基于“鼻-肺-肠”共有黏膜免疫系统探索加味小青龙汤对哮喘大鼠淋巴细胞归巢过程及结局的影响

Childhood asthma is one of the most common chronic lung diseases,which has a serious hazard on the physical and mental health of children.There is a good effect on the treatment of asthma by Traditional Chinese medicine.Our research team have confirmed that Xiaoqinglong Decoction achieves its anti-inflammatory effect by regulating the inflammatory factors of asthma.It is discovered that there is a close correspondence between the pathogenesis of asthma and the immune system of "nasal - lung - intestinal mucosa".According to the principle of"treat nose-lung-intestine at the same time",Modified Xiaoqinglong Decoction was created.In this study,our research team use the lymphocyte homing of"nasal-lung-intestinal"CMIS as the research point,bring the question that whether the mechanism of Modified Xiaoqinglong Decoction on asthma is realized by regulating the process and outcome of homing as a scientific hypothesi,take the method of the in vitro and in vivo experiments,select process of α4β7, L-selectin/MAdCAM-1 pathways in CMIS lymphocyte homing and stimulating factors IL-5,IL-6 and IL-10 in homing outcome of SIgA as potential therapeutic targets to explore the effects of Modified Xiaoqinglong Decoction on lymphocyte homing in CMIS process and outcome related cytokines,in order to find the mechanism of Modified Xiaoqinglong Decoction’s effect on asthma and provide a new scientific experimental basis for the prevention and treatment of asthma with Chinese medicine.

儿童支气管哮喘是最常见的慢性肺部疾病之一，严重危害患儿身心健康。中医药对哮喘的治疗有良好疗效，既往课题组证实小青龙汤主要通过对哮喘炎症因子调控实现抗炎作用，亦发现哮喘发病机制与“鼻-肺-肠”共有黏膜免疫系统（CMIS）密切相关，基于此，临床以“鼻肺肠同治”原则，创立加味小青龙汤。本课题以“鼻-肺-肠”CMIS中淋巴细胞归巢为研究点，加味小青龙汤对哮喘的作用机制是否通过调控归巢过程及结局来实现作为课题科学假说，采用体内与体外动物实验结合的研究方法，选取CMIS中淋巴细胞归巢过程中α4β7、L-selectin/MAdCAM-1信号通路及归巢结局SIgA刺激因子IL-5、IL-6、IL-10为治疗靶点，探索加味小青龙汤对淋巴细胞归巢过程及结局相关细胞因子作用，发现其对哮喘黏膜免疫的作用机制，为中医药更好的防治哮喘提供新的科学实验依据。

儿童支气管哮喘是最常见的慢性肺部疾病之一，严重危害患儿身心健康，中医药对哮喘的治疗有良好疗效。哮喘的发病机制与免疫失衡关系密切，特别是“鼻-肺-肠”黏膜免疫失衡，它们构成哮喘发病过程中的共有黏膜免疫系统(CMIS ) 。课题组以“鼻肺肠同治”为指导原则，创立加味小青龙汤。本研究中，我们运用分子生物学、细胞生物学、病理学等技术探讨了加味小青龙汤治疗支气管哮喘的黏膜免疫机制。主要研究内容包括哮喘大鼠“鼻-肺-肠”CMIS 淋巴细胞归巢过程、结局中细胞因子的变化及加味小青龙汤对其的影响，以及加味小青龙汤含药血清对哮喘 T、B 淋巴细胞及血管内皮细胞上相关细胞因子的影响。研究结果显示，加味小青龙汤可降低对哮喘大鼠鼻咽肺泡灌洗液、小肠液中IL-6、IL-10的水平进而影响SIgA的分泌，也提示鼻、肺、肠有相同黏膜免疫。体外实验方面，研究结果显示加味小青龙汤含药血清可减少哮喘大鼠淋巴细胞中α4β7、L-selectin、MAdCAM-1及IL-5、IL-6、IL-10的水平。证实加味小青龙汤对哮喘的作用机制是通过调节淋巴细胞归巢过程中α4β7、L-selectin /MAdCAM-1 通路及 IL-5、IL-6、IL-10 因子而影响 SIgA 分泌来实现。在研究中也发现加味小青龙汤组方中半夏的有效成分2-十一烷酮，可通过抑制NF-κB通路的异常激活改善哮喘大鼠肺部炎症细胞浸润、杯状细胞增生和气道平滑肌厚度，降低哮喘大鼠炎症细胞数量，延缓哮喘进程。综上所述，加味小青龙汤、2-十一烷酮、都可能为治疗哮喘的重要靶点，其可能为哮喘的科学研究及临床诊治提供新的思路。