PERINATAL PULMONARY HYPERTENSION--DEVELOPMENTAL MEDIATOR

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)和肺血流增加儿童发病率和死亡率的主要来源。肺血管张力在一定程度上受到血管内皮细胞局部产生的血管活性物质的复杂相互作用的调节，如一氧化氮(NO)和内皮素-1(ET-1)。继发于CHD并伴有肺血流增加的内皮损伤破坏了这些调节机制，并被认为是肺动脉高压发生的一个潜在因素。为了探讨早期内皮功能障碍在CHD继发肺动脉高压的病理生理学中的作用，我们建立了一种独特的肺动脉高压伴肺血流量增加的模型，利用胎羊体内放置大的主-肺分流术。根据我们的初步数据，我们假设肺血流量增加会导致ET介导的血管收缩和有丝分裂的进行性增加，而这最初是被激活的NO级联反应所反对的。然而，随着血流和压力增加继发进一步的内皮功能障碍，NO级联反应减少。这导致非对立的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进行性发展。在这一应用中，我们将利用我们独特的动物模型，以及顺序和集成的生理学、生化、分子和解剖学方法来研究这一假说。具体地说，我们将研究：(A)在生命的头两个月，NO和ET-1级联反应的正常成熟变化；(B)NO和ET-1级联反应的早期变化在继发于肺血流增加的肺动脉高压中的作用；以及(C)在正常和异常的肺血管系统中，NO和ET-1级联反应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，并更好地预测那些因血管反应性增加而导致手术前后并发症增加的冠心病患者。这将深刻地影响手术矫正的时机和可行性，并将导致改善对肺动脉高压的治疗和预防策略。

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.