PERINATAL PULMONARY HYPERTENSION--DEVELOPMENTAL MEDIATOR

围产期肺动脉高压——发育介质

• 批准号: 6390084
• 负责人: JEFFREY R FINEMAN
• 金额: $ 33.97万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6390084
• 关键词: RNase protection assay; congenital heart disorder; disease /disorder model; embryo /fetus; endothelin; enzyme activity; gene expression; guanylate cyclase; hormone receptor; immunocytochemistry; in situ hybridization; newborn animals; nitric oxide; nitric oxide synthase; pathologic process; phosphodiesterases; pulmonary circulation; pulmonary hypertension; receptor expression; sheep; vascular endothelium; vasoconstriction; western blottings

Pulmonary hypertension and its associated altered vascular reactivity, are a major source of morbidity and mortality for children with congenital heart disease (CHD) and increased pulmonary blood flow. Pulmonary vascular tone is regulated, in part, by a complex interaction of vasoactive substances produced locally by the vascular endothelium, such as nitric oxide (NO) and endothelin-1 (ET-1). Endothelial injury secondary to CHD with increased pulmonary blood flow disrupts these regulatory mechanisms, and has been implicated as a potential factor in the development of pulmonary hypertension. To investigate the role of early endothelial dysfunction in the pathophysiology of pulmonary hypertension secondary to CHD, we established a unique model of pulmonary hypertension with increased pulmonary blood flow, utilizing in utero placement of a large aortopulmonary shunt in the fetal lamb. Based on our preliminary data, we hypothesize that increased pulmonary blood flow produces a progressive increase in ET-mediated vasoconstriction and mitogenesis that is initially opposed by an activated NO cascade. However, with further endothelial dysfunction secondary to increased flow and pressure, the NO cascade is decreased. This leads to unopposed ET-mediated vasoconstriction and mitogenesis and the progressive development of pulmonary hypertension and vascular remodeling. In this application, we will utilize our unique animal model, and a sequential and integrated physiologic, biochemical, molecular, and anatomic approach, to investigate this hypothesis. Specifically, we will examine: (a) the normal maturational changes in the NO and ET-1 cascades during the first two months of life; (b) the role of early alterations in the NO and ET-1 cascades in the development of pulmonary hypertension secondary to increased pulmonary blood flow; and (c) the interactions between the NO and ET-1 cascades, and their regulatory mechanisms, in the normal and abnormal pulmonary vasculature. Correlations between endothelial dysfunction, increased vascular reactivity, and vascular remodeling will be made, and predictors of increased vascular reactivity will be sought. This information may improve our ability to recognize early pulmonary vascular changes, and better predict those patients with CHD who will suffer increased peri- and post-operative morbidity secondary to increased vascular reactivity. This would profoundly affect the timing and feasibility of surgical correction, and should lead to improved treatments and prevention strategies for pulmonary hypertension.

肺动脉高压及其相关的血管反应性改变是先天性心脏病（CHD）儿童（CHD）和肺部血流增加的主要来源。 由血管活性物质的复杂相互作用（例如一氧化氮（NO）和内皮素-1（ET-1））局部产生的血管活性物质的复杂相互作用，部分调节了肺血管张力。 CHD继发的内皮损伤随着肺部血流的增加而破坏了这些调节机制，并已被视为肺动脉高压发育的潜在因素。 为了研究早期内皮功能障碍在继发于冠心病的肺高血压病理生理学中的作用，我们建立了一种肺动脉高压的独特模型，肺部血流增加，利用子宫内胎儿的大型主动脉分支，胎儿中的大型主动脉分支。 根据我们的初步数据，我们假设增加的肺血流会导致ET介导的血管收缩和有丝分裂发生的逐渐增加，最初与活化的NO级联反对相反。但是，随着进一步的内皮功能障碍继发于增加流量和压力，无级联反应减少。 这导致无反应的ET介导的血管收缩和有丝分裂发生以及肺动脉高压和血管重塑的逐步发展。在此应用中，我们将利用我们独特的动物模型，以及一个顺序和综合的生理，生化，分子和解剖方法，来研究这一假设。 具体而言，我们将研究：（a）生命的头两个月内NO和ET-1级联的正常成熟变化； （b）早期改变在NO和ET-1级联反应中的作用在肺部血流增加的肺动脉高压发展中的作用； （c）在正常和异常的肺脉管系统中，NO和ET-1级联反应及其调节机制之间的相互作用。 将寻求内皮功能障碍，血管反应增加和血管重塑之间的相关性，并将寻求增加血管反应性的预测指标。 这些信息可能会提高我们识别早期肺血管变化的能力，并更好地预测那些冠心病患者将遭受增加血管反应性的术后和术后发病率增加。 这将严重影响手术校正的时间和可行性，并应导致改进的肺动脉高压治疗和预防策略。