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) 和肺血流量增加儿童发病和死亡的主要原因。 肺血管张力在一定程度上是由血管内皮局部产生的血管活性物质（例如一氧化氮 (NO) 和内皮素-1 (ET-1)）复杂的相互作用来调节。 继发于冠心病的内皮损伤伴随肺血流量增加，破坏了这些调节机制，并且被认为是肺动脉高压发生的潜在因素。 为了研究早期内皮功能障碍在继发于先心病的肺动脉高压的病理生理学中的作用，我们利用在胎儿羔羊的子宫内放置大型主动脉肺分流器，建立了一种独特的肺动脉高压模型，肺血流量增加。 根据我们的初步数据，我们假设肺血流量的增加会导致 ET 介导的血管收缩和有丝分裂发生逐渐增加，而这最初是由激活的 NO 级联所对抗的。然而，随着流量和压力增加继发的进一步内皮功能障碍，NO 级联减少。 这导致不受对抗的 ET 介导的血管收缩和有丝分裂，以及肺动脉高压和血管重塑的逐渐发展。在此应用中，我们将利用我们独特的动物模型以及连续且综合的生理学、生化、分子和解剖学方法来研究这一假设。 具体来说，我们将检查： (a) 生命最初两个月内 NO 和 ET-1 级联的正常成熟变化； (b) NO和ET-1级联的早期改变在肺血流量增加继发的肺动脉高压发展中的作用； (c) 正常和异常肺血管系统中 NO 和 ET-1 级联之间的相互作用及其调节机制。 将建立内皮功能障碍、血管反应性增加和血管重塑之间的相关性，并寻找血管反应性增加的预测因素。 这些信息可以提高我们识别早期肺血管变化的能力，并更好地预测那些因血管反应性增加而导致围手术期和术后发病率增加的先心病患者。 这将深刻影响手术矫正的时机和可行性，并应改进肺动脉高压的治疗和预防策略。