香烟烟雾(CS)是常见环境污染物，慢性阻塞性肺病(COPD)是CS重要的危害结果，而肺气肿又是COPD的主要病理特征，已证明巨噬细胞分泌基质金属蛋白酶(MMPs)在CS所致肺气肿中有重要作用，但其分子机制尚不清楚。本项目拟探讨不同浓度香烟烟雾抽提物(CSE)处理原代分离肺泡巨噬细胞(AM)和THP-1细胞，观察MMPs分泌水平及细胞外基质(ECM)分解情况；用circRNA_HIPK3 siRNA和miR-224模拟物处理及挽救实验、MKK6 siRNA和穿心莲内酯等处理细胞实验；CS致小鼠肺气肿实验模型、circRNA_HIPK3 siRNA和穿心莲内酯的干预处理；不同程度吸烟和肺气肿人群队列研究，系统探讨circRNA_HIPK3通过miR-224介导巨噬细胞分泌MMPs在吸烟所致肺气肿中作用及穿心莲内酯的干预效果。以揭示吸烟所致肺气肿的部分分子机制，为寻找早期生物标志提供科学依据。

Cigarette smoke (CS) is one of the common environmental pollutants. The chronic obstructive pulmonary disease (COPD), which pathological feature is emphysema, is the most common and severe disease caused by CS. It has been demonstrated that the matrix metalloproteinases (MMPs) secreted by macrophage plays important roles in CS-induced emphysema, but the molecular mechanism is still unclear. This project is to investigate the roles and interventions of macrophage-secreated MMPs mediated by circRNA_HIPK3 via miR-224 in emphysema induced by cigarette smoking in three levels of cells, animals, and population using the following experiments: Primary alveolar macrophage (AM) and THP-1 cells were treated by different concentrations of cigarette smoking extract (CSE) to observe the secretion level of MMPs and the decomposition of extracellular matrix (ECM). We further investigated the effects of some interventions, such as circRNA_HIPK3 siRNA, MKK6 siRNA, miR-224 mimic, their rescue experiments, and andrographolide, on these cellar experiments. Animal model of mice emphysema induced by CS, which was treated by the interventions of circRNA_HIPK3 siRNA or andrographolide. A population cohort study of different levels smoking and emphysema. Our results will reveal some molecular mechanisms of cigarette smoking-induced emphysema, which will provide scientific basis to find early biomarkers.