从“肺朝百脉”探讨补肺活血法调控HIF-1复合信号通路对COPD肺血管影响的机制研究

Pulmonary vascular disease is one of the COPD characteristic pathology, is the key factor to the development of pulmonary heart disease. HIF-1 plays a key role in hypoxic pulmonary vascular lesion formation. Our research group proposed pathogenesis of COPD pulmonary vascular disease: "all vessels converging in lung" disorders Qi deficiency and blood stasis, Pulmonary vascular disease appeared gradually; using invigorating lung activating blood circulation can slow disease progression in patients with COPD. Based on this, puts forward HIF-1 pathway may be the material basis of lung "toward" all vessels, the invigorating lung activating blood circulation herbs may be through regulation of HIF-1 composite channel, improve the alveolar hypoxia, prevention and treatment of COPD with pulmonary vascular disease hypothesis. . To establish a mouse model of COPD, dynamic observation and modeling of disease progression, the expression of HIF-1 complex pathway of key molecules, lung tissue, pulmonary and right heart function. Based on "all vessels converging in lung" using lungs blood activating herbs intervention, To investigate the effect of traditional Chinese medicine for activating blood and lungs of COPD pulmonary vascular lesions in the regulation of HIF-1 complex from the perspective of access. . This study helps to rich scientific connotation of "all vessels converging in lung"; explore the mechanism which Invigorating lung Activating Blood Circulation intervention COPD pulmonary vascular disease, provide a method of COPD pulmonary vascular disease.

肺血管病变是慢阻肺特征性病理学改变之一，是发展至肺心病的关键环节。缺氧诱导因子-1（HIF-1）在缺氧性肺血管病变形成中起重要作用。课题组前期研究发现慢阻肺患者“肺朝百脉”不利，气虚血瘀，逐渐出现肺血管病变；采用补肺活血法干预，能够延缓疾病进展。基于此，提出HIF-1复合通路可能是肺脏发挥“朝”百脉功能的物质基础，补肺活血中药可能通过调控HIF-1复合通路，改善肺泡缺氧，达到防治慢阻肺肺血管病变的假说。. 拟通过建立慢阻肺小鼠模型，动态观察造模及疾病进展过程中，HIF-1复合通路关键分子的表达及肺组织、肺动脉和右心功能的变化；基于“肺朝百脉”理论采用补肺活血中药干预，从调控HIF-1复合通路的角度探讨补肺活血中药对慢阻肺肺血管病变的影响。. 本研究有助于丰富中医学“肺朝百脉”理论的科学内涵，探讨补肺活血法干预慢阻肺肺血管病变的机制，提供一种防治慢阻肺肺血病变的方法。

中医学“肺朝百脉”理论体现了“气为血之帅”，“五脏一体观”的思想。本研究基于HIF-1复合通路探讨肺脏发挥“朝”百脉功能的物质基础及补肺活血中药防治慢阻肺肺血管病变的机制。.研究一：以香烟烟雾暴露结合鼻腔滴入内毒素法建立COPD模型，于造模6周、12周观察大鼠肺功能、右心及肺动脉超声、肺组织病理变化以及肺组织中HIF-1复合信号通路关键因子HIF-1α、HSP90、VEGF、ET-1、iNOS表达水平变化。结果：造模6周后，模型大鼠较正常组大鼠支气管结构仍较为完整，但在黏膜下出现明显的炎细胞浸润，肺泡壁变薄或断裂导致部分肺泡扩大融合形成肺大泡，肺血管有不同程度增生，管壁增厚或管腔变形，微血管数量明显增多。大鼠肺功能明显下降，三尖瓣反流、肺动脉瓣反流、肺动脉血流速度、平均肺动脉压明显升高，提示右心功能和肺动脉结构都发生异常。HIF-1复合信号通路蛋白表达明显升高。至造模12周后，肺组织病理改变较6周时均有一个明显加重趋势。右心及肺动脉超声指标和HIF-1复合信号通路蛋白表达进一步明显升高。上述改变提示模型组大鼠COPD及肺血管病变较6周时更加严重，且严重程度与造模时长呈正相关。.研究二：建立COPD稳定期大鼠模型，补肺活血中药干预4周，并设罗氟司特对照组。经过干预后的大鼠较模型组大鼠肺组织中支气管结构更加完整，黏膜下炎细胞浸润减少，肺泡扩张程度降低，肺血管增生减少，管腔形状规整，管壁变薄，微血管数量减少。肺功能明显升高，右心及肺动脉超声指标和HIF-1复合信号通路基因及蛋白表达均显著降低，补肺颗粒与罗氟司特比较无显著差异。.结论：COPD肺血管病变的发生、发展与HIF-1复合信号通路的表达相关，且随着COPD肺血管病变时间的延长，HIF-1复合信号通路的表达也逐渐升高。调节HIF-1复合信号通路相关因子水平的表达可能是补肺活血中药补肺颗粒颗粒治疗COPD肺血管病变的作用机制之一。.项目资助发表论文1篇，已录用待发表论文4篇。培养硕士研究生4名，博士研究生1名。项目投入经费15.22万元，支出2.78万元，剩余经费用于本项目研究后续支出。