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）是一个重要的健康问题，每年的医疗保健费用为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差距是了解调节肺泡单位（此处定义为肺泡上皮细胞和底层微血管床）发育的相互作用信号，以及这些相互作用信号如何被高氧破坏。我们的长期目标是了解BPD中肺泡单位发育中断的机制。我们的主要目标是通过血管抑制的研究，使用候选分子方法，对肺泡单位的正常和氧损伤的发展进行机制性的了解。我们的主要候选人是色素上皮衍生因子（PEDF）及其上游调节因子Kringle 5（K5）。微血管化和肺泡化的过程是密切相关的。血管生成受促血管生成信号和抗血管生成信号之间的平衡密切调节。高氧对这种平衡的破坏可引起肺泡单位的异常发育。我们证明，新生儿高氧肺损伤与PEDF增加有关，特别是在肺泡嵴，II型细胞和内皮细胞中，而血管内皮生长因子（VEGF）减少。我们将在体内和体外研究PEDF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，导致适当肺泡化所需的微血管发育受损。我们拟研究PEDF对新生小鼠肺和小鼠肺内皮细胞肺泡化和血管生成的抑制作用。我们将确定PEDF下调VEGF产生和活性的机制，以及PEDF发挥作用的机制。最后，我们将研究PEDF上游的近端血管抑素，特别是Kringle 5。Kringle 5由基质金属蛋白酶9（MMP-9）作用产生，我们发现它在新生儿肺氧损伤中显著上调并阻止肺泡形成。我们将确定高氧下的血管抑制作用是否由MMP-9 - K5 - PEDF途径驱动。这些研究具有创新性，因为它们为研究改变BPD肺泡单位发育的机制开辟了新方向。这一提议的影响将是开发一种新的BPD机制途径，这可能导致新的治疗策略。

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.