基于“大肠主津”探讨结肠AQP3/AQP9在STC发病中的作用机制研究

Slow transit constipation(STC) is a common disease in department of colorectal surgery and gastroenterology,which tends to be prevalent in elders and women,posing a potential threat to health of Chinese residents. However,the mechanism of STC remains unclear, which tends to be related with fecal water content. Accumulating evidences demonstrate that aquaporins（AQPs） as well as its regulation may play a vital role in fluid homeostasis. More importantly,it has been gradually elucidated regarding water transfer in the colon mediated by AQP3/AQP9. Our previous study suggested that cathartic Chinese patent medicine may modulate the expression of AQP3 in the colon,which inhibits colonic water absorption leads to a laxative effect. The purpose of this project is to explore the pathogenesis of STC. Therefore, under the guidance of theory“large intestine governs fluid” in Traditional Chinese Medicine. Our group intends to mimic “fluid deficiency” syndrome in constipated rats,so as to observe the changes in the function and expression of AQP3/AQP9 as well as the level of neurotransmitters and other factors in the colon. After that,to examine the intervention by Zengyetang“increase water to facilitate the vehicle” in rats model. By discussing the “dose-effect” and “time-effect”, “using formula to verify syndrome”,it is expected to validate the abnormal colonic water metabolism mediated by AQP3/AQP9 as well as the disorder of its regulation in the pathogenesis of STC. Overall,it is expected to discover novel theory in the pathogenesis of STC and potential therapeutic target in treatment of STC by means of this project. Moreover,it may also serve as references for new drug development and pharmacology,and provide evidences for understanding the mechanism of Zengyetang in treating constipation.

慢传输型便秘（STC）是肛肠、消化科的常见疾病，以老人和妇女多见，已对我国居民健康构成潜在威胁，其发病机制尚不明，笔者认为总与粪便含水量有关。研究表明水通道蛋白（AQPs）的功能及其调节机制与机体水液代谢密切相关，而AQP3/AQP9介导结肠吸收及分泌水分的作用逐渐得到认可。前期研究发现通便中成药调控AQP3表达，抑制结肠吸收水分而产生通便效应。为进一步探讨STC发病机制，本项目拟在“大肠主津”理论指导下，复制“津亏”便秘动物模型，检测造模后AQP3/AQP9功能和表达的变化，以及肠神经递质等调节因素的活性水平，并观察“增液行舟”法的干预作用，通过其“剂量-效应”、“时间-效应”关系，“以方测证”，证实AQP3/AQP9介导的结肠水代谢紊乱及调控失效是STC发病的重要环节之一，以期发现STC发病新理论、治疗新靶点，为通便药研发提供参考，同时为研究中药的通便机制提供依据。

慢传输型便秘（STC）是肛肠、消化科的常见疾病，以老人和妇女多见，已对我国居民健康构成潜在威胁，其发病机制尚不明，笔者认为总与粪便含水量有关。研究表明水通道蛋白（AQPs）的功能及其调节机制与机体水液代谢密切相关。本研究在“大肠主津”理论指导下，复制“津亏”便秘动物模型，检测造模后AQP3/AQP9功能和表达的变化，以及肠神经递质等调节因素的活性水平，并观察“增液行舟”法的干预作用，通过其“剂量-效应”、“时间-效应”关系，“以方测证”。. 结果显示：近端结肠组织中AQP3含量增加及远端结肠组织中AQP9含量下降可能是STC的发病机制之一；随着增液汤浓度的增加及用药时间的延长，72小时后及给予中剂量药物后，AQP3下降明显，AQP9上调明显，药物作用效果明显增强，120小时后以及给予高剂量药物后，AQP3下降显著，药物作用效果达到顶峰，144小时后及给予高剂量后AQP9上调显著，说明增液汤干预治疗可下调结肠粘膜 AQP3 、上调结肠粘膜AQP9 的表达水平，而AQP3表达下降可抑制结肠水分吸收，AQP9表达上升可刺激结肠水分吸收，这可能是增液汤治疗慢传输型便秘的作用机制之一。血清中VIP、SP、5-HT、NO、Ach、PGE2、TNF-α活性水平的变化可能是“津亏”慢传输型便秘的发病机制之一，增液汤通过调节各种肠神经递质、炎性因子的表达来治疗“津亏”慢传输型便秘，可能是其发挥“增液行舟”效应的作用机制之一。