从VIP-cAMP-PKA-AQP3信号通路研究肺肠合治法治疗支气管哮喘的分子机制

Bronchial asthma is a clinical refractory disease.The mainly pathological features are airway epithelial barrier damage caused by chronic inflammation, high reactivity and restructuring.VIP and AQP3 should be important targets that can inhibit inflammation and high reactivity of airway, control airway remodelling, and repair epithelial barrier.The research group have studied the molecular mechanisms of 'lung being connected with large intestine' and the therapy of relaxing bowels and purgation for the treatment of constipation.According to these studies：the research shows that VIP and AQP3 are material basis that maintain the relationship between lung and large intestine about physiological function and pathological influence. The AQP3 can be adjusted by VIP through the cAMP-PKA in bowel tissues, and constipation can be treated with therapy of relaxing bowels and purgation through the VIP-cAMP-PKA-AQP3.Dose the adjustment mechanism exist between VIP and AQP3 in lung tissue? It isn,t clearly that this adjustment mechanism is related to the mechanisms of therapy of relaxing bowels and purgation for the treatment of asthma.Therefore, this study plan to copy asthmatic rats as experimental animal models, through the analysis of related genes in VIP-cAMP-PKA-AQP3 signaling pathways, observes the role of this signaling pathways in the pathogenesis of asthma and the influence with both Lung and Intestine therapy, then clarifies the molecular mechanisms of both Lung and Intestine therapy for the treatment of asthma, and digs the scientific connotation of 'lung being connected with large intestine'.

支气管哮喘是由气道上皮屏障破坏导致的以气道慢性炎症、高反应性和重构为主要病理特征的临床难治性疾病。VIP、AQP3是抑制气道炎症和高反应性，控制气道重构，修复上皮屏障的重要靶点。课题组研究肺与大肠相表里的分子机制及通肠泻下法治疗便秘的作用机制时发现：VIP和AQP3是维持肺与大肠在生理功能上相互联系、病理上相互影响的物质基础；肠组织VIP可通过cAMP-PKA调节AQP3，通肠泻下法可通过VIP-cAMP-PKA-AQP3治疗便秘。在肺组织VIP与AQP3之间是否也存在这样的调节机制？通肠泻下法治疗哮喘的作用机制是否与此相关？尚不清楚。因此本研究拟复制大鼠哮喘模型，通过对VIP-cAMP-PKA-AQP3信号通路中相关基因的检测，观察该信号通路在哮喘发病机制中的作用以及肺肠合治法对该通路的影响，阐明肺肠合治法治疗哮喘的分子机制，挖掘“肺合大肠”理论的科学内涵。

中医药论治支气管哮喘历史悠久、疗效确切，以“肺合大肠”理论为指导的肺肠合治法是临床治疗支气管哮喘的常用方法，但其机制尚不完全清楚。我们前期发现的VIP是肺与大肠相表里的物质基础，在肠道VIP可通过cAMP-PKA调节AQP3，通肠泻下法可以刺激肠道提高内源性VIP供给，可通过VIP-cAMP-PKA-AQP3信号通路治疗便秘的基础上，结合对VIP、AQP3在支气管哮喘发病和治疗中发挥了重要作用的认识，以VIP-cAMP-PKA-AQP3信号通路为切入点，研究肺合大肠的物质基础以及肺肠合治法治疗支气管哮喘的作用机制。主要研究了：研究正常状态和支气管哮喘疾病发展进程中，大鼠肺组织 VIP、AQP3、cAMP、PKA 的表达变化以及对气道炎症和气道重塑的影响；观察肺肠合治法对大鼠肺组织 VIP-cAMP-PKA-AQP3 信号通路的影响，明确肺肠合治法是否可以通过该通路发挥治疗作用。结果证实：在肺组织 VIP-cAMP-PKA-AQP3 信好通路在哮喘的发病机制中参与了炎症和气道水肿、气道重塑和气道高反应性，调控这条通路可以起到治疗哮喘的作用；肺肠合治法可通过VIP-CAMP-PKA-.AQP3信号通路，通过增加内源性VIP的表达上调cAMP、PKA、AQP表达，改善哮喘症状，减轻气道炎症，减少气道重塑，从而起到治疗支气管哮喘的作用。VIP-CAMP-PKA-AQP3信号通路是肺与大肠相表里的物质基础之一。该研究结论丰富了肺肠合治法的科学内涵，为从肠治肺病提供了科学依据，为肺系疾病的治疗提供了新的思路，丛现代医学的角度揭示了中医肺与肠之间的关系，也为丰富了现代医学肺与肠之间的对话机制。