肺气肿是慢性阻塞性肺疾病（COPD）的主要病理改变，其特征为细胞外基质（ECM）丢失，一旦形成目前无法逆转。健全的成纤维细胞损伤修复功能在维持完整肺泡结构中起着关键作用。课题组前期研究提示COPD患者肺成纤维细胞增殖能力减弱、弹性蛋白沉积减少，并且ECM成分VCAN能阻碍弹性蛋白沉积。进一步在小鼠COPD肺泡组织成纤维细胞基因芯片检测发现凋亡可能是肺气肿部位细胞修复功能障碍的原因，而生物信息学分析筛选到p53和肺气肿发生及弹性蛋白表达有关。由此推测p53依赖的成纤维细胞凋亡在肺气肿ECM丢失的反馈循环中起着重要作用。本项目拟在完善人体、动物、细胞三个层面的肺气肿-肺泡成纤维细胞-ECM研究平台的基础上：①阐明凋亡是否参与了烟草烟雾/细颗粒物所致的成纤维细胞修复功能障碍，明确p53在其中的作用，寻找潜在干预措施；②明确异常ECM对成纤维细胞生物学行为的影响，丰富对ECM功能的了解。

Emphysema is the main pathological manifestation of chronic obstructive pulmonary disease (COPD), characterized by the loss of extracellular matrix (ECM), which cannot be reversed once formed. The coordinated injury repair capacity of fibroblast plays a key role in maintaining intact alveolar structures. Our previous studies suggested that the proliferation of lung fibroblasts and the elastin deposition were reduced in pulmonary fibroblasts isolated from COPD patients; and and VCAN, a major ECM component, can impede elastin deposit. We then isolated and cultured the fibroblasts from alveolar tissue, which is more consistent of emphysema phenotype as contrasted to airway fibroblasts. Gene chip analysis indicated that the primary fibroblasts from mouse COPD alveolar might have apoptosis, which may be an important cause of cell repair dysfunction in emphysema. Candide genes for the development of emphysema was also screened using bioinformatics analysis, and p53 might be involved in the genesis of emphysema and is associated with elastin expression. Therefore, we speculated that p53-dependent apoptosis of alveolar fibroblasts plays an important role in the ECM deficiency of emphysema, and ECM in turn would affect the repair capacity. This project aims to verify this hypothesis at three levels of human, animal and cell. Firstly, we will investigate whether apoptosis is involved in the injury repair dysfunction of fibroblasts caused by tobacco smoke/fine particles. Then, the role of p53 in it is to be studied and potential interventional reagents are to be tested. Finally, the impact of abnormal ECM microenvironment on the biological behavior of fibroblasts is to be studied, which will enrich the understanding of ECM function.