miR-29b在病毒感染促进COPD炎症和重构中的作用及机制研究

Cigarette smoke-induced inflammation and remodeling in the lung is the pathological base of progressive air-flow limitation in chronic obstructive pulmonary disease (COPD). Virus-induced exacerbations are the major cause of accelerated disease progression. Previous studies have suggested that viruses and smoke can interact in the lung to promote the inflammation and remodeling in COPD, however the exact mechanisms are not clear. Recent studies have suggested that microRNA-29b (miR-29b) can regulate the expression of interferon-γ, pro-apoptotic factors and collagen. One recent study also showed that miR-29b was decreased in the lung of COPD patients. However, its role in COPD is unclear. Our studies found that viruses and smoke synergistically inhibited miR-29b in the mouse lung. We speculate that miR-29b may play an important role in the pathogenesis of exaggerated inflammation and remodeling induced by viral infections in COPD. In the present proposal, we are going to study the association between miR-29b and COPD by detecting its expression in clinical samples, and the role of miR-29b in the pathogenesis of virus-exacerbated inflammation and remodeling in COPD by using animal and cellular models. The results of this study could help to clarify the molecular mechanisms of accelerated disease progression caused by viral infections in COPD and may provide a new molecular target for treating this disease.

香烟烟雾所致的肺部炎症和重构是COPD气流受限的病理学基础，病毒诱发的急性加重是导致疾病加速进展的重要因素，先前的研究提示病毒与烟雾可在肺部相互作用促进COPD炎症和重构，但其分子机制尚待阐明。微小RNA-29b（miR-29b）能调节γ-干扰素、促凋亡因子和胶原的表达，且最近有文献报道其在COPD患者肺部的表达显著降低，但作用并不清楚，我们发现病毒与烟雾可协同抑制miR-29b在小鼠肺组织中的表达，推测其可能在病毒感染促进COPD炎症和重构中起重要作用。本课题将通过对患者临床标本中miR-29b的检测来研究其与疾病临床特征的相关性，同时结合我们前期的工作基础，用COPD病毒感染模型、细胞共培养及转基因小鼠模型来研究miR-29b在病毒与烟雾相互作用促进COPD炎症和重构中的作用及其相关机制，将有助于阐明病毒感染导致疾病加速进展的分子机制，并有可能为COPD治疗提供新的分子靶点。

慢性阻塞性肺疾病（慢阻肺）是一种常见的慢性气道炎症性疾病，其发病机制尚未完全阐明，临床治疗效果有限。文献提示微小RNA参与炎症的调节，于是我们研究了微小RNA-29b（miR-29b）在慢阻肺气道炎症中的作用。我们检测了慢阻肺患者肺组织和血浆中的miR-29b表达水平。通过预测软件发现miR-29b的一个重要靶基因为BRD4（转录调节因子），于是我们又检测了肺组织中BRD4的表达水平，以及炎症细胞因子白介素-6和白介素-8的表达水平。我们总共收集了不吸烟不患慢阻肺者10例，吸烟不患慢阻肺者24例，吸烟患慢阻肺者26例。通过检测发现无论是肺组织还是外周血血浆，miR-29b的表达水平在慢阻肺患者中都是显著低于吸烟者和非吸烟者的，相关性分析发现miR-29b的表达水平与慢阻肺患者的肺功能以及炎症细胞因子表达水平具有显著相关性。肺组织中BRD4的表达水平在慢阻肺患者中都是显著高于吸烟者和非吸烟者的，相关性分析发现其与miR-29b以及白介素-8具有显著相关性。体外细胞实验研究发现miR-29b可以通过靶向BRD4调节烟雾提取物诱导的白介素-8表达。抗氧化剂乙酰半胱氨酸可以预防烟雾提取物诱导的miR-29b的下降和BRD4以及白介素-8表达的升高。这些研究结果提示miR-29b可能通过靶向BRD4来调节炎症细胞因子的表达从而参与慢阻肺气道炎症过程，而氧化应激可能是烟雾暴露导致miR-29b下降的机制之一。上述研究结果可为寻找慢阻肺新的治疗靶点提供实验线索。