Vascular collagen accumulation & mechanical mechanisms in pulmonary hypertension

血管胶原蛋白堆积

基本信息

批准号：
7822382
负责人：
Naomi C Chesler
金额：
$ 2.26万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7822382
关键词：
Affect Animals Arteries Arts Asthma Biomechanics Blood Circulation Blood Vessels Caliber Chronic Chronic Obstructive Airway Disease Clinical Clinical Research Clinical Treatment Collagen Cystic Fibrosis Data Disease Elastin Engineering Failure Fibrillar Collagen Figs - dietary Genetically Engineered Mouse Heart Hypoxia In Situ Knowledge Lead Left Ventricular Dysfunction Left ventricular structure Life Lung Lung diseases Maintenance Measurement Measures Mechanics Morbidity - disease rate Mus Outcome Patients Physiologic pulse Pilot Projects Play Prevention Pulmonary Circulation Pulmonary Hypertension Pulmonary Vascular Resistance Pulmonary artery structure Recovery Research Personnel Right Ventricular Dysfunction Right Ventricular Function Right ventricular structure Role Secondary to Sleep Apnea Syndromes Smooth Muscle Myocytes Stress Structure Systemic Scleroderma Systolic Pressure Testing Thinking Vascular remodeling Ventricular Ventricular Function Wild Type Mouse Work X-Ray Computed Tomography arterial stiffness cardiovascular risk factor electric impedance hemodynamics insight mortality new therapeutic target novel pressure prevent programs pulmonary arterial hypertension pulse pressure wave research study response

项目摘要

Pulmonary vascular remodeling is a consequence of pulmonary hypertension that can lead to right ventricular failure. However, the mechanisms by which remodeling causes ventricular failure are unknown. Previous conventional thinking was that arteriolar muscularization led to reduced lumen diameters and increased steady ventricular work, but recent evidence has challenged that view. Our overarching hypothesis is that pulmonary vascular collagen accumulation is responsible for increased pulsatile ventricular work, which severely impairs function, and does so via arterial stiffening. In the systemic circulation, arterial stiffening has been recognized as an independent risk factor for cardiovascular mortality. The impact of arterial stiffening on right ventricular function represents a major knowledge gap in the field. Here, we seek to test the specific hypotheses that vascular collagen accumulation in response to pulmonary hypertension (1) increases pulmonary arterial stiffness, (2) increases pulmonary arterial pulse wave reflections, and (3) impairs right ventricular function. Furthermore, we seek to show that the return to normal arterial, hemodynamic and ventricular function during recovery is dependent on the degradation of collagen and that preventing vascular collagen accumulation (with a novel anti-fibrotic treatment agent) prevents progression. We will test our hypotheses with state-of-the-art biomechanical and hemodynamic experiments on wild type and genetically-engineered mice. We will also explore the clinical correlates of these endpoints in a clinical pilot study. Our specific aimsare: 1. To determine the role of vascular collagen accumulation in pulmonary arterial stiffening - via pressure- diameter measurements in isolated pulmonary arteries and the pulmonary vascular network. 2. To determine the role of vascular collagen accumulation in pulmonary arterial wave reflections - via pulsatile pressure-flow measurements in isolated, ventilated and perfused lungs. 3. To determine the role of vascular collagen accumulation in right ventricular function - via pressure- volume measurements in the right ventricle of live mice in situ. 4. To examine the pulmonary vascular hemodynamics and right ventricular function of patients with pulmonary hypertension, focusing on those with excessive collagen accumulation. The successful completion of this project will yield important insights into the progression of, treatment for and recovery from pulmonary hypertension. Furthermore, these studies will answer critical questions regarding the mechanical mechanisms of right ventricular dysfunction secondary to pulmonary vascular remodeling in pulmonary hypertension.

肺血管重塑是肺动脉高压的结果，可能导致右心室衰竭。但是，重塑导致心室衰竭的机制尚不清楚。以前的常规思维是，小动脉肌肉化导致管腔直径降低和增加稳定的心室工作，但最近的证据挑战了这一观点。我们的总体假设是肺血管胶原蛋白积累负责增加搏动性心室工作，严重损害了功能，并通过动脉僵硬来做到这一点。在系统性循环中僵硬被认为是心血管死亡率的独立危险因素。影响右心室功能上的动脉僵硬代表了该领域的主要知识差距。在这里，我们寻找为了测试特定的假设，即响应肺动脉高压的血管胶原蛋白积累（1）增加肺动脉刚度，（2）增加肺动脉脉搏波的反射，（3）损害右心功能。此外，我们试图证明恢复正常动脉，恢复过程中的血液动力学和心室功能取决于胶原蛋白的降解，并且防止血管胶原蛋白积累（具有新型的抗纤维化治疗剂）可防止进展。我们将通过对野生型的最先进的生物力学和血液动力学实验来检验我们的假设和遗传工程小鼠。我们还将在临床中探索这些终点的临床相关性试点研究。我们的特定瞄准片： 1。确定血管胶原蛋白在肺动脉僵硬中的作用 - 通过压力分离的肺动脉和肺血管网络中的直径测量。 2。确定血管胶原蛋白在肺动脉波反射中积累的作用 - 通过分离，通风和灌注肺中的脉冲压力流量测量。 3。确定血管胶原蛋白积累在右心室功能中的作用 - 通过压力 - 现场活小鼠的右心室中的体积测量。 4。检查患者患者的肺血管血流动力学和右心功能肺动脉高压，重点是胶原蛋白过度积累的高血压。该项目的成功完成将产生有关疗法的进展的重要见解和从肺动脉高压中恢复。此外，这些研究将回答关键问题关于继发于肺血管的右心室功能障碍的机械机制肺动脉高压中的重塑。