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）的发展可能与 肺部长期发炎 在这种情况下， 高血压不仅使疾病的有效治疗复杂化， 但也可能成为主要问题。 制定有效 治疗本病，首先要了解其发病机制， 生理、生物化学、结构、细胞和分子水平。 在 在此应用中，我们建议测试以下假设：急性 肺部炎症引起微血管内皮损伤， 粒细胞隔离、血管收缩和外周血减少 血管容积 这些炎症介导的变化导致增加 肺血管压力，并最终持续发作 肺动脉高压和特征性结构重塑 肺大动脉和肺小动脉 我们进一步提出，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 作为早期和持续的血管收缩剂，以及 几种生长因子负责的结构重塑的 动脉 为了验证这些假设，我们将主要在 CPH的大型动物模型，慢性插管绵羊接受 连续空气栓塞 我们提出实验来测试 以下步骤：1）确定是否给予弹性蛋白酶抑制剂， 重组分泌性白细胞蛋白酶抑制剂rSLPI改变了 CPH的功能和结构变化; 2）确定rSLPI是否 在CPH的发展过程中改变肺中的弹性蛋白稳态; 3） 探索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发作时的作用部位; 5）确定内皮素是否 在肺血管收缩和血管重塑中起作用 测定ET-1对肺血管细胞的调节作用 在体外生长并刺激弹性蛋白合成; 7）启动研究， 大鼠，以确定是否在肺的ET-1的高表达 血管系统导致CPH的功能和结构变化。 等 这些信息将有助于我们了解 CPH并最终开发用于治疗 这种毁灭性的疾病。