咳喘六味合剂抑制A-FABP-JAK1/STAT6通路修复肥胖型哮喘小鼠气道屏障损伤的机制研究

Obesity asthma is a kind of refractory asthma. The effect of Obesity asthma is poorer by conventional treatment and it would be reappeared easier. Adipocyte type fatty acid binding protein (A-FABP) is a key protein which involved in lipid metabolism, and highly expressed in the asthmatic airway epithelial cells. It may cause inflammatory reaction by regulating JAK1/STAT6 to accelerate the progress of obesity asthma. Phlegm-dampness volts lung is a perennial occurrence of asthma in the theory of Traditional Chinese Medicine.Fat man have more Phlegm-dampness.so, Phlegm-dampness was the same pathological factors between asthma and obesity. Kechuan Liuwei mixture was created by Professor Wu Yingen according the theory of" Phlegm disease should be treated by warming drugs”,and it has definite clinical effect in treating asthma.Previous studies showed that can repair the dysfunction of airway epithelial cell. A-FABP-JAK1/STAT6 is a key signal pathway which can induce the occurrence and development of obesity asthma, and the deterioration of airway epithelial dysfunction. Kechuan Liuwei mixture can inhibit the A-FABP-JAK1/STAT6 pathway, repair the damage of airway barrier,and it can cure obesity asthma.This study intends to establish a mouse model of obesity asthma, detecte the expression of A-FABP, JAK1 and STAT6 by molecular biology and other research methods,and explore the mechanism of inhibited A-FABP-JAK1/STAT6 signaling pathway and repaired the damage of airway barrier in obesity asthma by Kechuan Liuwei mixture,and enrich the theoretical connotation of “Phlegm disease should be treated by warming drugs”.It will provide new ideas for prevention and treatment for obesity asthma.

肥胖型哮喘是一种难治性哮喘，在哮喘气道上皮中高表达的脂肪型脂肪酸结合蛋白（A-FABP）是参与脂质代谢的关键蛋白，通过调控JAK1/STAT6引发炎症反应，从而诱发加重哮喘。痰饮伏肺是哮病发生的宿根，且肥人多痰湿，痰饮是肥胖与哮喘的共同病理因素。咳喘六味合剂是吴银根教授据“病痰饮者当以温药和之”理论创制，治以温肾散寒平喘，临床疗效显著，前期研究表明其可修复气道上皮损伤。就此提出假说：A-FABP-JAK1/STAT6是诱发肥胖型哮喘的关键通路，诱导气道屏障损伤，咳喘六味合剂可抑制该通路，修复气道屏障损伤，控制哮喘的发生。本研究拟建立肥胖型哮喘模型，运用细胞和分子生物学等方法检测A-FABP、JAK1、STAT6等的表达，探索咳喘六味合剂抑制A-FABP-JAK1/STAT6通路修复肥胖型哮喘气道屏障损伤的作用机制，丰富和发展“病痰饮者当以温药和之”的理论内涵，为难治性哮喘的防治提供新思路。

支气管哮喘是由多种细胞及其细胞组分参与的气道慢性炎症性疾病。全球约有3.34亿哮喘患者，每年死于哮喘的患者约有25人，我国哮喘的患病率为1%-4%。肥胖被GINA定为哮喘发生和加重的重要宿主因素之一，但其机制仍不明确。.咳喘六味合剂是吴银根教授根据“病痰饮者，当以温药和之”理论，并结合多年临床经验在麻黄附子细辛汤的基础上创立，标本兼顾，寒温并用，宣肃同施。前期研究表明咳喘六味合剂临床有效率达到85.51%，且能有效抑制病毒性哮喘大鼠气道高反应性，促进气道上皮细胞结构和功能的完整性，也证明了这一理论的正确性。.本研究通过建立肥胖型哮喘小鼠模型，采用系统的细胞、分子生物学研究方法，深入研究A-FABP和JAK1/STAT6信号通路调控肥胖型哮喘的机理，并在此基础上研究咳喘六味合剂介导A-FABP- JAK1/STAT6信号途径调控肥胖性哮喘的机制，结合评估气道炎症、气道重构与肥胖程度（Lee’s指数）、Muc5ac、A-FABP表达的关系，揭示肥胖型哮喘之“病痰饮者当以温药和之”的现代生物学内涵，进一步阐释咳喘六味合剂调控肥胖型哮喘这一特殊类型哮喘的机理。.体内研究结果表明咳喘六味合剂对肥胖型哮喘模型小鼠产生了良好的治疗效果，体外研究结果显示，咳喘六味合剂通过A-FABP-JAK1/STAT6信号通路影响肥胖型模型动物气道上皮细胞Muc5ac表达，抑制气道粘液的分泌。本研究有力的阐释了咳喘六味合剂调控肥胖型哮喘这一特殊类型哮喘的机理，为咳喘六味合剂治疗肥胖型哮喘提供理论依据。