基于sfTSLP/lfTSLP平衡的麻芥平喘巴布剂“经皮治肺”调控哮喘的效应机制研究

The harmful effect of asthma on people's health is increasing in China, it has been demonstrated that external therapy with traditional Chinese medicine plays a positive role in the treatment and prevention of asthma. Majiepingchuan cataplasm was developed by our team which was used in treating asthma by regulating the Th1/Th2 and Th17/Treg balance. Our previous study showed that the total amount of drugs in the blood after transdermal administration accounted for a quarter of that after oral administration.The result indicated that MJPC might play a therapeutic role through a specific regulatory pathway between the lungs and the skin. There are two subtypes of TSLP, sfTSLP and lfTSLP, which play roles in inhibiting and promoting inflammation respectively. In addition, TSLP plays an important role in the adaptive immune response mediated by DC cells and the innate immune response mediated by ILC2 cells. These provide key factors and a new perspective to illustrate the pathogenesis of asthma. Based on these studies, with the establishment of asthma model by gene deficient mice and cells, the effects of MJPC on the balance of sfTSLP/lfTSLP and the regulation of downstream inflammatory response were discussed from the aspects of tissue, cell, molecule and gene. By explaining the mechanism of Majiepingchuan cataplasm in treating asthma through skin, this study will contribute to defining the overall relationship between the lungs and the skin under the influence of the immune system in asthma. Meanwhile, this will provide some experimental basis for exploring the theory of "lung associating with skin" in traditional Chinese medicine.

哮喘对我国人民健康的危害日益加剧，中药外治法防治本病疗效确凿。项目组前期研制了麻芥平喘巴布剂（MJPC），该药可改善TH1/Th2及Th17/Treg平衡失调而对抗哮喘。同等生药量下，经皮给药成分入血总量虽只有口服的1/4却有更好疗效。说明MJPC可通过肺与皮肤间特异调控通路发挥治疗作用。TSLP有sfTSLP和lfTSLP两个亚型，分别发挥抑炎与促炎作用。TSLP对DC细胞为主的适应性免疫和ILC2细胞介导的固有免疫反应均有重要影响，为阐释哮喘发病的提供了关键因子和新视角。基于此，本项目拟借助基因缺陷型小鼠和细胞建立哮喘模型，从组织、细胞、分子、基因等多维层面探讨MJPC对sfTSLP/lfTSLP平衡的影响及其对下游炎症反应的调控通路。研究阐释了MJPC“经皮治肺”的效应机制，有助于明确哮喘状态下肺与皮肤免疫系统相互影响的整体关系，并为探讨中医“肺合皮毛”理论提供一定实验依据。

哮喘日益危害我国人民健康，中药外治法防治本病疗效确凿。项目组前期研制了麻芥巴布膏，研究发现同等生药量下，经皮给药成分入血总量虽只有口服的1/4却有更好疗效。说明MJPC可通过肺与皮肤间特异调控通路发挥治疗作用。TSLP 是联系皮肤与肺免疫反应的重要中间因子，TSLP有sfTSLP和lfTSLP两个亚型，分别发挥抑炎与促炎作用。TSLP对DC细胞为主的适应性免疫和ILC2细胞介导的固有免疫反应均有重要影响，为阐释哮喘发病的提供了关键因子和新视角。基于此，本项目建立OVA诱导的支气管哮喘动物模型，并用麻芥巴布膏进行治疗，验证其疗效。麻芥巴布膏可降低哮喘模型小鼠肺、皮、肠组织中TSLP含量，且肺和皮组织中TSLP含量变化具有一定相关性。sfTSLP 对过敏性鼻炎小鼠具有良好的保护作用，麻芥巴布膏通过调控“sfTSLP/lfTSLP”平衡缓解屋尘螨诱导的支气管上皮细胞上皮屏障的破坏。麻芥巴布膏可直接调控Th1/Th2分化，并可促进M2诱导模型中M1分化。麻芥巴布膏可以缓解木瓜蛋白酶诱导的适应性免疫缺陷小鼠先天免疫反应介导的哮喘炎症，其可能通过调控TSLP等上皮源性细胞因子和先天淋巴细胞等发挥作用。麻芥巴布膏还可抑制炎性神经肽的释放，减少神经源性炎症反应。项目从组织、细胞、蛋白、分子等多维层面，阐释麻芥巴布膏“经皮治肺”的效应机制，为进一步研发经皮治肺的创新药物奠定理论基础，并为阐释“肺主皮毛”现代生物学内涵提供一定的科学依据。