异佛司可林对慢性阻塞性肺病中T细胞亚群的调节作用及其分子机制

Air pollution, high smoking rate, infection risks, career enviromental exposures and aging of population et al., cause increased mortality and morbidity of chronic obstructive pulmonary diseases (COPD) in China, while being faced risk with lack of the drugs. Isoforskolin (ISOF), an analog of forskolin (FSK), is isolated from plant of Coleus forskohlii native to Yunnan as a major active ingredient. The applicant group has obtained two grants about ISOF from Natural Science Foundation of China (NSFC) to investigate the protective effect of ISOF on immune inflammation in lung. We demonstrated that the protective effect of ISOF on animal lung function against COPD was associated with its inhibition of secretion of cytokine IL-17 et al. from lymphocyte, and activation of adenylyl cyclase (AC) resulting in increase of cAMP in mononuclear leukocyte (ML). However, it is still not clear about the effect of ISOF on T cell subsets and the respective molecular mechanism in COPD. In the present project, we plan to reveal in depth the modulation of T cell subsets by ISOF and its molecular network mechanism against COPD from three levels, i.e. animal, cell and molecular. We will investigate the modulation of ISOF on the imbalance of T cell subsets (Th1, Th2,Th17,Treg and Tc) in ratio and functions induced by COPD, and inhibition of pro-inflammatory cytokine production and augmentation of anti-inflammatory cytokine secretion by ISOF, balance of Th17/Treg and their related cytokine secretion by ISOF, and especially inhibition of IL17 secreted by Th17 by ISOF. In addition, we also plan to investigate the modulation of T cell subsets by ISOF might be involved in specific AC isoforms (AC1-10) and signal pathway of cAMP/mTOR. These investigations might reveal pharmacological molecular mechanism of ISOF against COPD in T cell subsets. Finally, the studies will provide some novel insights in COPD clinical application of ISOF, in the related new drug screening and finding based in AC targets and agonists from the path of Th17/IL17 and signal pathway cAMP/mTOR, and also in the therapeutic target networks of COPD.

空气污染、吸烟、感染及人口老龄化等因素,导致我国慢性阻塞性肺病(COPD)高发,并缺乏防治药物。前期发现:云南特有药用植物毛喉鞘蕊花主要活性成分—异佛司可林(ISOF)激动腺苷酸环化酶(AC),改善COPD动物肺功能,其拮抗COPD慢性炎症与淋巴细胞及细胞因子IL-17等相关,但对T细胞亚群的影响尚未知。本项目将揭示ISOF通过激动T细胞亚群(主要是Th17细胞)上特异AC亚型酶,调节T细胞亚群(Th1、Th2、Th17、Treg及Tc细胞)及其功能,调控Th17/Treg细胞平衡及其促炎、抗炎因子分泌,特别是通过Th17/IL-17途径,抑制Th17细胞分泌IL-17,从而拮抗COPD慢性炎症;且其作用与AC下游通路cAMP/mTOR相关。本研究为基于AC靶点,从调节T细胞亚群方面,特别是从Th17/IL-17途径,干预COPD、研发COPD新药、ISOF防治COPD等,提供科学依据。

空气污染、吸烟、感染及人口老龄化等因素, 导致慢性阻塞性肺病(COPD)高发。前期研究发现: 云南特有药用植物毛喉鞘蕊花主要活性成分—异佛司可林(ISOF)激动腺苷酸环化酶(AC), 改善COPD动物肺功能, 与其拮抗COPD慢性炎症相关, 有待深入揭示ISOF对T细胞亚群的影响及其分子机制。本项目深入研究ISOF拮抗COPD慢性炎症反应与其调节T细胞亚群间的分子机制，按照计划完成各项研究内容，主要包括：在人CD4+、CD8+ T细胞上，实验筛查AC亚型酶表达情况；在CD4+、CD8+ T细胞模型上，实验探讨ISOF对T细胞亚群分泌功能的影响；在三种COPD动物模型上，实验确认ISOF对COPD慢性炎症反应中T细胞亚群及其功能的调节作用。通过本项目研究，揭示ISOF拮抗COPD慢性炎症反应的分子机制，揭示ISOF对COPD中T细胞亚群及其分泌功能的免疫调节作用，为ISOF用于临床防治COPD提供科学依据。本项目研究基本揭示了人T细胞上高表达的AC亚型酶，深入揭示COPD发病机理与T细胞亚群及AC亚型酶的关系。研究体外体内实验证明ISOF通过调控COPD中T细胞亚群及其功能，调控Th17/Treg细胞平衡及其促炎、抗炎细胞因子分泌，特别是通过Th17/IL-17途径，抑制Th17细胞分泌IL-17，从而拮抗COPD中慢性炎症反应的分子机制。ISOF调节COPD中T细胞功能与其激动T细胞上AC7等亚型酶及其下游信号通路cAMP/mTOR有关。通过本项目研究，为临床COPD防治提供新的干预靶点和干预方法。为基于AC亚型酶靶点，通过Th17-IL-17途径及cAMP/mTOR信号通路，从AC激动剂中研发新型抗COPD新药，提供技术方法及研究基础。本项目已经超出预期指标完成研究目标，正式发表论文共11篇，其中SCI 收录期刊论文5篇，中科院一区、TOP及JCRQ1期刊论文共5篇，北大中文核心期刊3篇。申请发明专利6项。获云南省科技进步一等奖等奖励2项。项目组成员入选云南省“青年千人”计划等3人，新获相关项目6项；培养博士后出站1名，博士研究生2名，硕士研究生5名。