缺氧，内皮素-1和一氧化氮对肺动脉平滑肌细胞增殖，迁移和胶原合成的影响及其细胞分子生物学机制的研究
摘要
肺血管收缩反应增强和肺血管结构重组是缺氧性肺动脉高压(HPH)的两个主要的病理生理特点，也是HPH发生和发展的重要基础。越来越多的研究表明HPH是一种结构性疾病，即肺血管结构重组对HPH的发病机制具有更重要的意义。在慢性肺泡缺氧条件下，肺循环的所有实质都存在结构变化，而且这种变化存在于动脉壁的所有结构层，这些变化包括a)血管内膜出现纵形的平滑肌；b)外膜内大量增生的胶原和弹性蛋白的异常堆积；c)肺泡内无肌性血管出现肌化和中层平滑肌细胞的肥大和增生。作为肺血管收缩反应的主要承担者和血管结构重组的重要参与者，肺动脉平滑肌细胞(PASMC)的分化，增殖，迁移以及胶原合成的变化，对缺氧性肺血管结构重组具有非常重要的意义，但目前对其细胞分子生物学机制还了解不多。
本研究在国内外首次提出并证明PASMC可以直接感受缺氧，缺氧可诱导PASMC进入分裂周期，促进PASMC的DNA合成和细胞的分裂增殖，增强PASMC对内皮素-1(ET-1)和血小板衍生生长因子(PDGF)的增殖反应和迁移反应，并且可促进PASMC的胶原合成，同时缺氧减弱了一氧化氮(NO)供应剂硝普钠(SNP)及中药单体764-3对PASMC DNA合成的抑制作用。对于缺氧作用的细胞分子生物学机制，我们也进行了初步探讨，发现缺氧可促进PASMC钙内流，增强原癌基因c-myc，生长因子基因PDGF-B链基因，以及应激蛋白基因hsp70在PASMC中的表达；缺氧还可促进PASMC丝裂原的自分泌作用，增强ET-1在PASMC中的表达和分泌，并促进内皮素A型受体(ETR_A)在PASMC中的表达，同时缺氧减弱了NO诱导的PASMC胞内cGMP水平的升高。这提示缺氧可能通过升高PASMC细胞内钙离子水平，促进增殖相关基因在PASMC中的表达，并增强PASMC丝裂原的自分泌作用，从而促进了PASMC的增殖，同时缺氧可能减弱PASMC中鸟苷酸环化
Increasing pulmonary vasoconstriction and pulmonary vascular remodeling are two important characteristics of hypoxic pulmonary hypertension (HPH). They are also important to the pathogenesis and progression of HPH. More and more studies demonstrated that HPH is a structural, not a functional disease. Under conditions of chronic generalized alveolar hypoxia, the complexity of pathologic structural remodeling has been demonstred throughout the entity of the pulmonary circulation and all the structural layers of the arterial wall. The changes include a) appearance of longitudinal oriented smooth muscle cells within the intima, b) the abnormal deposition of increased amounts of collagen and elastin within the adventitia, and c) muscularization of non-muscular intra-acinar vessels and medial smooth muscle cell hypertrophy and hyperplasia. Pulmonary artery smooth muscle cell (PASMC) is the main undertaker of pulmonary
本研究在国内外首次提出并证明PASMC可以直接感受缺氧，缺氧可诱导PASMC进入分裂周期，促进PASMC的DNA合成和细胞的分裂增殖，增强PASMC对内皮素-1(ET-1)和血小板衍生生长因子(PDGF)的增殖反应和迁移反应，并且可促进PASMC的胶原合成，同时缺氧减弱了一氧化氮(NO)供应剂硝普钠(SNP)及中药单体764-3对PASMC DNA合成的抑制作用。对于缺氧作用的细胞分子生物学机制，我们也进行了初步探讨，发现缺氧可促进PASMC钙内流，增强原癌基因c-myc，生长因子基因PDGF-B链基因，以及应激蛋白基因hsp70在PASMC中的表达；缺氧还可促进PASMC丝裂原的自分泌作用，增强ET-1在PASMC中的表达和分泌，并促进内皮素A型受体(ETR_A)在PASMC中的表达，同时缺氧减弱了NO诱导的PASMC胞内cGMP水平的升高。这提示缺氧可能通过升高PASMC细胞内钙离子水平，促进增殖相关基因在PASMC中的表达，并增强PASMC丝裂原的自分泌作用，从而促进了PASMC的增殖，同时缺氧可能减弱PASMC中鸟苷酸环化
Increasing pulmonary vasoconstriction and pulmonary vascular remodeling are two important characteristics of hypoxic pulmonary hypertension (HPH). They are also important to the pathogenesis and progression of HPH. More and more studies demonstrated that HPH is a structural, not a functional disease. Under conditions of chronic generalized alveolar hypoxia, the complexity of pathologic structural remodeling has been demonstred throughout the entity of the pulmonary circulation and all the structural layers of the arterial wall. The changes include a) appearance of longitudinal oriented smooth muscle cells within the intima, b) the abnormal deposition of increased amounts of collagen and elastin within the adventitia, and c) muscularization of non-muscular intra-acinar vessels and medial smooth muscle cell hypertrophy and hyperplasia. Pulmonary artery smooth muscle cell (PASMC) is the main undertaker of pulmonary
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