久咳要药五味子治疗慢性咳嗽高敏综合征的药效物质基础及药理机制研究

Chronic cough hypersensitivity syndrome (CHS) is one of the most common syndromes in respiratory clinic which seriously impacts on patient’s quality of life and currently no effective treatment are available. Thus, the most widely used drugs such as antibiotics and antitussives would result in enormous waste of public resources. Schisandra chinensis, an important Traditional Chinese Medicine, has been extensively prescribed for patients with persistent cough. However, the pharmacological study of Schisandra chinensis remained largerly unexplored. Our preliminary research indicated that Schisandra chinensis extracts can decrease cough frequency, attenuate airway inflammation and suppress the expression of transient receptor potential channels (TRPA1 and TRPV1) in cigarette smoke induced CHS model of guinea pigs. The active compounds were lignans, polysaccharide and volatile oil, et al (2015, JEP). The antitussive efficacy of Schisandra chinensis was comparable to that of codeine. In our present study, we aim to investigate the antitussive effect of chemical compounds from Schisandra chinensis, evaluating the cough frequency and airway inflammation in CHS model guinea pigs. High-throughput screening model would be established, depended on pathogenesis of CHS, so as to explore the mechanism of active compounds. This study will provide sufficient scientific evidence for clinical application of Schisandra chinensis. Additionally, the discovery of new active fractions and compounds will gain benefit for the usage of Schisandra chinensis and lays the foundation of developing new drugs for CHS.

慢性咳嗽高敏综合征（CHS）是呼吸科门诊最常见的病征之一，严重影响患者生活质量，尚无有效治疗药物，反复无效的镇咳及抗生素治疗造成了公共卫生资源的极大浪费。五味子Schisandra chinensis临床广泛用于治疗慢性咳嗽，但相关的药学研究极少。我们前期研究发现五味子提取物能显著降低CHS豚鼠模型的咳嗽次数、减轻气道炎症、抑制气道瞬时受体电位阳离子通道（TRPA1、TRPV1）表达，有效成分可能为木脂素、多糖、挥发油等，而可待因仅表现出单纯的镇咳作用（2015，JEP）。为明确五味子治疗CHS确切的药效物质及药理机制，本项目拟继续采用CHS豚鼠模型，以咳嗽次数及气道炎症为指标评价各类化学成分的药效；根据CHS发病机制建立系列高效体外模型，探讨活性成分的作用机制。本项目将为五味子临床应用提供更充分的科学依据，新活性部位及化合物的发现利于五味子药材的资源利用，为研发CHS新药奠定理论基础。

慢性咳嗽是临床常见的难治性慢性疾病，由于病因复杂，目前尚无有效的治疗药物。五味子Schisandra chinensis是治疗久咳的传统中药，然而有关其止咳药效物质研究甚少，止咳机制也尚未明确。课题组建立香烟烟雾诱导的咳嗽高敏豚鼠模型、柠檬酸诱导的豚鼠急性咳嗽模型、双氧水诱导的小鼠咳嗽模型等动物模型进行咳嗽活性评估；建立了系列细胞模型进行咳嗽机制探讨；采用植物化学的分离、分析、鉴定方法进行五味子止咳成分分析、分离。明确了五味子治疗CHS的药理活性，并确定了提取活性成分的最佳提取方法为乙醇提取和乙醇-水提取，采用HPLC法推测其活性成分可能为木脂素和多糖；将两个活性提取物分为六个化学部位，进行慢性咳嗽活性评估，找到三个活性部位，并进行了质谱分析和化学分离，得到10个化合物，均为木脂素类化合物；优化了总木脂素的制备工艺（含量大于50%），并研究了总木脂素的止咳活性及机制；对含量较大的五个木脂素单体的止咳活性及抗氧化机制进行了详细研究；制备了总多糖，并研究了总多糖的止咳活性及机制；对总多糖进行了分离纯化及化学分析；制备了五味子挥发油，并研究了其止咳活性；对各化学部位进行了安全性验证。本项目为五味子的临床应用提供了更充分的科学依据，五味子多糖部位、木脂素部位的止咳活性发现将有利于五味子药材的资源利用，为研发CHS新药奠定了基础。