急性加重是导致慢性阻塞性肺疾病（慢阻肺）患者死亡、加速疾病进展的重要事件，部分患者倾向出现频繁急性加重，但机制不清楚。肺泡巨噬细胞是机体重要免疫细胞。β2-微球蛋白（β2M）是有核细胞表面主要组织相容性复合物Ⅰ类抗原的轻链亚单位组份。我们前期研究发现并报道了慢阻肺患者血清β2M水平增高，且β2M作为衰老相关蛋白参与了肺气肿的形成。初步数据还显示β2M水平增高可能与频繁急性加重有关。在此，我们假设β2M可能通过作用肺泡巨噬细胞，促其炎症因子高分泌并使细胞衰老、吞噬能力与提呈能力减弱等参与慢阻肺的频繁急性加重。为验证假说，我们利用已建立的慢阻肺队列，首先验证血清β2M与频繁急性加重间的关系；借助分子生物学方法技术探讨β2M调节巨噬细胞功能改变的信号通路及其分子机制；利用小鼠慢性烟雾暴露模型，模拟急性加重，进一步验证上述假说。本项目实施将丰富对慢阻肺急性加重机制的认识，有助于探寻新的治疗靶点。

Exacerbations of chronic obstructive pulmonary disease (COPD) are important events because of inducing death and accelerating progression of the disease. Some COPD patients are particularly susceptible to frequent acute exacerbation, but the mechanism is unclear. Alveolar macrophages are important immune cells in the body against pathogens and foreign substances. β2-microglobulin (β2M) is a small light chain expressed as a subunit of the major histocompatibility complex (MHC) classⅠantigen. We have previously reported that the concentrations of serum β2M were elevated in COPD patients and that β2M might participate in the formation of emphysema as a pro-aging protein. Our recent preliminary data showed that the increased level of β2M was associated with frequent exacerbations of the COPD patients. Herein, we hypothesize that β2M participates in frequent exacerbation of COPD through acting on alveolar macrophages, such as promoting production of proinflammatory cytokines, inducing cell senescence, impairing ability of phagocytosis, antigen-presentation and so on. To address this, we first analyze the relationship between serum β2M and frequent exacerbations based on the established COPD cohort; then explore the potential signalling pathways of the relevant molecules involved in regulation of β2M on alveolar macrophage ex vivo and in vitro; finally further investigate the effects of β2M on frequent exacerbation of COPD using a murine model of chronic exposure to cigarette smoke and stimulated acute exacerbation. We believe that the present study will contribute to enrich understanding of the pathogenesis of COPD subjects with frequent exacerbations, and to benefit innovative treatment of the disease.