PATHOGENESIS OF CHRONIC PULMONARY HYPERTENSION

慢性肺动脉高压的发病机制

• 批准号: 2224606
• 负责人: BARBARA O MEYRICK
• 金额: $ 27.54万
• 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/2224606
• 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）的发展可能与此有关