CD147/miR-302/IL-6信号通路调控香烟烟雾诱导的气道炎症在慢性阻塞性肺疾病中的作用和机制研究

Airway inflammation plays a key role in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, the underlying mechanisms have not been fully elucidated. In our previous studies, we found persistent cigarette smoke exposure led to airway inflammation of mice, which was accompanied by increasing expressions of CD147, IL-6 and other chemokines. On the other hand, cigarette smoke extract(CSE) promoted the expressions of IL-6 and downstream chemokines in HBE, a strain of normal airway epithelial cell line, which could be inhibited by knocking down CD147. Furthermore, down-regulated expressions of miR-302 family members were also observed in HBE treated by CSE, with the help of miRNA chips. This phenomenon was confirmed in another cell line, Beas2b, and animal model. By comparing database, we found both CD147 and IL-6 were the targets of miR-302 family members. Based on these, we put forward our hypothesis that CD147 promoted IL-6 expression by competitively binding to miR-302 family members, which activated downstream signaling pathways and ultimately induced airway inflammatory reaction. In order to testify our hypothesis, we plan to establish animal and cell model, and modify miR-302 expression level via miR-302 mimics/inhibitors. We aim to determine the role of miR-302 family members in airway inflammation induced by cigarette smoke and related mechanisms involved in regulating CD147-IL-6 signaling pathway. Our research will contribute to further understanding of COPD pathogenesis and provide novel pharmacological targets for prevention and therapy of this disease.

气道炎症是慢性阻塞性肺疾病（COPD）发生发展的核心环节，目前其机制仍未完全阐明。我们前期的研究表明：1. miRNA芯片高通量检测结果提示气道上皮细胞HBE经香烟烟雾提取物（CSE）干预后，miR-302家族成员的表达水平下降，Beas2B细胞和小鼠模型中有类似结果。2.体内外研究提示香烟烟雾诱导IL-6以及下游趋化因子的表达，CD147可促进炎症反应。经比对数据库，CD147，IL-6均含miR-302家族成员的作用靶点。据此我们推测，CD147通过竞争性结合miR-302家族成员，促进IL-6的表达，激活下游信号通路，引发气道炎症反应。为验证上述假设，我们拟利用动物模型以及细胞转染的方法，从体内外两方面研究miR-302家族成员在香烟烟雾诱导气道炎症反应中的作用以及相关机制。我们的研究有助于深化对COPD发病机制的认识，并为该病的防治提供新的药物靶点。

慢性阻塞性肺疾病（COPD）是一种常见的慢性呼吸道疾病。持续的气道炎症是COPD患者症状难以控制，肺功能下降的重要原因，然而其机制尚未完全阐明。我们此前的研究发现使用香烟烟雾暴露模拟COPD的动物模型中CD147的表达水平明显升高。因此，在本项目中，我们进一步研究CD147在香烟烟雾诱导的气道炎症中的作用以及相关机制。利用CD147基因杂合敲除（CD147+/-）动物，通过小干扰RNA（siRNA）敲减气道上皮细胞系中CD147水平，证实了CD147促进了香烟烟雾诱导的气道炎症反应。这一过程部分依赖于自噬信号通路。通过检测体内外模型中miR-302家族成员的表达水平，发现香烟烟雾暴露可使多个miR-302家族成员的表达水平下降。为进一步明确miR-302在此过程中的作用，课题组将miR-302模拟物（miR-302 mimic）转染进入气道上皮细胞，再经CSE干预后，炎症因子的表达与分泌水平有明显下降，提示miR-302家族成员抑制香烟烟雾诱导的气道炎症。在敲减CD147的同时，将miR-302抑制物（miR-302 inhibitor）转染进入气道上皮细胞，再经CSE干预后，炎症因子的表达与分泌水平较单纯敲减CD147时有所升高，提示CD147促进了香烟烟雾诱导的气道炎症反应过程中依赖于miR-302家族成员的作用。综上所述，我们的研究首次揭示了CD147在香烟烟雾诱导的气道炎症反应中的作用，并探索了相关的机制。我们的研究有助于深化对COPD发病机制的认识，为开发新的药物靶点提供依据。