QX-314通过TRPV1/S1P受体通道抑制食管酸敏感的机制研究

酸反流导致的食管高敏感是胃食管反流病患者症状难以缓解的主要原因，但其机制尚不明确。研究者在前期工作发现，食管酸暴露主要通过活化TRPV1通道介导食管高敏感的产生，而炎症时S1P的增加也可能通过破坏上皮屏障功能增加神经末梢的酸暴露，进一步促进食管酸敏感。研究发现QX-314可经活化开放的TRPV1通道进入细胞内，通过结合钠离子通道发挥神经阻滞作用，也可通过下调Gαq表达产生抗炎功效，但其对食管感觉传导的机制尚不明确。本课题拟通过研究QX-314对食管酸感觉功能及上皮屏障功能的影响，证实食管酸暴露时，外源性QX-314能通过被酸激活的TRPV1通道进入胞内阻滞感觉神经传导，也可通过Gαq途径抑制S1P介导的炎症反应，从而改善食管酸敏感导致的难治性反流症状，为GERD的临床治疗提供新思路。

Esophageal hypersensitivity induced by acid reflux was the main cause of refractory symptoms in GERD patients, however, the mechanism of reflux hypersensitivity was not clear. Our previous study confirmed that esophageal hypersensitivity could be induced by acid through activating TRPV1 channel. Increased expression of S1P could also damage epithelial barrier, which allowed more nerve endings exposed to acid and induced hypersensitivity. QX-314 could inhibit nerve conduction by blocking Na+ channels when directly into the cytoplasm through activated TRPV1 channel. It could also inhibit inflammation by down-regulate the expression of Gαq. However, its role in esophagus was unknown. The aim of this study was to confirm that exogenous QX-314 could improve esophageal hypersensitivity by blocking sensory nerve conduction in esophagus through activated TRPV1, and inhibiting esophageal inflammation and damaged epithelial barrier through Gαq/S1PR3 pathway. Usage of XQ-314 might provide new treatment for patients suffer from refractory GERD.