基于内质网应激CHOP通路调控肺泡上皮细胞凋亡的补肺益肾方治疗COPD的作用机制研究

Chronic obstructive pulmonary disease (COPD) has become a global public health problem that seriously affects human health. Alveolar epithelial cell (AEC) apoptosis is known to be one of the most important mechanisms of its pathogenesis, while endoplasmic reticulum stress CHOP pathway mediated AEC apoptosis is involved in the formation of emphysema in COPD. Previous studies have shown that Bufei Yishen formula is effective in the treatment of COPD, and it could improve oxidative stress and inflammatory response in COPD rats, and oxidative stress has been confirmed to be one of the main causes of endoplasmic reticulum stress. So we speculate that Bufei Yishen formula may exert its pharmacological effects by inhibiting AEC apoptosis regulated by endoplasmic reticulum stress CHOP pathway. Therefore, we intend to combine animal and cell experiments in vivo and in vitro to explore the effects of endoplasmic reticulum stress CHOP pathway in AEC apoptosis, and to clarify the mechanism of Bufei Yishen formula on AEC apoptosis regulated by this pathway by using gene interference, gene knockout mice, in situ hybridization technology, apoptosis detection and other molecular biological methods. The goals of this project are to find new targets for the treatment of COPD and provide a scientific theoretical basis for the application of Bufei Yishen formula.

慢性阻塞性肺疾病（COPD）已成为严重影响人类健康的全球性公共卫生问题，肺泡上皮细胞凋亡是其发病的重要机制之一，而内质网应激CHOP通路调控的肺泡上皮细胞凋亡参与了COPD中肺气肿的形成。前期的研究表明补肺益肾方治疗COPD疗效显著，能够改善COPD大鼠体内氧化应激及炎症反应，而氧化应激已被证实是内质网应激的主要诱因之一，推测补肺益肾方可能通过内质网应激CHOP通路调控的肺泡上皮细胞凋亡发挥药效。因此，本项目拟结合体内动物及体外细胞实验，应用基因干扰、基因敲除小鼠、原位杂交技术、凋亡标志物检测及其他分子生物学技术，深入探讨内质网应激CHOP通路在COPD肺泡上皮细胞凋亡中的作用，并阐释补肺益肾方基于此通路调控的肺泡上皮细胞凋亡治疗COPD的作用机制。该研究可为COPD的治疗寻找新的作用靶点，并为补肺益肾方的应用提供科学的理论依据。

慢性阻塞性肺疾病（COPD）发病率、死亡率逐年攀升，其已成为全球第三大致死性疾病，阐明其发病机制并寻找有效治疗药物迫在眉睫。本课题组前期实验结果显示，补肺益肾组分方Ⅲ明显改善COPD大鼠肺功能、肺组织结构，但分子机制尚未阐明。本研究以肺泡上皮细胞凋亡为切入点，结合体外细胞实验和体内动物实验研究，利用药理学工具药、基因沉默等分子生物学技术，从分子、细胞和整体水平阐明了COPD中肺泡上皮细胞凋亡的调控分子机制，以及补肺益肾组分方III改善肺泡上皮细胞凋亡治疗COPD的分子通路及其药效作用机制。首先，本研究明确了香烟烟雾能够引起肺泡上皮细胞ROS过度累积，进而引起内质网应激CHOP通路激活及线粒体损伤，导致细胞凋亡；其次，本研究阐明了香烟烟雾能够通过激活肺泡上皮细胞JNK/SAB信号通路，引起线粒体功能异常并导致细胞凋亡；最后，本研究揭示了补肺益肾组分方III通过调节JNK/SAB通路相关蛋白表达，恢复线粒体功能，改善细胞凋亡治疗COPD的调控机制。本研究为基于肺泡上皮细胞凋亡的COPD治疗药物研发提供了新思路，并为补肺益肾组分方III的临床应用提供了科学依据。