慢阻肺是一种常见老年性疾病，但衰老本身在该疾病形成中作用尚不明确。项目组前期首先报道，支气管上皮细胞Klotho是抑制慢阻肺形成的重要蛋白，Klotho敲降后，细胞对香烟提取物和H2O2等刺激造成的损伤和炎症反应更明显。近期发现，衰老小鼠肺组织细胞周期蛋白 BMI1和支气管上皮细胞Klotho表达均明显下降，且衰老和BMI1基因敲除小鼠均更易形成慢阻肺；BMI1可能通过p16Ink4a，调控Klotho表达。我们进一步提出假说：随机体衰老，支气管上皮细胞BMI1表达下降，通过上述通路，使细胞对吸烟等外界损伤因素更加敏感，促进慢阻肺形成。本研究拟从人体、小鼠及体外原代细胞培养等层面，进一步研究机体衰老时，支气管上皮细胞BMI1表达及其对细胞功能影响（包括屏障功能、增殖分化、炎症等），探讨其在疾病形成中作用。本项目实施将有助于阐明衰老这一重要个体因素对慢阻肺形成的影响，并了解其中可能机制。

Chronic obstructive pulmonary disease(COPD) is a common disease related to aging. However, it is still not clear on the role of aging in COPD formation. We previously showed that Klotho expression in bronchial epithelial cells(BEC) is critically inhibited in COPD formation and further demonstrated the increased response of injury and inflammation by the cells due to cigarette smoke extracts(CSE) and hydrogen peroxide stimulation. Now we have further shown the reduced BECs expression of Klotho and BMI1 in lung tissues from senile mice which are more susceptible to COPD as well as BMI1 knockout mice. BMI1 might regulate the expression of Klotho through p16Ink4a. Therefore, we made the hypothesis that, during aging process, through the pathway, the reduced expression of BMI1 makes BECs be more susceptible to the risk factors, including cigarette smoking, which might contribute to COPD formation. In this study, human lung tissue, mice and primary cell culture will be employed to investigate the effect of reduced BMI1 expression on the cell function related to COPD, including the barrier, proliferation, differentiation and inflammation. This study would further demonstrate the role of aging, the important host factor, on COPD formation, as well as the underlying mechanism.