization are relatively recent and limited in scope. Lack of information regarding lung vascular growth and its connection with alveolar growth is unfortunate, because developmental abnormalities of the pulmonary circulation contribute to the pathogenesis of several important neonatal cardiopulmonary disorders including pulmonary hypertension in the newborn. Further, there is growing recognition that the importance of understanding basic mechanisms of lung vascular growth in the context of human disease may be best highlighted in the setting of bronchopulmonary dysplasia (BPD). BPD is a significant health care problem associated with acute and long-term pulmonary consequences. Recent data from animal and clinical studies suggest that impaired vascular growth may contribute to abnormalities of lung architecture, especially decreased alveolarization, and thus play a critical role in the pathogenesis of BPD. However, little is known about the mechanisms of pulmonary vascular injury in the immature lung, the impact of this injury on growth and development of the lung, or its contribution to the pathogenesis of BPD and pulmonary hypertension. The overall goal of this proposal is to generate clinical and basic information that will provide insight into the mechanisms contributing to the pulmonary vascular abnormalities that characterize BPD, to evaluate currently available therapies aimed at reducing lung injury and restoring vascular and lung growth and to examine in animal models new approaches aimed at ameliorating perinatal lung injury and restoring vascular and lung growth. Three clinical and two basic projects are proposed. The clinical projects will evaluate the impact of inhaled nitric oxide (iNO) on BPD, the role of specific genetic factors in predisposing infants to BPD, and the development of improved techniques to assess the presence of pulmonary hypertension and the responses to therapy in infants with pulmonary hypertension. Two basic projects will dissect the mechanisms contributing to lung vascular remodeling in murine, rodent, and ovine models and evaluate the effects of novel pharmacologic agents on lung vascular disease in these models. The long-term goal is to utilize information derived from these models to develop new and improved therapies for the infant with BPD.