Control of Angiogenesis in neonatal Hyperoxic Lung Injury

描述(由申请人提供)：支气管肺发育不良(BPD)是一个严重的健康问题，每年的医疗费用为40亿美元。这在儿童保健费用中仅次于哮喘。了解BPD发病机制的一个主要空白是对调节肺泡单位(这里定义为肺泡上皮和微血管床)发育的相互作用信号的了解，以及这些相互作用信号是如何被高氧破坏的。我们的长期目标是了解BPD中肺泡单位发育受阻的机制。我们的主要目标是通过对血管抑制的研究，利用候选分子方法，从机制上深入了解肺泡单位的正常和氧气损伤的发育。我们的主要候选者是色素上皮源性因子(PEDF)及其上游调节因子Kringle5(K5)。微血管形成和肺泡化的过程密切相关。血管生成受到促血管生成信号和反血管生成信号之间的平衡的密切调控。高氧破坏了这种平衡，可能会导致肺泡单位的异常发育。我们证明，新生儿高氧性肺损伤与PEDF增加有关，尤其是肺泡顶、II型细胞和内皮细胞，而血管内皮生长因子(VEGF)减少。我们将在体内和体外研究PEDF的诱导或抑制对肺泡化和微血管形成的影响，并研究其抑制血管生成的机制。我们假设，新生儿肺中的高氧损伤破坏了血管生成和血管抑制信号的正常平衡，导致适当的肺泡化所需的微血管发育受损。我们建议研究PEDF对新生小鼠肺和小鼠肺内皮细胞的肺泡化和血管生成的抑制作用。我们将确定PEDF下调血管内皮生长因子产生和活性的机制，以及PEDF发挥作用的机制。最后，我们将观察PEDF上游的近端血管抑素，尤其是Kringle 5。Kringle 5是由基质金属蛋白酶9(MMP9)作用产生的，我们发现它在新生儿肺氧损伤中显著上调，并阻止肺泡生成。我们将确定高氧中的血管抑制效应是否由基质金属蛋白酶-9-K5-PEDF途径驱动。这些研究具有创新性，因为它们为研究BPD中改变肺泡单位发育的机制开辟了新的方向。这一提议的影响将是为BPD开发一种新的机制途径，这可能导致新的治疗策略。 公共卫生相关性：治疗早产儿所需的高氧量也会导致慢性肺部疾病支气管肺发育不良(BPD)，这种疾病会继续在儿童中造成慢性肺部疾病合并哮喘。这项建议的目的是调查BPD是否与一种重要的蛋白质--色素上皮衍生因子(PEDF)的数量和作用增加有关。了解PEDF促进BPD发展的机制将为预防BPD和随后的哮喘发展提供一种新的方法。

DESCRIPTION (provided by applicant): Bronchopulmonary Dysplasia, (BPD) is a significant health problem, accounting for $4 Billion in annual health care costs. This is second only to asthma in child health care costs. A major gap in understanding the pathogenesis of BPD is knowledge of interacting signals regulating the development of the alveolar unit (defined here as the alveolar epithelium and the underlying microvascular bed), and how these interacting signals are disrupted by hyperoxia. Our long term goal is to develop an understanding of the mechanisms of disrupted development of the alveolar unit in BPD. Our main objective is to develop mechanistic insight into normal and oxygen-injured development of the alveolar unit through study of angiostatic, using a candidate molecule approach. Our primary candidates are Pigment Epithelium Derived Factor (PEDF), and its upstream regulator Kringle 5 (K5). The processes of microvascularization and alveolarization are closely connected. Angiogenesis is closely regulated by a balance between pro- and anti-angiogenic signaling. Disruption of this balance by hyperoxia could cause abnormal development of alveolar units. We demonstrated that neonatal hyperoxic lung injury is associated with increased PEDF, particularly in alveolar crests, type II cells, and endothelial cells, while vascular endothelial growth factor (VEGF) is decreased. We will study the effect of PEDF induction or inhibition in vivo and in vitro on alveolarization and microvascularization, and study the mechanisms by which it inhibits angiogenesis. We hypothesize that hyperoxic injury in the neonatal lung disrupts the normal balance of angiogenic and angiostatic signaling, causing impaired microvascular development needed for proper alveolarization. We propose to study inhibition by PEDF of alveolarization and angiogenesis in neonatal mouse lungs and mouse lung endothelial cells. We will determine the mechanisms by which PEDF downregulates VEGF production and activity, and by which PEDF exerts its action. Finally, we will look upstream of PEDF at proximal angiostatins, particularly Kringle 5. Kringle 5 is produced by matrix metalloproteinase 9 (MMP-9) action, which we showed is significantly upregulated in neonatal lung oxygen injury and arrests alveologenesis. We will determine if angiostatic effects in hyperoxia are driven by a MMP-9 - K5 - PEDF pathway. These studies are innovative since they develop a new direction for studying mechanisms altering development of the alveolar unit in BPD. The impact of this proposal will be the development of a novel mechanistic pathway for BPD which could lead to new therapeutic strategies. PUBLIC HEALTH RELEVANCE: High oxygen amounts needed to treat premature infants also cause the chronic lung disease bronchopulmonary dysplasia (BPD), which persists to create chronic lung disease with asthma in children. The goal of this proposal is to investigate whether BPD is related to an increased amount and action of an important protein, pigment epithelium derived factor (PEDF). Understanding the mechanism by which PEDF contributes to development of BPD will allow a novel approach to the prevention of BPD and subsequent development of asthma.