HIF-1α、ET-1、iNOS在新生大鼠HPH发病机制中的作用研究

发布时间：2018-09-12 21:20

【摘要】：目的：了解缺氧诱导因子-1α（Hypoxia Inducible Factor-1alpha, HIF-1α）及其调控因子：内皮素-1（Endothelin-1, ET-1）、诱导型一氧化氮合酶（inducible Nitric OxideSynthase, iNOS）在缺氧性肺动脉高压（Hypoxia-induced Pulmonary Hypertension,HPH）新生大鼠血清中的含量及肺组织中的表达水平，探讨HIF-1α在新生大鼠HPH发病机制中的作用及肺血管重塑随时间变化的关系。方法：建立新生大鼠HPH模型：将120只新生Wistar大鼠随机分为HPH组和同日龄常氧对照组，两组分别于缺氧3、5、7、10、14、21天取缺氧组及对照组同日龄新生大鼠各10只测定其平均肺动脉压（mean Pulmonary Arteria Pressure, mPAP），处死大鼠测定其右心室肥大指数（RightVentricle Hypertrophy Index, RVHI），血清HIF-1α、iNOS、ET-1含量及上述基因mRNA在肺组织的表达水平，测定血管重塑指标MT%、MA%，观察肺血管超微结构。结果：（1）缺氧3、5、7、10、14、21天，新生大鼠mPAP持续增高，，较对照组有明显差异（P＜0.05）；（2）缺氧组新生大鼠血清HIF-1α含量在缺氧3、5、7、10、14天明显高于对照组，差异有统计学意义（P＜0.05），肺组织HIF-1α mRNA表达在缺氧3、5、7天明显高于对照组，差异有统计学意义（P＜0.05）；血清ET-1含量在缺氧3、5、7、10、14、21天均明显高于对照组，差异有统计学意义（P＜0.01），肺组织ET-1mRNA表达在缺氧3天显著增高，差异有统计学意义（P＜0.05）；血清iNOS含量于缺氧3天明显高于对照组（P＜0.05），缺氧5、7、10天与对照组相比差异无统计学意义（P＞0.05），至缺氧14、21天血清iNOS含量低于对照组，差异有统计学意义（P＜0.05）；肺组织iNOS mRNA表达在缺氧3、5、7天显著增高，差异有统计学意义（P＜0.05）；（3）缺氧7天后MT%、MA%、RVHI明显高于对照组（P＜0.05），提示出现血管重塑及右心室肥厚。结论：（1）在新生大鼠HPH的发生过程中HIF-1α可能作为核心因子上调了ET-1及iNOS表达，致ET-1与NO平衡失调，在HPH发生中起了重要的作用。HIF-1α、ET-1及iNOS共同参与了新生大鼠HPH的发生、发展；（2）新生大鼠缺氧3~5天肺动脉压力增高，处于肺血管痉挛阶段；缺氧7天后肺血管出现重塑，右心肥厚，出现不可逆变化；随着缺氧时间延长，上述变化加剧。
[Abstract]:Objective: to investigate the content of hypoxia inducible factor-1 伪 (Hypoxia Inducible Factor-1alpha, HIF-1 伪 and its regulatory factors, endothelin 1 (Endothelin-1, ET-1) and inducible nitric oxide synthase (inducible Nitric OxideSynthase, iNOS) in serum and lung tissue of neonatal rats with hypoxic pulmonary hypertension (Hypoxia-induced Pulmonary Hypertension,HPH). To investigate the role of HIF-1 伪 in the pathogenesis of HPH in neonatal rats and the relationship between pulmonary vascular remodeling and time. Methods: the HPH model of neonatal rats was established. 120 neonatal Wistar rats were randomly divided into HPH group and normoxic control group of the same age. The mean pulmonary artery pressure (mean Pulmonary Arteria Pressure, mPAP),) was measured in 10 neonatal rats of the control group and the hypoxia group on the 21st day after hypoxia. The right ventricular hypertrophy index (RightVentricle Hypertrophy Index, RVHI), serum HIF-1 伪, iNOSS-ET-1, and the gene mRNA were measured in the rats of the two groups, the right ventricular hypertrophy index (RightVentricle Hypertrophy Index, RVHI),) and the above gene mRNA were measured in the control group and in the control group respectively on the 21st day after hypoxia. In the lung tissue, The vascular remodeling index (MT%,MA%,) was measured to observe the ultrastructure of pulmonary vessels. Results: (1) the level of serum HIF-1 伪 in neonatal rats in hypoxia group was significantly higher than that in control group (P < 0. 05, P < 0. 05). The content of serum HIF-1 伪 in neonatal rats in hypoxia group was significantly higher than that in control group at 14 days after hypoxia (P < 0. 05), and it was significantly higher than that in control group (P < 0. 05). The expression of HIF-1 伪 mRNA in lung tissue was significantly higher than that in control group on the 7th day after hypoxia (P < 0. 05), and the level of serum ET-1 was significantly higher than that in the control group on the day 1421 after hypoxia (P < 0. 05), and the expression of HIF-1 伪 mRNA in lung tissue was significantly higher than that in the control group on the 7th day after hypoxia (P < 0. 05). The expression of ET-1mRNA in lung tissue increased significantly after 3 days of hypoxia (P < 0. 05). The level of serum iNOS was significantly higher than that of the control group on the 3rd day after hypoxia (P < 0. 05). There was no significant difference between the control group and the control group on the 10th day of hypoxia (P > 0. 05). The serum iNOS content was lower than that in the control group on the day 14: 21 of hypoxia (P < 0. 05). The expression of iNOS mRNA in lung tissue was significantly increased on the 7th day after hypoxia (P < 0. 05); (3). After 7 days of hypoxia, the expression of MT%,MA%,RVHI in lung tissue was significantly higher than that in control group (P < 0. 05), indicating that vascular remodeling and right ventricular hypertrophy appeared. Conclusion: (1) the expression of ET-1 and iNOS may be upregulated by HIF-1 伪 as a core factor in the pathogenesis of HPH in neonatal rats, which leads to the imbalance of ET-1 and NO, and plays an important role in the pathogenesis of HPH. HIF-1 伪, ET-1 and iNOS are involved in the development and development of HPH in neonatal rats. (2) the pulmonary artery pressure increased at the stage of pulmonary vasospasm after hypoxia for 3 days in neonatal rats, the pulmonary vessels were remodeled after 7 days of hypoxia, the right heart was hypertrophy and irreversible changes were found, and the above changes were aggravated with the prolongation of hypoxia time.
【学位授予单位】：新疆医科大学
【学位级别】：硕士
【学位授予年份】：2012
【分类号】：R722.1

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