cGMP Regulation in the Developing Pulmonary Vasculature

发育中肺血管系统的 cGMP 监管

• 批准号: 7620060
• 负责人: ROBIN H. STEINHORN
• 金额: $ 45.49万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 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 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7620060
• 关键词: Affect; Amniotic Fluid; Anatomy; Applications Grants; Biological Availability; Birth; Blood Vessels; Breathing; Clinical; Cyclic GMP; Data; Development; Diagnostic Procedure; Ductus Arteriosus; Future; Gases; Generations; Human; Hydrogen Peroxide; In Vitro; Infant; Isoprostanes; Lead; Ligation; Lung; Mechanical ventilation; Mediating; Modeling; NADPH Oxidase; Newborn Infant; Nitric Oxide Synthase; Oxygen; Pathogenesis; Peroxonitrite; Persistent Fetal Circulation Syndrome; Physiological; Production; Pulmonary Vascular Resistance; Reactive Oxygen Species; Recombinants; Regulation; Reporting; Role; Soluble Guanylate Cyclase; Source; Superoxide Dismutase; Superoxides; Supplementation; Syndrome; Testing; Therapeutic; Vascular remodeling; Vasoconstrictor Agents; Ventilation Test; high risk; human NOS3 protein; improved; in vivo; inhaled nitric oxide; neonatal pulmonary hypertension; prevent; research study; rosin; treatment strategy; Affect; Amniotic Fluid; Anatomy; Applications Grants; Biological Availability; Birth; Blood Vessels; Breathing; Clinical; Cyclic GMP; Data; Development; Diagnostic Procedure; Ductus Arteriosus; Future; Gases; Generations; Human; Hydrogen Peroxide; In Vitro; Infant; Isoprostanes; Lead; Ligation; Lung; Mechanical ventilation; Mediating; Modeling; NADPH Oxidase; Newborn Infant; Nitric Oxide Synthase; Oxygen; Pathogenesis; Peroxonitrite; Persistent Fetal Circulation Syndrome; Physiological; Production; Pulmonary Vascular Resistance; Reactive Oxygen Species; Recombinants; Regulation; Reporting; Role; Soluble Guanylate Cyclase; Source; Superoxide Dismutase; Superoxides; Supplementation; Syndrome; Testing; Therapeutic; Vascular remodeling; Vasoconstrictor Agents; Ventilation Test; high risk; human NOS3 protein; improved; in vivo; inhaled nitric oxide; neonatal pulmonary hypertension; prevent; research study; rosin; treatment strategy

DESCRIPTION (provided by applicant): Persistent pulmonary hypertension of the newborn (PPHN) is a serious clinical problem that occurs when pulmonary vascular resistance does not decrease normally during the transition to gas breathing at birth. We have reported that activity of endothelial nitric oxide synthase (NOS) and sGC are decreased in a lamb model of PPHN, but the specific mechanisms producing these changes have not been well characterized. Although inhaled nitric oxide is now standard therapy infants with PPHN, the beneficial effects are minimal or transient in almost 50% of treated infants. Therefore, a better understanding of the mechanisms involved in the development of PPHN and new treatment strategies are urgently needed. We have preliminary data that strongly suggest: 1) a role for reactive oxygen species (ROS) in the pathogenesis of PPHN; and 2) ROS scavengers, such as recombinant human superoxide dismutase (rhSOD) dramatically improve oxygenation. Therefore, this grant proposal will focus on the role of ROS in PPHN, and whether treatment with specific scavengers such as rhSOD might reverse the vascular changes of PPHN. A lamb model of PPHN will be studied created by antenatal ligation of the ductus arteriosus. This model has many of the anatomic and physiologic alterations observed in human infants with PPHN. We propose two specific aims: (1) To examine the role of ROS in promoting pulmonary vascular reactivity in PPHN, and (2) To determine the mechanisms of SOD-mediated amelioration of PPHN. To accomplish the first specific aim, we will use a combination of in vivo and in vitro approaches to better characterize the specific ROS that are produced in PPHN lambs following delivery and mechanical ventilation, and test the hypothesis that superoxide and hydrogen peroxide derived from NADPH oxidase promote pulmonary vascular reactivity in PPHN lambs. To accomplish specific aim 2, we will primarily use in vivo studies to test the hypothesis that scavenging superoxide with rhSOD increases endogenous NO production via changes in NOS expression and/or activity.

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，当肺血管耐药性在出生时向气体呼吸过渡期间正常降低肺血管耐药时会发生。我们报告说，在PPHN的羔羊模型中，内皮一氧化氮合酶（NOS）和SGC的活性降低，但是产生这些变化的特定机制尚未得到很好的表征。尽管吸入的一氧化氮现在是PPHN的标准治疗婴儿，但在几乎50％的治疗婴儿中，有益作用是最小或短暂的。因此，迫切需要更好地了解PPHN发展和新的治疗策略的机制。我们有强烈建议的初步数据：1）活性氧（ROS）在PPHN发病机理中的作用； 2）ROS清除剂，例如重组人类超氧化物歧化酶（RHSOD），可以显着改善氧合。因此，该赠款提案将集中于ROS在PPHN中的作用，以及对RHSOD等特定清除剂的治疗是否可能逆转PPHN的血管变化。将研究由动脉桥的产前连接而产生的PPHN羔羊模型。该模型具有PPHN的人类婴儿中观察到的许多解剖和生理改变。我们提出了两个具体的目的：（1）检查ROS在PPHN中促进肺血管反应性中的作用，以及（2）确定SOD介导的PPHN改善的机理。为了实现第一个特定目的，我们将使用体内和体外方法的组合更好地表征PPHN羔羊中在PPHN羔羊和机械通气后产生的特定ROS，并检验以下假说，即从NADPH氧化酶促进了PPHN Lambs中肺血管反应性的超氧化物和氢过氧化物。为了完成特定的目标2，我们将主要使用体内研究来检验以下假设，即通过NOS表达和/或活性的变化，将超氧化物清除超氧化物增加了内源性NO的产生。