从蛋白质代谢稳态失衡角度探讨COPD外周骨骼肌消耗病变规律及健脾益肺法干预机制研究

Chronic obstructive pulmonary disease (COPD) is a systemic disease. Peripheral skeletal muscle wasting (PSMW) is an important extra-pulmonary feature of COPD and it influences COPD patients. The imbalance of PI3K/Akt and IKK/NF-κB signal pathway breaks protein metabolism homeostasis in peripheral skeletal muscle of COPD patients, and then PSMW will occur. “Lung relates to spleen” and “Spleen relates to limb muscle” are traditional theories in traditional Chinese Medicine. Our research group found that the Jianpiyifei Chinese medicine could improve the PSMW of COPD. Based on this, we hypothesize that the Jianpiyifei Chinese medicine might treat PSMW by regulating the PI3K/Akt and IKK/NF-κB signal pathway, so as to rebuild protein metabolism homeostasis. We will make COPD mice model and treat them with Jianpiyifei Chinese medicine. In the process of making model and treating, we will mainly observe the expression of key molecules in the PI3K/Akt and IKK/NF-κB signal pathway in peripheral skeletal muscle, combining them with pulmonary function, pathological slices, local and systemic inflammatory markers and so on, in order to clarify the variation rules of key molecules in the PI3K/Akt and IKK/NF-κB signal pathway during the pathological process of the PSMW of COPD, to clear the mechanism of effect of Jianpiyifei Chinese medicine on imbalance of protein metabolism homeostasis by regulating the key molecules in the PI3K/Akt and IKK/NF-κB signal pathway. This study will help us understand the importance of the method of Jianpiyifei in the treatment of COPD, supplement scientific connotation of “Peitushengjin” in traditional Chinese medicine, and promote clinical application value of “Peitushengjin”.

慢性阻塞性肺疾病（COPD）是一种全身性疾病，外周骨骼肌消耗（PSMW）是COPD重要肺外表现，对患者的影响甚至超过肺功能损伤。PI3K/Akt与IKK/NF-κB通路间平衡失调，导致蛋白质代谢稳态失衡是COPD-PSMW重要发病机制。课题组在中医“肺脾相关”和“脾主四肢肌肉”理论指导下发现健脾益肺中药能改善COPD-PSMW。基于此，本研究提出健脾益肺中药可能通过调控两通路间平衡，恢复蛋白质代谢稳态，以治疗COPD-PSMW的假说。拟建立COPD小鼠模型，造模时观察骨骼肌两通路关键分子表达情况，阐明其在PSMW形成过程中的动态变化规律，深化对中医传统理论“肺脾相关”和“脾主四肢肌肉”的认识；并用健脾益肺中药干预，将两通路指标与全身、局部指标相结合，从整体到微观逐步揭示健脾益肺中药对COPD-PSMW蛋白质代谢稳态失衡的调控作用机制，丰富中医学“培土生金”法的科学内涵，提升其临床应用价值。

慢性阻塞性肺疾病(COPD)是一种全身性疾病，外周骨骼肌消耗(PSMW)是其常见肺外表现，对患者的不良影响甚至超过肺功能损伤。PI3K/Akt和IKK/NF-κB信号传导通路间平衡失调，导致蛋白质代谢稳态失衡是COPD-PSMW重要发病机制。课题组前期研究证实健脾益肺中药能改善COPD-PSMW。基于此，本研究提出健脾益肺中药可能通过调控两通路间平衡，恢复蛋白质代谢稳态，以治疗COPD-PSMW的假说。通过香烟烟雾暴露的方法建立COPD小鼠模型，造模时观察骨骼肌两通路关键分子表达情况，阐明其在PSMW形成过程中的动态变化规律，并用健脾益肺中药干预，将两通路指标与全身、局部指标相结合，观察健脾益肺中药对COPD-PSMW蛋白质代谢稳态失衡的调控作用及机制。研究发现：1.COPD疾病病程中存在明显的肺部炎症反应→血清炎症因子表达增高，促进肌肉生长因子表达减弱→外周骨骼肌组织炎症反应增强，促进肌肉生长因子水平下降→PI3K/Akt和IKK/NF-κB信号传导通路平衡失调→外周骨骼肌组织蛋白合成代谢减弱，分解代谢增强→外周骨骼肌消耗病变形成的传变规律。2.健脾益肺中药干预COPD模型小鼠能够有效改善饮食、大便、呼吸、毛发光泽度、行为活动状态、精神状态等一般情况，减少体重下降；延缓肺功能恶化；抑制肺部炎症和气肿形成；减轻外周骨骼肌组织炎症和萎缩进展。3. 健脾益肺中药缓解COPD-PSMW的作用机制之一是其能够降低肺组织、血清和外周骨骼肌组织中IL-6及TNF-α的表达，升高血清和外周骨骼肌组织中IGF-1的表达，通过提高外周骨骼肌组织中PI3K-p85α、p-Akt、p-mTOR、p-4EBP1、p-P70S6K、p-GSK-3β和p-FoxO3A的蛋白和基因表达水平，减弱p-IKK、p-IκB、NF-κB-p65、Atrogin-1和MuRF-1的蛋白和基因表达水平，调控PI3K/Akt和IKK/NF-κB信号通路间平衡，进而增强外周骨骼肌组织的蛋白合成代谢，同时抑制分解代谢，以恢复其蛋白质代谢稳态。上述研究结果有助于深化中医学“肺脾相关”和“脾主四肢肌肉” 的理论认识，从整体到微观揭示了健脾益肺中药对COPD-PSMW的调控作用机制，丰富了中医学“培土生金”法的科学内涵，提升了其临床应用价值。