Collagen Accumulation & Mechanical Mechanisms in Pulmonary Hypertension

描述(由申请人提供)：肺动脉高压(PAH)是一种进行性和迅速致命的疾病，即使用现代疗法也是如此。死亡原因通常是右室(RV)衰竭。小的远端肺动脉狭窄被认为是引起PAH的原因。最近，近端大动脉(PAS)僵硬程度的增加被认为是预测PAH死亡率的有力指标。然而，PA远端和近端重塑在从健康的RV到衰竭的RV的关键转变中的影响仍然是一个主要的知识空白。在最初的资助期间(2008-2012)，我们重点研究了具有机械重要性的蛋白胶原蛋白对近端动脉硬化、肺血流动力学以及随后的缺氧性肺动脉高压(HPH)患者右室功能变化的影响。在这里，我们从三个重要方面扩展这项工作。首先，我们使用新的方法不仅产生RV功能障碍，而且产生RV失败，直到最近这一直是小鼠PH模型的限制。其次，我们设计了一种新的实验方法来分离和区分近端PA硬化和远端PA狭窄的影响，这两种效应在临床上是紧密耦合的，但可能通过独立的机制损害RV功能。第三，我们研究了右室胶原含量和交联度在右室功能障碍和向衰竭转变中的作用。我们的目的是：1.证明在轻中度PAH中，适应性RV肥厚(增厚但不衰竭的RV)依赖于PA远端狭窄和独立于PA近端硬化，因为我们假设，在轻中度PAH中，由于PA远端狭窄导致的平均肺动脉压的增加是必要的且充分的导致适应性RV肥厚。目的2.为了证明重度PAH患者右室不适应性重构(RV失败)依赖于PA远端狭窄和近端PA硬化的共同作用，因为我们假设平均肺动脉压的增加是必要的，但不足以导致重度PAH的RV重构不良；我们假设近端PA硬化引起的脉压升高也是必要的。目的3.探讨右室功能与右室纤维化的关系，因为我们假设右室纤维化程度较高的右室远端PA狭窄和近端PA硬化比纤维化程度较轻的右室更严重。临床和科学 研究PAH的社区最近致力于提高我们对RV功能对肺血管变化的依赖性的理解。我们的目标是研究在PAH进展过程中，近端和远端PA以及RV本身的关键机械生物学变化，这些变化推动了从肥大的功能性RV向衰竭的RV的转变，特别强调胶原的作用，这可能会影响这种快速致命疾病的治疗选择。

DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) is a progressive and rapidly fatal disease, even with modern therapies. The cause of death is typically right ventricular (RV) failure. Narrowing of the small, distal pulmonary arteries is know to cause PAH. Recently, increased stiffness of the large, proximal pulmonary arteries (PAs) was identified as a powerful predictor of mortality in PAH. However, the impact of distal and proximal PA remodeling on the critical transition from a healthy RV to a failing RV remains a major knowledge gap. Over the initial funding period (2008-2012), we focused on the vascular impact of the mechanically important protein collagen on proximal arterial stiffening, pulmonary hemodynamics and subsequent changes in RV function with hypoxia-induced pulmonary hypertension (HPH). Here we extend the work in three important ways. First, we employ novel methods to generate not only RV dysfunction but also RV failure, which has been a limitation of mouse PH models until recently. Second, we designed a novel experimental approach to uncouple and therefore distinguish the effects of proximal PA stiffening from distal PA narrowing, which are tightly coupled clinically but may impair RV function through independent mechanisms. Third, we investigate the role of RV collagen content and cross-linking in RV dysfunction and the transition to failure. Our aims are: Aim 1. To demonstrate the dependence of adaptive RV hypertrophy (thickened but not failing RV) on distal PA narrowing and independence from proximal PA stiffening in mild/moderate PAH, because we hypothesize that increases in mean pulmonary arterial pressure due to distal PA narrowing are necessary and sufficient to cause adaptive RV hypertrophy in mild to moderate PAH. Aim 2. To demonstrate the dependence of maladaptive RV remodeling (failing RV) on the combination of distal PA narrowing and proximal PA stiffening in severe PAH, because we hypothesize that increases in mean pulmonary arterial pressure are necessary but not sufficient to cause maladaptive RV remodeling in severe PAH; we hypothesize that increases in pulse pressure induced by proximal PA stiffening are also necessary. Aim 3. To investigate the relationship between RV function and RV fibrosis because we hypothesize that a more fibrotic RV is more impaired by distal PA narrowing and proximal PA stiffening than a less fibrotic RV. The clinical and scientific communities investigating PAH were recently charged with improving our understanding of the dependence of RV function on pulmonary vascular changes. Our goals are to investigate critical mechanobiological changes in proximal and distal PAs as well as the RV itself that drive the transition from a hypertrophied, functional RV to a failing RV during PAH progression, with a particular emphasis on the role of collagen, which in the future may impact treatment options for this rapidly fatal disease.