基于caveolin-1-p38MAPK信号通路研究调补肺肾法改善体外诱导COPD气管支气管软化症机制

Tracheobronchomalacia is a dynamic airway stenosis caused by airway cartilage degeneration, necrosis, and loss of support of the wall. Chronic obstructive pulmonary disease is one of the main causes resulting in tracheobronchomalacia. Our pre-experiment showed that the method of regulating and tonifying lung and kidney is clinically effective, and it can reduce chondrocyte degeneration by down-regulate caveolin-1, p-p38MAPK and MMP3 levels. Numerous studies have shown that caveolin-1-p38MAPK signaling pathway plays a key role in the pathogenesis of osteoarthritis chondrocytes. So we put forward the hypothesis: The method of regulating and tonifying lung and kidney can treat tracheobronchomalacia by blocking Caveolin -1-p38MAPK signaling pathway overactivation..In this study, we adopting the trachea or bronchial cartilage of the chronic obstructive pulmonary disease model in rats to establish chondrocyte system in vitro culture, and we used IL-1β to induce degeneration. In order to explore the targets and mechanism of the method of regulating and tonifying lung and kidney to protect tracheal cartilage, research methods like pathology, serum pharmacology and molecular biology were also used, and we observing the key protein and gene changes of caveolin-1-p38MAPK signaling pathway and their effects. This research will enrich the theoretical connotation and governance of the kidney being in charge of bone.

CODD所致气管支气管软化症是一种因气道软骨变性、坏死，管壁失去支撑所致的动态性气道狭窄。前期研究显示调补肺肾法临床确有疗效，该法能够下调该caveolin-1、p38MAPK和MMP3表达，改善气道软骨细胞退变。既往研究已证实caveolin-1-p38MAPK信号通路激活在骨关节炎等软骨细胞的退变中具有关键作用，因此我们提出假说：调补肺肾法能够阻断caveolin-1-p38MAPK信号通路治疗COPD气管支气管软化症。本研究通过建立COPD大鼠模型，构建体外培养的气道软骨细胞体系，并采用IL-1β进行诱导退变，运用病理学、血清药理学、分子生物学等方法，通过观察caveolin-1-p38MAPK信号通路关键蛋白和基因变化及其效应关联，揭示调补肺肾法保护气道软骨退变的机制；从“补肾生骨”角度研究调补肺肾法治疗COPD合并气管支气管，丰富了中医“肾主骨”的理论内涵及治则治法体系。

CODD相关性气管支气管软化症是一种因气道软骨变性、坏死，管壁失去支撑所致的动态性气道狭窄。目前，本病缺乏有效治疗方法。前期研究证实调补肺肾方临床确有疗效，能改善慢阻肺相关性气管支气管软化症患者肺功能及生活质量。前期基础研究显示调补肺肾方能够下调caveolin-1、p38MAPK和MMP3表达，改善气道软骨细胞退变。本研究通过建立COPD相关性TBM大鼠模型，并基于caveolin-1-p38MAPK信号通路来揭示调补肺肾方保护气道软骨退变的机制；本研究显示调补肺肾方含药血清可提高大鼠COPD相关性TBM细胞模型软骨细胞的蛋白聚糖、II型胶原含量和细胞活性，同时减少软骨细胞凋亡。其作用可能与该方抑制caveolin-1-p38MAPK信号通路中关键信号分子caveolin-1、p-p38MAPK的表达，降低下游效应产物MMP-13、1L-1β、TNF-α的表达水平；同时抑制凋亡基因Bax的表达水平，提高Bcl-2和miR-140-5p基因的表达水平等机制有关。本研究首次提出了慢阻肺相关性气管支气管软化症疾病模型制备方法，为进一步研究该病的发病机制提高了方法学支撑，同时本研究首次系统阐释了调补肺肾方治疗COPD相关性气管支气管软化症的作用机制，为中医药治疗COPD及其相关性气道软化疾病提供了科学基础，提升了中医药治疗水平，进一步丰富了中医“肾主骨”的理论内涵及治则治法体系；此外，对于降低慢阻肺疾病社会经济负担将具有重要意义。