PATHOGENESIS OF CHRONIC PULMONARY HYPERTENSION

慢性肺动脉高压的发病机制

• 批准号: 6183641
• 负责人: BARBARA O MEYRICK
• 金额: $ 32.08万
• 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 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6183641
• 关键词: air embolism; aspartic endopeptidases; disease /disorder etiology; disease /disorder model; endothelin; growth factor receptors; hormone biosynthesis; hormone receptor; insulinlike growth factor; muscle cells; pulmonary artery; pulmonary hypertension; sheep; tissue /cell culture; transforming growth factors; vascular smooth muscle

The development of chronic pulmonary hypertension (CPH) is often secondary to other chronic lung diseases, such as congestive heart failure, obstructive lung disease, lung fibrosis and the acute respiratory distress syndrome. To develop more effective treatment for these patients, its pathogenesis must be more fully understood. In this application, we propose biochemical, physiological, cellular and molecular studies to examine the role of the endothelin-1/endothelin converting enzyme (ET-1/ECE) system of pulmonary artery smooth muscle cells to the pathogenesis of CPH. We will use a chronically catheterized model of CPH, the sheep receiving continuous air embolization (CAE) into the pulmonary artery for these studies and smooth muscle cells isolated from the intimal (L1) and inner medial (L2) layers of the main and mid-region pulmonary artery from control and hypertensive animals. The following hypotheses will be tested: a) local levels of ET-1 contribute to the onset of CAE-induced CPH; b) cell-and site-specific differences in the ET-1/ECE system and ET-1 receptors of normal main and mid-region pulmonary artery modulate smooth muscle cell function; c) cell and site-specific alterations in the ET-1/ECE system and ET-1 receptors contribute to the structural and functional changes of CPH; d) the L1 cells are more synthetically active than the L2 cells and L2 cells are more responsive to exogenous ET-1; e) ECE gene expression and activity in L1 and L2 cells is modulated by ET-1; and f) local synthesis of growth factors modulates the ET-1-stimulated ET-1/ECE system. We propose two specific aims to address these hypotheses. The first will determine whether alterations in cell- and site-specific differences in the ET-1/ECE system and ET-1 receptor populations in normal main and mid-region pulmonary artery contribute to the onset of CAE-induced CPH. The second will determine whether the ET-1/ECE system and ET-1 receptors are distinct in L1 and L2 cells isolated from main and mid-region pulmonary artery from control and hypertensive sheep, and whether exogenous ET-1 modulates the ET-1/ECE system and, in turn, whether growth factors, e.g., transforming growth factor-beta and insulin-like growth factor-1 modulate ET-1 stimulated ET-1 synthesis. Such studies will contribute to our understanding of the pathogenesis of CPH and ultimately to the development of new and novel therapies for this devastating disease.

慢性肺动脉高压（CPH）的发展通常是 继发于其他慢性肺部疾病，例如充血性心脏 衰竭，阻塞性肺疾病，肺纤维化和急性 呼吸窘迫综合征。 为了开发更有效的治疗方法 这些患者必须更充分了解其发病机理。 在这个 应用，我们建议生化，生理，细胞和 分子研究检查内皮素-1/内皮素的作用 转换肺动脉平滑肌的酶（ET-1/ECE）系统 细胞到CPH的发病机理。 我们将长期使用 CPH的导管模型，接收连续空气的绵羊 这些研究的栓塞（CAE）进入肺动脉和 从内膜（L1）和内侧（L2）分离的平滑肌细胞 主区域和中部肺动脉的层，由对照和 高血压动物。 将测试以下假设：a）本地 ET-1的水平有助于CAE诱导的CPH发作； b）细胞和 ET-1/ECE系统和ET-1受体的位点特异性差异 正常的主和中区肺动脉调节平滑肌细胞 功能; c）ET-1/ECE系统中的单元格和位点特异性变化 ET-1受体有助于结构和功能变化 CPH； d）L1细胞比L2细胞更合成活性 L2细胞对外源ET-1的反应更敏感。 e）ECE基因 L1和L2细胞中的表达和活性由ET-1调节；和f） 生长因子的局部合成调节ET-1刺激的ET-1/ECE 系统。 我们提出了两个具体目标来解决这些假设。 这 首先将确定细胞特异性和位点特异性的改变 ET-1/ECE系统和ET-1受体种群的差异 正常的主和中区肺动脉有助于发作 CAE诱导的CPH。 第二个将确定ET-1/ECE系统是否 ET-1受体在从主分离的L1和L2细胞中不同 以及来自对照和高血压绵羊的中区肺动脉，以及 外源ET-1是否调节ET-1/ECE系统，然后 生长因素，例如转化生长因子 - β和 胰岛素样生长因子1调节ET-1刺激ET-1合成。 这样的研究将有助于我们对发病机理的理解 CPH，最终开发新的和新颖的疗法 这种毁灭性的疾病。