PATHOGENESIS OF CHRONIC PULMONARY HYPERTENSION

慢性肺动脉高压(CPH)的发生可能与 患有长期的肺部炎症。在这种情况下， 高血压不仅使这种疾病的有效治疗复杂化 但也可能成为主要问题。要开发出有效的 治疗本病，首先要了解其发病机制 生理、生化、结构、细胞和分子水平。在……里面 在这一应用中，我们建议检验以下假设 肺部炎症会导致微血管内皮损伤， 粒细胞隔离、血管收缩和外周血细胞减少 血管体积。这些炎症介导的变化会导致 肺血管压力，并最终持续到发病 肺动脉高压及其特征性结构重构 大的和小的肺动脉。我们进一步提出，中性粒细胞 弹性蛋白酶和内皮素-1(ET-1)参与了CPH的发生、发展。 弹性蛋白酶在早期炎症变化和ET-1中的作用 起到早期和持久的血管收缩作用，以及 导致经济结构重塑的几个增长因素 动脉。为了验证这些假设，我们将主要在一个 慢性插管绵羊CPH的大动物模型 持续空气栓塞术。我们建议进行实验来测试 以下：1)确定是否给药弹性酶抑制剂， 重组分泌型白细胞蛋白酶抑制剂rSLPI改变 CPH的功能和结构变化；2)决定rSLPI是否 改变CPH发展过程中肺内弹性蛋白的稳态；3) 重组人SLPI对弹性蛋白mRNA细胞定位的影响 在大、小肺动脉和肺泡壁；4)确定 雾化rSLPI在正常肺中的定位及评价 CPH发病时的作用部位；5)确定内皮素是否 在肺血管收缩和血管重塑中起作用 6)确定ET-1是否对肺血管细胞有调节作用 在体外生长并刺激弹性蛋白合成；7)启动研究，在 以确定ET-1在肺组织中的高表达 血管系统导致CPH的功能和结构改变。是这样的 这些信息将有助于我们了解该病的发病机制 CPH和最终用于治疗的新疗法的开发 这种毁灭性的疾病。

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.