我们前期发现，大气污染物NO2与慢性阻塞性肺疾病急性加重（AECOPD）密切相关（申请人等. ESPR, 2014; 2016）；NO2暴露能导致大鼠肺气肿，但致病机理不清。本项目拟对NO2致肺气肿的分子机制进行深入研究。基质金属蛋白酶（MMPs）及其内源性抑制剂（TIMPs）是调节细胞外基质降解合成、维持其内环境稳态的关键酶类；是影响肺气肿发生发展的重要分子。本项目围绕NO2是否通过对MMPs/TIMPs表达和功能的影响而促进了肺气肿的发生发展，拟做以下研究：1）建立NO2致肺气肿模型（我们预实验已初步建成）；2）NO2对MMPs/TIMPs表达的调控作用；3）甲基化修饰对MMPs/TIMPs表达的影响；4）甲基化修饰药物对肺气肿病情发展的抑制作用。原代培养大鼠及人肺泡上皮细胞和肺成纤维细胞进一步验证上述理论，本研究有助于揭示NO2致肺气肿的分子机制，为大气污染物防治提供新的干预靶点。

In our previous study, we identified that NO2 played a pivotal role in acute exacerbation of chronic obstructive pulmonary disease (AECOPD), but the exact mechanism remained unsolved (Zili Zhang, et al. ESPR, 2014; 2016). Matrix metalloproteinase (MMPs) and Tissue inhibitors of metalloproteinase (TIMPs) are the two major enzymes of controlling extra cellular matrix degradation-synthesis, maintaining the stability of the internal environment, as well affecting the development of Emphysema. We planned to perform following experiments to uncover the mechanism of MMPs/TIMPs in NO2-induced Emphysema: 1) to build the NO2-induced Emphysema mice model (it has been partly finished); 2) to study the expression of MMPs/TIMPs in NO2-induced Emphysema; 3) the methylation mechanism of MMPs/TIMPs in NO2-induced Emphysema; 4) the improvement effects of methylation reversal drugs (5-AZA) on the development of Emphysema. Then cell models were also conducted to verify the above hypothesis. The present project will deepen the understanding of the pathogenesis of Emphysema and find new control targets, as also to provide theoretical basis in this field.