LncRNA-CCAT1/miR-152通过ERK信号通路介导COPD气道炎症的作用机制研究

Airway inflammation plays a central role in the pathogenesis and progression of COPD. Long non-coding RNA (lncRNA) is important in regulating inflammation. We have recently found that the level of lncRNA-CCAT1 was obviously increased in the lung tissue of subjects with COPD and was closely related to pulmonary inflammation. The bioinformatics software demonstrated that CCAT1 directly target miR-152. Downregulation and upregulation of CCAT1 confirmed that CCAT1 is inversely correlated with the expression of miR-152. Moreover, miR-152 has been proved to negatively regulate extracellular signal-regulated kinase (ERK) signaling pathway. ERK signaling pathway was demonstrated to be important in inflammatory response in airway epithelium. Therefore, we build hypothesis that smoking-induced upregulation of CCAT1 can activate ERK signaling pathway by inhibiting miR-152, which may participate in the airway inflammation of COPD. In the present study, we will detect the role of CCAT1 in airway inflammation and elucidate the detailed mechanism of CCAT1 in regulating ERK signaling pathway by targeting miR-152. This study will contribute to further understanding the pathogenesis of airway inflammation in COPD.

气道炎症是慢性阻塞性肺疾病（COPD）发病及进展的核心机制。长链非编码RNA（lncRNA）在机体炎症调控中发挥重要作用。我们前期研究发现lncRNA-CCAT1在COPD患者肺组织中显著升高，与肺部炎症水平呈正相关。通过生物信息学软件及文献检索发现CCAT1可负向调控miR-152。miR-152能抑制ERK信号通路的表达及活化，而后者在COPD气道炎症调控中起重要作用。据此，我们提出假说：吸烟引起支气管上皮细胞中的CCAT1异常升高，通过靶向抑制miR-152的表达激活ERK信号通路，进而参与COPD的气道炎症。本课题拟从人体肺组织、细胞以及动物水平等多层次明确CCAT1在COPD气道炎症中的作用；探讨CCAT1通过miR-152调节ERK信号通路，最终影响气道炎症反应的具体机制。本研究将从lncRNA这个新视点探讨COPD气道炎症的发生机制，为COPD的防治提供新思路。

慢性气道炎症是慢性阻塞性肺疾病（Chronic obstructive pulmonary disease，COPD，又称慢阻肺）发病的核心机制之一，长链非编码RNA（Long non-coding RNA，lncRNAs）在炎症调控中扮演着重要角色。本课题通过慢阻肺患者、动物模型和细胞三个层面对lncRNA CCAT1在慢阻肺气道炎症中的作用及其调控机制进行了研究。结果显示CCAT1 在COPD患者肺组织中高表达，同时miR-152-3p水平下调，而ERK信号通路激活，伴随炎症基因的转录表达升高。进一步的体外研究显示香烟提取物（Cigarette smoke extract，CSE）能够显著促进CCAT1在气道上皮细胞中的表达，而CCAT1表达上调能通过抑制miR-152-3p的表达，促进ERK信号通路的激活，进而促进气道上皮细胞炎症因子的表达和释放。在香烟烟雾暴露诱导的肺气肿小鼠模型中，敲低CCAT1能上调miR-152-3p的表达，并抑制ERK信号通路，进而抑制气道炎症，从而减轻小鼠肺气肿改变并改善小鼠肺功能。本研究证实吸烟引起的CCAT1异常升高，通过靶向抑制miR-152-3p的表达，进而促进ERK信号通路的表达及活化，最终诱导气道上皮细胞分泌炎症因子，参与COPD的发病机制。这为COPD发生发展的研究奠定了新的理论基础，同时也为疾病的治疗提供了新思路及发展新方向。

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