Lung Vascular Disease in Infants and Children: Mechanisms and Treatment

描述（由申请人提供）： 与肺分支形态发生相反，调节肺血管发育和将毛细血管生长与肺泡化联系起来的机制的研究相对较新且范围有限。 不幸的是，缺乏关于肺血管生长及其与肺泡生长的联系的信息，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，在人类疾病的背景下，了解肺血管生长的基本机制的重要性可能是最突出的支气管肺发育不良（BPD）的设置。BPD是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，从而在BPD的发病机制中发挥关键作用。然而，对于未成熟肺中肺血管损伤的机制、这种损伤对肺的生长和发育的影响、或其在BPD和肺动脉高压的发病机制中的作用知之甚少。本提案的总体目标是生成临床和基本信息，以深入了解BPD特征性肺血管异常的机制，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。提出了三个临床项目和两个基础项目。临床项目将评估吸入一氧化氮（iNO）对BPD的影响，特定遗传因素在诱发婴儿BPD中的作用，以及改进技术的发展，以评估肺动脉高压的存在和对肺动脉高压婴儿治疗的反应。两个基本的项目将剖析机制，促进肺血管重塑小鼠，啮齿动物和绵羊模型，并评估新的药理学药物对肺血管疾病在这些模型中的作用。长期目标是利用这些模型的信息为BPD婴儿开发新的和改进的治疗方法。(End摘要） 个别项目和核心单位 项目1：早产儿非侵入性吸入NO（Kinsella，John） 描述（由申请人提供）： 吸入一氧化氮（iNO）治疗已被证明是一种安全有效的治疗足月新生儿PPHN和低氧性呼吸衰竭。近年来的研究主要集中在iNO在预防支气管肺发育不良（BPD）中的潜在作用，但其对早产儿肺循环的影响却较少受到关注。早产儿特别容易受到氧中毒和肺部炎症的不良影响，这些不良影响导致肺实质、气道和肺血管损伤，所有这些都有助于BPD和肺动脉高压的发展。BPD仍然是早产儿发病和死亡的主要原因，其特征在于慢性结构和功能性肺血管异常。iNO在患有低氧性呼吸衰竭的插管早产儿中的临床试验迄今为止产生了相互矛盾的结果。我们在早产儿（N = 793）中进行的iNO多中心试验即将完成，这将有助于阐明iNO在需要机械通气治疗低氧性呼吸衰竭的婴儿人群中的作用，然而，越来越多的儿科医生避免对大多数早产儿进行常规插管和机械通气，而是选择采用早期无创持续气道正压通气（早期CPAP，eCPAP），期望这种呼吸支持模式将减少急性肺损伤和BPD。不幸的是，初步的观察并没有证明这种方法可以明显减少BPD的发展。尽管eCPAP降低了VILI的风险，但它可能不会改变未成熟肺中由氧毒性和肺部炎症引起的损伤。我们假设，在eCPAP期间非侵入性输送低剂量iNO将减少出生后24小时内不需要机械通气的早产儿BPD的发生率，并将减少作为BPD特征的肺动脉高压的早期和晚期发现。为了验证这一假设，我们设计了一项单中心随机、对照、盲法的非侵入性iNO治疗试验。本研究的具体目的是：1）确定iNO是否降低出生后24小时内不需要插管的早产儿（出生体重500 - 1250克）的BPD/死亡率的联合终点; 2）确定非侵入性iNO治疗是否降低该人群的早期和晚期肺血管异常。(End摘要）

DESCRIPTION (provided by applicant): 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. (End of Abstract) INDIVIDUAL PROJECTS AND CORE UNITS PROJECT 1: Non-Invasive Inhaled NO In Premature Newborns (Kinsella, John) DESCRIPTION (provided by applicant): Inhaled nitric oxide (iNO) therapy has proven to be a safe and effective treatment for term newborns with PPHN and hypoxemic respiratory failure. Recent studies have focused on the potential role of iNO in the prevention of bronchopulmonary dysplasia (BPD), however, its effect on the pulmonary circulation in premature newborns has received less attention. Premature infants are particularly susceptible to the adverse effects of oxygen toxicity and lung inflammation which cause pulmonary parenchymal, airway, and pulmonary vascular injury, all of which contribute to the development of BPD and pulmonary hypertension. BPD remains a major cause of morbidity and mortality in premature newborns, and is characterized by chronic structural and functional pulmonary vascular abnormalities. Clinical trials of iNO in intubated premature newborns with hypoxemic respiratory failure have yielded conflicting results to date. Our multicenter trial of iNO in premature newborns (N=793) is near completion and will help clarify the role of iNO in this population of infants who require mechanical ventilation for hypoxemic respiratory failure, however, neonatologists are increasingly avoiding routine intubation and mechanical ventilation for even the most premature infants, opting instead to employ early, non-invasive continuous positive airway pressure (early CPAP, eCPAP) with the expectation that this mode of respiratory support will reduce acute lung injury and BPD. Unfortunately, preliminary observations have not demonstrated that this approach markedly reduces the development of BPD. Although eCPAP reduces the risk from VILI, it may not modify the injury caused by oxygen toxicity and lung inflammation in the immature lung. We hypothesize that low-dose iNO delivered non-invasively during eCPAP will reduce the incidence of BPD in premature newborns who do not require mechanical ventilation in the first 24 hours of life, and will reduce the early and late findings of pulmonary hypertension that characterize BPD. To test this hypothesis, we have designed a single-center randomized, controlled, masked pilot trial of non-invasive iNO treatment. Specific aims of this study are: 1) to determine if iNO reduces the combined endpoint of BPD/mortality in premature newborns (500-1250 grams birth weight) who do not require intubation in the first 24 hours of life; and 2) to determine if non-invasive iNO treatment decreases early and late pulmonary vascular abnormalities in this population. (End of Abstract)