基于HDAC2和Nrf2从抗炎和抗氧化角度探讨补肾益气方干预慢性阻塞性肺疾病的机制

Chronic obstructive pulmonary disease (COPD) is a disease with high morbidity and mortality. Its underlying mechanism is not clear, but it shows obvious inflammatory characteristics and there is no effective drug to treat it. Studies have shown that histone deacetylase 2 (HDAC2) plays an important role in the inhibition of the inflammatory response; nuclear factor E2-related factor 2 (Nrf2) is an important transcription factor involved in the regulation of cellular antioxidant stress response; COPD patients show lower HDAC2 and consequently Nrf2 antioxidant capacity also weakens. Here we investigated whether molecular mechanism of replenishing Shen and strengthening Qi Formula on COPD is anti-inflammatory and antioxidant. We use cigarette smoking to establish a stable and ideal COPD rat model, which is treated with the traditional Chinese medicine of replenishing Shen and strengthening Qi and its active components，dynamically analyzing the changes of inflammation and oxidative stress of rats; investigating the characteristics of inflammation and oxidative stress in Beas-2B cells intervened by CSE and afterwards by the active components of the traditional Chinese medicine of replenishing Shen and strengthening Qi. Through a comparative study analyze the role and efficacy of the Formula, and explore the possible mechanism around HDAC2, Nrf2 and GR and other COPD marker of inflammation (inflammatory cells, media, factors and CRP, etc.), pulmonary function and the extra-pulmonary indicators (coronary, weight, skeletal muscle, etc.).To explore the combination of the anti-inflammatory and antioxidant combination may be the molecular mechanism of the treatment on COPD by replenishing Shen and strengthening Qi Formula.

慢性阻塞性肺疾病（COPD）发病率、病死率高，其发病机制尚不完全明确，但它的炎症特征明显；其治疗尚无特效药物。研究表明，组蛋白去乙酰化酶2（HDAC2）在抑制炎症反应中发挥重要作用；核因子E2相关因子2（Nrf2）是参与调节细胞抗氧化应激反应的重要转录因子；COPD患者的HDAC2降低，Nrf2抗氧化能力亦随之减弱。本研究通过烟熏法建立稳定、理想的COPD大鼠炎症模型，用补肾益气中药及其有效组分干预，动态分析COPD大鼠炎症和氧化应激变化；探讨经CSE处理后用补肾益气中药有效组分干预的Beas-2B细胞的炎症及氧化应激特征；通过对比研究，分析补肾益气方的作用与疗效，围绕HDAC2、Nrf2、GR等阐述补肾益气方可能作用机理，及其与COPD炎症指标（炎症细胞、介质、因子及CRP等）、肺功能、肺外指标（冠脉、体重、骨骼肌等）的关系；探讨抗炎和抗氧化结合可能是补肾益气方治疗COPD的分子机理。

慢性阻塞性肺疾病（COPD）发病率、病死率高，其发病机制尚不完全明确，但它的炎症特征明显，其治疗尚无特效药物。临床观察发现，中医补肾益气法防治COPD效果较好。前期研究表明，组蛋白去乙酰化酶2（HDAC2）在抑制炎症反应中发挥重要作用；核因子E2相关因子2（Nrf2）是参与调节细胞抗氧化应激反应的重要转录因子；COPD患者的HDAC2降低，Nrf2抗氧化能力亦随之减弱。补肾益气方药调节气道炎症的作用及机制有待进一步确认和深入研究。. 本研究建立了稳定的COPD大鼠模型。从多个方面确认了补肾益气方及其组分淫羊藿苷、生地梓醇、黄芪甲苷和组分复方调节COPD气道炎症、改善氧化应激及气道重塑等方面的作用，且随着干预时间的延长，其作用效果更加显现。其中补肾益气方疗效最佳，这可能与本方药所含化学组分能多靶点、多途径协同发挥抗炎、抗氧化、抗重塑及提高机体免疫力等作用密切相关。从动物实验和体外研究多个方面确认了补肾益气方药干预COPD模型的主要分子机制可能是（1）补肾益气方药能激活抑炎因子(HDAC2、GR)、抑制促炎因子(NF-kB)发挥抗炎作用；（2）补肾益气方药能增强内源性抗氧化因子(Nrf2、HDAC2)发挥抗氧化作用。