补肾益气和清热活血方药拮抗慢性阻塞性肺疾病气道炎症与重塑的实验研究

The airway inflammation and remodeling of COPD is a crucial pathogenesis leading to irreversible airflow obstruction and progressive pulmonary dysfunction, which is characterized by chronic inflammation, smooth muscle cell proliferation as well as angiogenesis, involves complicated changes at the histological, cellular and molecular level including Th1/Th2，airway smooth muscle cell, pulmonary vascular smooth muscle cell, pulmonary microvascular endothelial cell, bronchial epithelial cell, MMPs/TIMPs, VEGF, TGF-β, and TGF-β-Smad signaling pathway. However, modern medicine lacks effective intervention on the airway inflammation and remodeling of COPD. Bu-Shen-Yi-Qi formula and herbal medicines inhibit both airway inflammation and remodeling, whereas Qing-Re-Huo-Xue formula and herbal medicines show better efficacy in remodeling. Based on the characterization of the airway inflammation and remodeling of COPD, such as the pathogenesis of epithelial wound, airway smooth muscle cell proliferation and angiogenesis, this program aims to observe the effect of Bu-Shen-Yi-Qi and Qing-Re-Huo-Xue formulae and herbal medicines as well as major active components on the airway inflammation and remodeling, elucidate their mechanism and potential targets at the histological，cellular and molecular level, which would lay a foundation for the utility of traditional Chinese medicine, Bu-Shen-Yi-Qi and Qing-Re-Huo-Xue formulae and herbal medicines in particular, in preventing and treating the airway inflammation and remodeling of COPD.

COPD气道炎症与重塑是造成不可逆性气流阻塞和肺功能下降的重要病理基础，慢性炎症、平滑肌增殖和血管新生是其重要特征，涉及组织、细胞、分子等不同层面的复杂变化，包括Th1/Th2、气道平滑肌细胞、肺血管平滑肌细胞、肺微血管内皮细胞、支气管上皮细胞和MMPs/TIMPs、VEGF 、TGF-β以及TGF-β-Smad 信号通路等。现代医学对COPD气道炎症与重塑缺乏有效干预手段，中医补肾益气方药对COPD炎症与重塑均有抑制作用，清热活血方药对重塑疗效更优。本项目在研究COPD炎症与重塑特征如上皮损伤、气道平滑肌增殖及血管新生等发生机制的基础上，观察补肾益气、清热活血方药及其主要活性成分对气道炎症与重塑等的作用，分别从动物水平、细胞水平和分子水平研究这些方药及其主要活性成分干预COPD气道炎症与重塑的作用机理和可能的靶位群，为中医药特别是补肾益气和清热活血方药防治COPD炎症与重塑提供理论依据。

气道炎症、气道重塑及氧化应激被认为是COPD的主要发病机制。现代医学缺乏有效的干预手段。团队前期研究证实补肾益气、清热活血方药干预COPD疗效确切，然而具体机制有待进一步确认和深入研究。本项目建立了稳定COPD大鼠模型，从多个方面确认了补肾益气、清热活血方药及其主要药效成分改善COPD气道炎症，气道重塑及氧化应激等方面的作用，表明中药干预具有多靶点、协同发挥作用的特点。从动物实验和体外实验多个方面阐释了补肾益气、清热活血方药及其主要药效成分干预COPD的主要分子机制可能是①补肾益气方药上调CSAD等氧化应激相关蛋白的表达，调节PI3/AKT通路发挥抗氧化作用。②补肾益气方药下调Collagen-1，fibronectin等细胞外基质成分表达，调节TGF-β1/smad2/3通路发挥抗重塑作用。③补肾益气方药主要药效成分淫羊藿苷调节JAK/STAT通路和线粒体分裂、融合相关蛋白表达，从而改善线粒体形态和功能发挥抗炎、抗氧化作用。④补肾益气方药主要药效成分黄芪甲苷通过MAPK通路，调节线粒体生物发生相关的PGC-1α-Nrf-TFAM通路发挥抗炎、抗氧化作用。⑤清热活血方及主要药效成分黄芩苷能改善血液流变学指标，缓解肺部缺氧微环境发挥抗炎作用。⑥黄芩苷、芍药苷可能通过减少PAI-1表达，恢复I-κB及HDAC2活性，抑制NF-κB发挥抗炎作用。综述所述，本项目采用系统生物学方法和相关分子生物学技术，研究补肾益气、清热活血方药及其主要药效成分拮抗COPD气道炎症、气道重塑及氧化应激的作用，初步阐释了其干预COPD的作用机理，为中医药防治COPD机制研究提供科学依据。