Kv1.3通道阻滞剂PAP-1通过抑制CD4+CD28nullT细胞活性治疗COPD的机制探讨

项目名称： Kv1.3通道阻滞剂PAP-1通过抑制CD4+CD28nullT细胞活性治疗COPD的机制探讨

项目编号： No.81500032

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 余维巍

作者单位： 华中科技大学

项目金额： 18万元

中文摘要： 吸烟是COPD最主要的致病因素，通过诱发慢性炎症反应导致气道阻塞，目前仍缺乏相关治疗手段。已知CD4+CD28nullT细胞能产生大量致炎物质如IFN-γ、TNF-α，还能诱导穿孔素、颗粒酶B的产生，具有明显的致炎及细胞杀伤效应。本团队发现：中重度COPD患者血液中这种T细胞增多，强烈提示该细胞可能在COPD发病中起作用。激活的这种T细胞高表达Kv1.3通道，而Kv1.3通道阻滞剂PAP-1能有效抑制该细胞的活性。气道上皮细胞是维持肺组织免疫稳态的细胞，COPD病程发展与其密切相关。本项目拟将气道上皮细胞与CD4+CD28null T细胞共培养，分析该T细胞对气道上皮细胞的细胞毒性、炎症反应、细胞间紧密连接等的影响，确认该T细胞在COPD病程中的作用。同时，通过香烟烟雾制备大鼠COPD模型，通过体内及体外实验证实PAP-1对气道上皮细胞的保护作用，为COPD提供新的治疗策略。

中文关键词： 慢性阻塞性肺疾病；CD4+CD28null；T细胞；Kv1.3钾通道阻滞剂PAP-1；人气道上皮细胞；香烟烟雾

英文摘要： The primary cause of chronic obstructive pulmonary disease (COPD) is tobacco smoke, which causes irreversible airway obstruction by inducing chronic inflammation; targeted treatment is currently still lacking. Substantial evidence has shown that CD4+CD28null T cells produce large amounts of inflammatory cytokines such as IFN-γ and TNF-α, and lytic granules such as perforin and granzymes, demonstrating strong inflammatory and cytotoxic effects. Our group has observed increased number of CD4+CD28null T cells in COPD patients, implicating a possible role in the pathogenesis of COPD. Our preliminary data showed that activated CD4+CD28null T cells express high levels of Kv1.3 potassium channels, and the Kv1.3 potassium channel blocker PAP-1 efficiently inhibits the activities of CD4+CD28null T cells. In this study, we will evaluate the impact of CD4+CD28null T cells on human airway epithelial cells (HAECs) using a coculture microsystem. The effects of CD4+CD28null T cells on the cytotoxicity, inflammation, and tight junction of HAEC will be analyzed to elucidate the role of CD4+CD28null T cells during the disease progression of COPD. Moreover, a rat COPD model will be established by exposing the animals to tobacco smoke. Using both in vitro and in vivo experiments, the protective effect of PAP-1 on preventing inflammation of airway epithelial cells will be validated, in order to provide the theoretical basis for using PAP-1 as a new treatment against COPD.

英文关键词： Chronic obstructive pulmonary disease (COPD);CD4+CD28null T cells;Kv1.3 potassium channel blocker PAP-1;Human Airway Epithelial Cells (HAECs);Cigarette Smoke (CS)