基于粘液分泌机制探讨清肺化痰汤治疗COPD研究

How to solve the COPD repeated attack is a worldwide problem, and airway mucus hypersecretion is one of the important pathological features. Preliminary experimental results show that: ①mucus hypersecretion, goblet cell hyperplasia and decline in lung function were found in COPD rats model; ②the expression of CFTR was reduce in COPD ;③the expression of MUC5AC mRNA was significantly increased in COPD; ④ Qingfei Huatan decoction can reduce MUC5AC and increase the level of CFTR in COPD. Reported that MUC5AC and CFTR are closely related with airway mucus hypersecretion. We speculate that Qingfei Huatan decoction can affect CFTR expression, effect of goblet cell hyperplasia and differentiation and the expression of MUC5AC on airway mucus hypersecretion. In order to prove the above conjecture, plans through 1) to establish COPD animal model of mucus hypersecretion, We observed that Qingfei Huatan decoction affect the expression of MUC5AC, CFTR and quantityof goblet cells in COPD; 2) With the method of serum pharmacology to test Qingfei Huatan decoction effect of MUC5AC and CFTR on the expression regulation in airway epithelial cells; 3 ) Qingfei Huatan decoction on Clara to goblet cell metaplasia effect. The research results will provide foundation for the clinical treatment of COPD.

COPD的反复发作是治疗难题，而气道黏液高分泌是其重要的病理特征之一。清肺化痰汤是临床治疗COPD的有效方。前期实验结果显示①COPD大鼠模型出现粘液高分泌、杯状细胞增生和肺功能下降；②COPD中CFTR表达降低；③COPD中MUC5AC mRNA明显升高；④清肺化痰汤能降低COPD中MUC5AC和升高CFTR的水平。文献报道CFTR和MUC5AC与气道粘液高分泌密切相关。我们推测清肺化痰汤通过影响CFTR的表达，影响杯状细胞的增生和分化及影响MUC5AC的表达来治疗COPD。为了证明上述推测，拟通过1)建立COPD粘液高分泌动物模型，观察清肺化痰汤对COPD中CFTR的表达、杯状细胞的数量以及MUC5AC的表达影响；2）血清药理学方法检测清肺化痰汤对气道上皮细胞株中CFTR和MUC5AC的表达调控；3）清肺化痰汤对Clara向杯状细胞化生的影响。研究结果将为清肺化痰汤的临床治疗提供依据。

COPD的反复发作是治疗难题，而气道黏液高分泌是其重要的病理特征之一。清肺化痰汤是临床治疗COPD的有效方。我们拟通过1)建立COPD粘液高分泌动物模型，观察清肺化痰汤对COPD中CFTR的表达、杯状细胞的数量以及MUC5AC的表达影响；2）血清药理学方法检测清肺化痰汤对气道上皮细胞株中CFTR和MUC5AC的表达调控；3）清肺化痰汤对Clara向杯状细胞化生的影响。研究结果发现清肺化痰汤对COPD大鼠肺功能有明显改善作用，对肺部的病变有明显的治疗作用，减少粘液增生。其原因为减少MUC5AC的表达，减少TNF-α、IL-1β和NF-κB的表达，其机制可能与抑制EGFR信号通路有关。随后进一步发现清肺化痰汤可上调COPD模型肺组织中CFTR的表达、增加CFTR Cl-电流，其机制可能是通过抑制JAK/STAT通路来上调CFTR的表达。最后，我们发现清肺化痰汤可上调CCSP表达，下调MUC5AC表达，阻止了Clara细胞向杯状细胞的转化，改善了肺功能和肺病理改变，其机制可能与清肺化痰汤抑制Notch信号通路有关。本课题以粘液高分泌为研究对象，通过干预粘液高分泌来治疗COPD，为临床上COPD的治疗提供新的思路。本研究结果将为清肺化痰汤的临床治疗提供依据。