支气管扩张患者肺衰老加速的机制与干预靶点

Airway infection, inflammation and structural damage are implicated in bronchiectasis pathogenesis, but the mechanisms responsible for pulmonary ageing remain unclear. More significant ageing of airway epithelial cells has been observed in bronchiectasis. However, it is unknown whether the expression levels of ageing-related biomarkers (i.e. telomere length, Sirtuin) of peripheral white blood cells and epithelial cells correlate with bronchiectasis severity. On the basis of our previous work, we hypothesized that the magnitude of pulmonary ageing correlated with airway inflammation, infection and disease severity in bronchiectasis. In this study, we will seek to compare the expression levels of ageing-related biomarkers between bronchiectasis patients and healthy subjects, determine the correlation between ageing-related biomarker expressions and airway inflammation, sputum bacteriology, oxidative stress and bronchiectasis severity. We will also compare the dynamic changes in ageing-related biomarker expression during clinical stability and exacerbations. The location and level of ageing-related biomarker expression within the airway epithelium will be examined. We will also determine the changes in ageing-related biomarker expression following exposure to infection, inflammation, oxidative stress and anti-oxidative stress treatment (i.e. inhaled hydrogen) or antiageing treatment (i.e. resveratol treatment), thereby addressing the key scientific issue of whether ageing-related biomarkers can serve as the biomarker for assessment of bronchiectasis. This is expected to offer novel therapeutic targets for future management of airway infection and destruction in bronchiectasis.

气道感染、炎症、结构破坏贯穿支气管扩张（支扩）的发病，但肺衰老与支扩发病的相关性仍未明确。有研究表明支扩患者气道上皮细胞衰老较正常人显著，但支扩外周血白细胞与气道上皮细胞中反映衰老的生物标记物（如端粒长度、去乙酰化酶等）水平是否与支扩严重程度相关？在本课题组的前期研究积累基础上，申请人假设：支扩患者的肺衰老程度与气道炎症、感染、支扩严重性相关。本研究拟比较支扩患者与正常人外周血白细胞衰老标记物表达；探讨其与气道炎症、细菌谱、氧化应激及支扩严重程度等指标的相关性；对比稳定期、急性加重外周血白细胞衰老标记物表达水平的改变；探讨气道上皮衰老标记物表达的部位及水平，通过体外实验研究感染、炎症、氧化应激对衰老标记物表达的影响，探讨抗氧化（如吸入氢气）、抗衰老治疗（如白藜芦醇）后气道上皮衰老标记物表达的水平，明确衰老标记物是否为支扩的生物标记物，为干预气道感染和破坏提供新的切入点。

支气管扩张症（支扩症）较为公认的发病机制为“恶性循环”学说，即气道感染、慢性炎症和气道树的结构破坏相互促进。尽管已有研究证实慢性气道疾病的肺衰老加速，但肺衰老与支扩发病的相关性仍未明确。. 本研究纳入支扩患者与正常人，收集外周血PBMC，探讨衰老标记物在支扩外周血单个核细胞中的表达水平，及其与支扩严重程度、急性加重和临床性指标的关系。研究采集了支扩患者与对照组患者不同解剖部位（大/中气道、小气道）的支气管粘膜，通过免疫组化方法的细胞染色阳性率以评估衰老标记物表达水平，探讨衰老标记物在肺组织的表达情况以及在大/中气道和小气道间是否存在表达差异；并通过模拟病原体感染气道上皮，建立体外细胞培养模型，观察炎症、感染、对气道上皮衰老标记物表达的影响。. 该研究核心发现：1）支扩患者外周血衰老标记物表达水平异常且与支扩严重程度相关；但基线期衰老标记物的表达水平不能预测随访1年期间支扩急性加重的风险；2）支扩气道上皮的衰老标记物sirtuin1表达下降，且其与p16和p21在大/中气道和小气道间表达无显著差异；3）通过模拟病原体感染气道上皮，建立诱导气道上皮细胞衰老加速的体外模型，发现了气道感染、炎症反应均引起气道上皮的衰老标志物表达异常。. 支扩外周血存在衰老标记物表达水平异常且与支扩严重程度相关，支扩气道上皮的衰老标记物sirtuin1表达下降，将可能作为传统“恶性循环” 学说的重要补充，为今后进行疾病干预提供新思路；体外模型实验初步展现了支扩患者气道上皮衰老加速的现象和潜在机制，未来可进一步探讨体外应用抗衰老药物能否缓解支扩患者肺衰老及相关的靶点机制，为临床药物开发提供新的思路。