基于神经肽VIP研究“肺肠合治法”治疗干燥综合征的机制

Clinical evidences show significant effect on treating Sjogren's Syndrome(SS) by using "combination of diffusing Lung and lubricating Intestine". Lung and Intestine are relatively interior and exterior ones in TCM theory, hence, we can strengthen the distribution of the fluid and humor in whole body by applying combination of diffusing Lung and lubricating Intestine. While it's scientific mechanism not clearly known, studies showed that diffusing Lung and lubricating Intestinecan enhance the expression of the vasoactive intestinal peptide(VIP) in lung and colon tissue from slow transit constipation(STC) model rat. The expression of VIP is not only reduced in colon tissue of STC model but also in exocrine glands of SS models. VIP regulates immune system significantly, including altering Th1/Th2 cells balance in favor of Th2, down-regulating Th17 cells, up-regulating Treg cells, and regulating AQP5 expression. Therefore, we suppose that the mechanism of treating SS by using "combination of diffusing Lung andlubricating Intestine" should be involved with up-regulating VIP expression. Basing on the previous works, we decided to observe whether the method of "combination of diffusing Lung and lubricating Intestine" can readjust the imbalance between Th1/Th2,Th17/Treg and abnormal expression of AQP5 in SS via up-regulating the VIP expression. To resolve above scientific problem, this study clarifies the mechanism when using "combination of diffusing Lung and lubricating Intestine" to treat SS, and provides the theoretic basis to elevate the level of treating SS in future.

根据中医肺与大肠相表里理论，我们提出干燥综合征的治疗应肺肠合治，宣肺布津、增液润肠，以该法组方的麦冬地芍汤用于治疗干燥综合征临床疗效显著，但其现代医学作用机理不明。文献报道宣肺和增液润肠法各能上调慢传输型便秘模型鼠肺与大肠组织的神经肽血管活性肠肽（VIP）的表达。VIP不仅在慢传输型便秘疾病中表达降低，在干燥综合征的外分泌腺中亦表达降低。VIP具有很强的免疫调节作用，可以促进淋巴细胞Th1向Th2转化，下调Th17细胞，上调Treg细胞，并能调节AQP5的表达。于是推测肺肠合治法治疗干燥综合征的机制可能与其可上调VIP表达相关。本课题拟在前期工作的基础上，观察肺肠合治法能否通过上调VIP的表达从而调节干燥综合征Th1/Th2、Th17/Treg免疫失衡及AQP5表达异常。本项目通过解决上述科学问题，阐明肺肠合治法治疗干燥综合征的作用机制，为提高治疗干燥综合征的临床疗效提供理论依据。

根据中医肺与大肠相表里理论，我们提出干燥综合征的治疗应肺肠合治，宣肺布津、增液润肠，以该法组方的麦冬地芍汤用于治疗干燥综合征临床疗效显著，但其现代医学作用机理不明。文献报道宣肺和增液润肠法各能上调慢传输型便秘模型鼠肺与大肠组织的神经肽血管活性肠肽（VIP）的表达。VIP不仅在慢传输型便秘疾病中表达降低，在干燥综合征的外分泌腺中亦表达降低。VIP具有很强的免疫调节作用，可以促进淋巴细胞Th1向Th2转化，下调Th17细胞，上调Treg细胞，并能调节水通道蛋白5（AQP5）的表达。于是推测肺肠合治法治疗干燥综合征的机制可能与其可上调VIP表达相关。本课题在前期工作的基础上，验证了肺肠合治法对干燥综合征模型小鼠的治疗作用，依据该法所拟方剂在改善NOD小鼠颌下腺分泌和淋巴细胞浸润，改善Th1/Th2、Th17/Treg免疫失衡及AQP5表达异常方面疗效显著，并且VIP在其中起到了关键作用，VIP能还通过cAMP/PKA/AQP5信号通路提高AQP5表达，增加颌下腺细胞分泌。本项目研究和阐释了肺肠合治法治疗干燥综合征的主要作用机制，大大增加“肺与大肠相表里”理论的应用范围，最终丰富了“肺与大肠相表里”的现代医学内涵，为提高治疗干燥综合征的临床疗效提供理论依据。