PATHOGENESIS OF CHRONIC PULMONARY HYPERTENSION

慢性肺动脉高压的发病机制

• 批准号: 3367639
• 负责人: BARBARA O MEYRICK
• 金额: $ 19.75万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-06-01 至 1997-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3367639
• 关键词: aerosols; air embolism; artery; biopsy; cell growth regulation; chronic disease /disorder; elastase inhibitor; elastases; electron microscopy; endothelin; gene expression; homeostasis; inflammation; laboratory rat; light microscopy; messenger RNA; nonsurgical revascularization; nucleic acid hybridization; pathologic process; pulmonary circulation; pulmonary hypertension; sheep; tissue /cell culture; tissue /cell preparation; vascular endothelium; vasoconstriction

Development of chronic pulmonary hypertension (CPH) may be associated with long standing inflammation of the lung. Under such circumstances, the hypertension not only complicates effective treatment of the disorder but may also become the principal problem. To develop effective treatment of this disease, we must first understand its pathogenesis at physiologic, biochemical, structural, cellular, and molecular levels. In this application, we propose to test the hypothesis that acute inflammation of the lung causes microvascular endothelial injury, granulocyte sequestration, vasoconstriction and decreased peripheral vascular volume. These inflammation mediated changes lead to increased pulmonary vascular pressures and, eventually, to the onset of sustained pulmonary hypertension and the characteristic structural remodelling of large and small pulmonary arteries. We further propose that neutrophil elastase and endothelin-1 (ET-1) contribute to the development of CPH, elastase playing a role in the early inflammatory changes and ET-1, by acting as an early and a sustained vasoconstrictor, as well as one of several growth factors responsible for structural remodelling of the arteries. To test these hypotheses, we will conduct studies mainly in a large animal model of CPH, the chronically catheterized sheep receiving continuous air embolization. We propose experiments to test the following: 1) Determine whether administration of the elastase inhibitor, recombinant secretory leukocyte proteinase inhibitor, rSLPI, alters the functional and structural changes of CPH; 2) Determine whether rSLPI alters elastin homeostasis in the lung during the development of CPH; 3) Explore the effects of rSLPI on the cellular localization of elastin mRNA in large and small pulmonary arteries, and alveolar walls; 4) Determine the localization of aerosolized rSLPI in the normal lung and assess its site of action during the onset of CPH; 5) Determine whether endothelin plays a role in the pulmonary vasoconstriction and vascular remodelling of CPH; 6) Determine whether ET-1 regulates pulmonary vascular cell growth in vitro and stimulates elastin synthesis; 7) Initiate studies, in rats, to determine whether hyperexpression of ET-1 in the lung's vasculature leads to the functional and structural changes of CPH. Such information will contribute to our understanding of the pathogenesis of CPH and ultimately to development of novel therapies for treatment of this devastating disease.

慢性肺动脉高压（CPH）的发生可能与 患有长期肺部炎症。 在这样的情况下， 高血压不仅使该疾病的有效治疗变得复杂 但也可能成为主要问题。 制定有效的 治疗此病，首先要了解其发病机制 生理、生化、结构、细胞和分子水平。 在 在这个应用程序中，我们建议测试以下假设：急性 肺部炎症导致微血管内皮损伤， 粒细胞隔离、血管收缩和外周血减少 血管容量。 这些炎症介导的变化导致 肺血管压力，最终导致持续的 肺动脉高压及其特征性结构重塑 大肺动脉和小肺动脉。 我们进一步建议中性粒细胞 弹性蛋白酶和内皮素-1 (ET-1) 有助于 CPH 的发展， 弹性蛋白酶在早期炎症变化和 ET-1 中发挥作用，通过 作为早期和持续的血管收缩剂，以及其中之一 几种负责结构重塑的生长因子 动脉。 为了检验这些假设，我们将主要在 CPH 大型动物模型，即长期插入导管的绵羊接受 持续空气栓塞。 我们提出实验来测试 以下： 1) 确定是否施用弹性蛋白酶抑制剂， 重组分泌性白细胞蛋白酶抑制剂 rSLPI 可改变 CPH 的功能和结构变化； 2) 判断是否rSLPI 在 CPH 发生过程中改变肺部弹性蛋白稳态； 3） 探讨rSLPI对弹性蛋白mRNA细胞定位的影响 在大、小肺动脉和肺泡壁中； 4）确定 雾化 rSLPI 在正常肺中的定位并评估其 CPH 发作期间的作用部位； 5) 判断是否有内皮素 在肺血管收缩和血管重塑中发挥作用 CPH； 6) 确定ET-1是否调节肺血管细胞 体外生长并刺激弹性蛋白合成； 7) 启动研究， 大鼠，以确定 ET-1 是否在肺组织中过度表达 脉管系统导致 CPH 的功能和结构变化。 这样的 这些信息将有助于我们了解该疾病的发病机制 CPH 并最终开发治疗 CPH 的新疗法 这种毁灭性的疾病。