PATHOGENESIS OF CHRONIC PULMONARY HYPERTENSION

慢性肺动脉高压(CPH)的发展通常 继发于其他慢性肺病，如充血性心脏病 衰竭、阻塞性肺疾病、肺纤维化和急性 呼吸窘迫综合征。开发更有效的治疗方法 这些患者，对其发病机制必须有更全面的认识。在这 应用，我们提出了生化、生理、细胞和 内皮素-1/内皮素作用的分子研究 肺动脉平滑肌转换酶(ET-1/ECEs)系统 细胞参与CPH的发病机制。我们将使用一个长期的 绵羊CPH插管模型持续换气 在这些研究中对肺动脉进行栓塞术(CAE) 分离自内膜(L1)和内中膜(L2)的平滑肌细胞 对照和对照的主、中区肺动脉各层 高血压动物。将检验以下假设：a)本地 ET-1水平参与CAE诱导CPH的发生；b)细胞和 ET-1/ECA系统和ET-1受体在不同部位的差异 正常主、中段肺动脉对平滑肌细胞的调节作用 功能；c)ET-1/ECA系统中的细胞和特定部位的改变 ET-1受体参与了结构和功能的改变 (D)L1细胞比L2细胞合成活性更高 L2细胞对外源性ET-1基因的反应更强 L1和L2细胞的表达和活性受ET-1的调节； 局部合成生长因子调节ET-1刺激的ET-1/ECEs 系统。我们提出了两个具体的目标来解决这些假设。这个 首先将确定细胞和部位特定的变化 ET-1/ECs系统和ET-1受体群体的差异 正常的主肺动脉和中段肺动脉参与了 CAE诱导的CPH。第二个将决定ET-1/欧洲经委会系统是否 和ET-1受体在分离的L1和L2细胞中不同 对照组和高血压绵羊的中段肺动脉，以及 外源性ET-1是否调节ET-1/ECA系统，进而， 生长因子，例如转化生长因子-β和 胰岛素样生长因子-1调节ET-1刺激的ET-1合成。 这些研究将有助于我们对其发病机制的理解。 并最终致力于开发新的和新的治疗方法 这种毁灭性的疾病。

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.