基于siRNA沉默JAKs/STATs相关基因的六味补气胶囊对COPD肺气虚证大鼠呼吸系统影响的研究

Deficiency of lung Qi is the initial syndrome in chronic obstructive pulmonary disease(COPD),which,further development,may develop multiple system and organ dysfunction,and become the initiatial cause of death in the elderly. The research group proposed the hypothesis of " impairment of dispersing and descending function of lung and losting management and regulation" according to the clinical and experimental research on the lung Qi deficiency syndrome in COPD for many years and found that the important pathogenesis was that there were imbalance between the Janus kinase/signal transducer,activator of transcription(JAK/STAT) and its suppressor of cytokine signaling(SOCS) pathway expre ssion,leading to the change of cytokine network,thus triggering the cellular inflammation reaction and immune response,which made the degree of lung Qi deficiency deeper and,eventually causing the total dysfunction in the lung,spleen and kidney. Based on the above mechanism, we propose the hypothesis that starting with small interfering RNA(siRNA) silencing the related genes of STAT-SOCS pathway, the occurrence and development of lung Qi deficiency syndrome of COPD can be controlled. And further,regulating the STAT-SOCS pathway can improve the COPD lung Qi deficiency syndrome. Therefore,by using the Chinese medicine compound Liuwei Buqi capsules to intervene JAK/STAT-SOCS pathway and hence to block or inhibit the activation of JAK/STAT pathway and regulate siRNA and cytokine network expression,the body's inflamm atory response can be regulated and controlled and then the function of lung governing management and regulation get reconstructed,finally the COPD lung Qi difeciency syndrome will be improved. The assumption will provide the experimental basis for totally improve the quality of long-term survival in patients with COPD.

肺气虚证是慢性阻塞性肺病（COPD）始动证型，其进一步发展可累及多系统、多脏器功能障碍成为老人死亡的始动因素。本课题组经过多年研究提出COPD肺气虚证“肺失宣降、治节障碍”的基本病机，并发现其发病重要机理就是Janus激酶/信号转导转录激活因子(JAK/STAT) 及其抑制因子（SOCS）信号通路表达失衡，导致细胞因子网络改变，引起细胞炎症反应和免疫应答不断发生和发展，气虚程度日深，最终出现肺脾肾等脏器全面功能障碍。因此我们提出siRNA沉默STAT-SOCS相关基因，可调控COPD肺气虚证的发展，调节STAT-SOCS通路可以改善COPD肺气虚证，并采用中药复方六味补气胶囊干预JAK/STAT-SOCS通路，阻断或抑制JAK/STAT通路活化、调节机体炎症反应，调控siRNA表达和细胞因子网络，使肺的治节功能重建，改善COPD肺气虚证，为整体提升COPD患者远期生存质量提供实验依据。

慢性阻塞性肺部疾病（Chronic obstructive pulmonary disease, COPD）是呼吸系统常见疾病。肺气虚证是COPD的始动证型，其进一步发展可累及多系统、多脏器功能障碍，已成为老年人死亡的首要原因。本课题组经过多年研究提出COPD肺气虚证“肺失宣降、治节障碍”、“邪之所凑，其气必虚”的基本病机，并基于此拟定的中药六味补气胶囊（由炙黄芪、人参、玉竹、益智仁、陈皮、肉桂组成）治疗COPD肺气虚证已取得良好疗效。临床研究发现，六味补气胶囊能明显改善COPD患者肺部症状体征，提高肺功能参数，改善患者干咳、咳痰、胸闷、气短等肺部症状体征。动物实验发现，六味补气胶囊能明显改善COPD肺气虚证大鼠肺部影像学及病理学病变，改善COPD大鼠呼吸系统症状及肺功能，降低巨噬细胞浸润，减少辅助性T细胞（Helper T cells, Th）1、Th17细胞数量，促进Th2和调节性T细胞（Regulatory T cells, Tregs）细胞极化，降低免疫炎症反应，调节胞外基质金属蛋白酶MMPs/TIMPs的平衡。本课题组前期研究发现COPD的重要发病机制是Janus激酶/信号转导转录激活因子(JAK/STAT)及其抑制因子（SOCS）信号通路表达失衡，导致细胞因子网络改变，引起细胞炎症反应和免疫应答不断发生和发展，气虚程度日深，最终出现肺脾肾等脏器全面功能障碍。因此，我们进一步通过动物和细胞实验明确了六味补气胶囊主要通过上调SOCS1、SOCS3的表达抑制JAK/STAT信号通路的激活，抑制炎性因子INF-γ、IL-1β、IL-6、TNF-α等的表达，抑制肺泡上皮细胞凋亡，从而改善COPD大鼠肺功能。本项目的实施和完成初步明确了六味补气胶囊治疗 COPD 肺气虚证的作用和分子机制，为丰富和完善中医药治疗COPD、为肺炎的防治、开辟一条适合中医药治疗COPD 肺气虚证的新途径提供实验和理论基础。