组蛋白去乙酰化酶2在香烟烟雾诱导骨骼肌细胞衰老中的作用及机制

Oxidative stress caused by cigarette smoking not only leads to the lung inflammation of chronic obstructive pulmonary disease (COPD) but also results in multi-system damage. Skeletal muscle dysfunction(SMD) is the most important extrapulmonary manifestation of COPD and seriously affects the patient's quality of life and prognosis. Our previous experiments have showed that cigarette smoke exposure (CSE) can induce premature senescence in murine skeletal muscle cells and this effect may be related to the reduction of histone deacetylase-2 (HDAC2) by oxidative stress. Accordingly, we propose the hypothesis that CSE can induce a reduction in HDAC2 causing senescence of skeletal muscle cells and skeletal muscle dysfunction. Based on preliminary work, this study will further investigate the effect and the mechanism of HDAC2 on CSE-induced the senescence of skeletal muscle cells. In cell culture and animal model, we will regulate the expression of HDAC2 and observe the effects on cellular senescence and the function of the senescent skeletal muscle cells induced by CSE. This study will contribute to a further understanding of the mechanism of skeletal muscle dysfunction in COPD and provide new ideas for the treatment of COPD. It has certain innovation and feasibility.

吸烟所致氧化应激不仅导致慢性阻塞性肺疾病（chronic obstructive pulmonary disease，COPD）肺部炎症而且引发全身多系统损害。骨骼肌功能异常是COPD最主要的肺外表现之一，严重影响患者的生活质量和预后。我们前期研究发现香烟烟雾暴露可诱导小鼠骨骼肌细胞出现过早衰老，这一作用可能与氧化应激降低HDAC2有关，据此提出香烟烟雾暴露可以诱导HDAC2降低致细胞衰老同时伴有骨骼肌功能障碍的假设。我们拟以骨骼肌细胞为研究对象，以香烟烟雾暴露下HDAC2诱导骨骼肌衰老机制为着眼点，在细胞实验和动物实验上观察干预HDAC2对香烟烟雾诱导的骨骼肌细胞衰老和骨骼肌细胞功能的影响，进一步探讨HDAC2在香烟烟雾诱导骨骼肌细胞衰老中的作用及机制。研究的开展将进一步认识COPD骨骼肌功能异常的机制，为COPD治疗提供新思路。本课题是我们前期工作的继续，具有一定可行性和创新性。

吸烟所致氧化应激不仅导致慢性阻塞性肺疾病（chronic obstructive pulmonary disease，COPD）肺部炎症而且引发全身多系统损害。骨骼肌功能异常是COPD最主要的肺外表现之一，严重影响患者的生活质量和预后。本课题在前期研究的基础上，以骨骼肌细胞为研究对象，应用慢病毒和siRNA载体干预HDAC2和NF-κB的表达，同时观察香烟烟雾暴露下骨骼肌细胞衰老和功能的变化和白藜芦醇对改善骨骼肌细胞衰老的治疗作用。我们发现在香烟烟雾暴露下，HDAC2通过NF-κB途径介导肺气肿小鼠中骨骼肌细胞的衰老和萎缩，白藜芦醇通过上调HDAC2改善骨骼肌细胞衰老。我们的研究对于阐明吸烟导致COPD骨骼肌功能异常的机制，并进一步探讨COPD骨骼肌功能障碍的治疗提供新思路。