从血管活性肠肽保护唾液腺及其致泻作用研究桔梗在治疗干燥综合征中“载津上行”的机制

The pathogenesis of Sjogren syndrome (SS) is closely related to the disorder of fluid generation and distribution. Previous studies have confirmed that Zengye Decoction can promote the generation of body fluid, improve SS symptoms of dry mouth, but also prone to cause diarrhea. The mechanism is related to up-regulated expression of vasoactive intestinal peptide, which can ameliorate imbalance of Th1/Th2, Th17/Treg, and abnormal expression of AQP5 in SS. At the same time, the expression of VIP in the intestines can induce diarrhea. Our team also found that the combination of Platycodon grandiflorum and ZengYe Decoction not only enhanced its efficacy, but did not increase the incidence of diarrhea, suggesting that Platycodon grandiflorum has the effect of carrying the body fluid up. However, the mechanism is not clear. We hypothesized that: Platycodon grandiflorum can specifically increase the VIP expression in salivary gland; the combine Platycodon grandidforum and ZengYe Doecoction can enhance the expression of VIP in the salivary gland, but less increase its expression in intestinal tissue. In this study, experiments in vivo and vitro will be used to reveal the relationship between Specific expression of VIP in tissue and the effect of carrying the body fluid up induced by Platycodon grandiflorum , and immunofluorescence, flow cytometry and serum pharmacology techniques will be used. This study is helpful to understand the mechanism of the improvement in the distribution of body fluid by Platycodon grandiflorum in SS, and it enrichs the connotation of “raising,lowering,floating and sinking” of traditional Chinese medicine.

干燥综合征（SS）与津液代谢障碍密切相关。前期研究证实增液汤可促进津液生成，在SS治疗中表现出较好疗效，但易致泻。其机制与上调血管活性肠肽（VIP）改善Th1/Th2、Th17/Treg免疫失衡以及调节AQP5表达从而保护唾液腺结构与功能相关，但上调肠组织中VIP产生腹泻副作用。课题组也发现：桔梗与增液汤合理配伍，不仅增强其疗效，且可减少腹泻发生率，提示桔梗有“载津上行”的效果，然而机制并不清楚。桔梗是否促进VIP在SS唾液腺病灶组织特异性表达，从而增强疗效减少副作用，是本项目拟研究的关键问题。本项目拟通过免疫荧光原位、流式细胞分选及血清药理学等技术，从体内外阐明桔梗特异性上调VIP在唾液腺中表达与“载津上行”的关系，深入诠释桔梗改善SS津液输布的疗效机制，同时丰富其“升降浮沉”的药性内涵。

干燥综合征与津液代谢障碍密切相关。前期研究证实增液汤可促进津液生成，在SS治疗中表现出较好疗效，但易致泻。课题组也发现：桔梗与增液汤合理配伍，不仅增强其疗效，且可减少腹泻发生率，提示桔梗有“载津上行”的效果，然而机制并不清楚。课题组根据前期结果提出科学假设：桔梗是能促进VIP在SS唾液腺病灶组织特异性表达是发挥其“载津上行”的关键机制，从而增强增液汤的疗效而减少副作用。本项目通过体内外实验证实：桔梗能特异性增强增液汤上调VIP在唾液腺中表达，但桔梗与增液汤配伍后却不增加肠道组织中VIP的表达，且从结肠菌群分析发现，桔梗与增液汤配后可以进一步保护干燥综合征模型小鼠肠道菌群的丰度，但单用增液汤对干燥综合征模型小鼠肠道菌群却无明显保护作用。拮抗VIP受体后，桔梗联合增液汤对干燥综合征模型小鼠的治疗作用却被削弱。因此本研究深入诠释桔梗改善干燥综合征津液输布的疗效机制，同时丰富其“升降浮沉”的药性内涵。本研究探索桔梗在治疗干燥综合征中独特疗效的作用机制，将有助于推动其在干燥综合征治疗中的临床应用和疗效的优化。