REDOX REGULATION IN THE PERINATAL PULMONARY VASCULATURE

围产期肺血管的氧化还原调节

• 批准号: 8651640
• 负责人: ROBIN H. STEINHORN
• 金额: $ 47.14万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8651640
• 关键词: REDOX; REGULATION; PERINATAL; PULMONARY; VASCULATURE

DESCRIPTION (provided by applicant): Persistent pulmonary hypertension of the newborn (PPHN) is a serious clinical problem that affects up to 10% of infants admitted to the Neonatal Intensive Care Unit, and occurs when pulmonary vascular resistance does not decrease normally during the transition to air breathing at birth. We have utilized a fetal lamb model of PPHN to study the vascular changes associated with PPHN, and to determine how these changes might interfere with the normal pulmonary vascular transition. Our preliminary data in PPHN lambs strongly suggest: 1) a central role for reactive oxygen species (ROS) in the pathogenesis of PPHN; 2) that hyperoxia enhances production of ROS by mitochondrial and cytosolic sources, which increase vascular reactivity, and 3) that the PPHN lamb is particularly vulnerable to the effects of hyperoxia, responding with exaggerated increases in ROS and vascular dysfunction. We hypothesize We propose three specific aims to further our knowledge of the pathogenesis and therapeutic opportunities for PPHN: 1. Determine abnormalities of vascular mitochondrial and cytosolic ROS production specific to PPHN. 2. Determine the effect of hyperoxia on ROS production in the PPHN vasculature. 3. Determine the effects of therapeutic strategies targeted at reducing ROS production in specific cellular compartments. An improved understanding of the mechanistic basis for this syndrome will potentially identify novel clinical approaches to managing the vascular dysfunction that characterizes PPHN. Such therapies could dramatically improve immediate and long-term clinical outcomes, while substantially reducing the health care costs associated with this syndrome. PUBLIC HEALTH RELEVANCE: We expect our studies to improve our understanding of the causes of persistent pulmonary hypertension, a serious medical condition that affects 10% of infants admitted for neonatal intensive care. Our research should lead to therapies that reduce oxygen toxicity, improve immediate and long- term clinical outcomes, and substantially reduce the health care costs associated with this syndrome.

描述（由申请人提供）：新生儿（PPHN）的持续性肺动脉高压是一个严重的临床问题，可影响到新生儿重症监护病房的婴儿中多达10％的婴儿，并且当肺血管耐药性在出生时呼吸过渡期间正常降低肺血管耐药时。我们利用PPHN的胎儿羔羊模型来研究与PPHN相关的血管变化，并确定这些变化如何干扰正常的肺血管过渡。我们在PPHN羔羊中的初步数据强烈表明：1）活性氧（ROS）在PPHN发病机理中的核心作用； 2）高氧通过线粒体和胞质源增强ROS的产生，从而提高血管反应性，3）PPHN羔羊特别容易受到高氧作用的影响，随着ROS和血管功能障碍的夸张响应。我们假设我们提出了三个特定的目的，以进一步了解PPHN的发病机理和治疗机会：1。确定具有PPHN的血管线粒体和胞质ROS产生的异常。 2。确定高氧对PPHN脉管系统中ROS产生的影响。 3。确定针对减少特定细胞室中ROS产生的治疗策略的影响。对该综合征的机械基础的改进理解将有潜在地识别出具有PPHN表征的血管功能障碍的新型临床方法。这种疗法可以大大改善即时和长期的临床结果，同时大大降低了与该综合征相关的医疗保健成本。 公共卫生相关性：我们希望我们的研究能够提高我们对持续性肺动脉高压的原因的理解，这是一种严重的医疗状况，影响10％的婴儿接受新生儿重症监护。我们的研究应导致降低氧气毒性，改善直接和长期临床结果的疗法，并大大降低与该综合征相关的医疗保健成本。