5-羟色胺-迷走神经C纤维通路在胃食管反流性咳嗽中的作用及机制

Gastroesophageal reflux cough (GERC) is one of the major factor of chronic cough. Airway neurogenic inflammation mediated by esophageal-bronchial reflex is the main pathological mechanisms, but the neuronal signaling pathway is still unclear. The vagus nerve C-fibre is the main esophageal afferent sensory nerves, and 5 - hydroxytryptamine (5-HT) selectively activates the vagal nodose C-fibre subtype in the esophagus. Recent studies have shown that esophageal 5-HT level and neuropeptide content of the lung tissue were increased, airway hyperresponsiveness was observed. However, the action of 5-HT on the pathogenesis of GERC is incompletely understood. The role of 5-HT and esophageal vagus nerve C-fibre signaling pathway and its molecular mechanism on the GERC need further study. The animal model, including repeated esophageal acid infusion mice, 5-HT endogenous knockout mice, 5-HT3 receptor gene knockout mice, and esophageal C-fibre degeneration mice are used in this study combined with pharmacological, morphological, molecular biological and genetics methods. We plan to clarify the effect of esophageal acid, 5-HT on the airway neurogenic inflammation, and to confirm the role of 5-HT-vagus nerve C-fibre-neuropeptide pathway in the GERC and its molecular mechanism, and also to understand the preventive effect of related drugs to GERC. It will helpful to verify the neural signaling pathway mediating cough induced by GER and provide us new insights into the prevention and treatment of GERC.

胃食管反流性咳嗽（GERC）是慢性咳嗽的重要原因，食管-支气管反射引起的气道神经源性炎症是其主要的病理机制，但神经信号通路尚未明了。迷走神经C纤维是主要的食管感觉传入纤维，而5-羟色胺（5-HT）具有选择性的刺激食管C纤维的特性。最近研究表明， GER时食管5-HT升高，肺组织神经肽含量增加，气道反应性增高。但5-HT是否参与GERC的发病？5-HT- 迷走神经C纤维通路在GERC发病中的作用及分子机制是什么？目前尚不清楚。我们通过建立食管酸灌注小鼠、5-HT和5-HT3受体基因敲除小鼠、食管C纤维变性小鼠模型，联合药理学、形态学、分子生物学和遗传学方法，研究食管酸、5-HT对气道神经源性炎症的影响；明确5-HT- 迷走神经C纤维-神经肽分泌途径在GERC中的作用及分子机制，分析相关药物对GERC的防治作用。以阐明GERC的神经信号传导通路，为GERC的防治提供新的思路。

胃食管反流性咳嗽（GERC）是慢性咳嗽的重要原因，食管-支气管反射引起的气道神经源性炎症是其主要的病理机制，但神经信号通路尚未明了。迷走神经C纤维是主要的食管感觉传入纤维，而5-羟色胺（5-HT）具有选择性的刺激食管迷走神经C纤维的特性，5-HT在GERC的作用和机制尚不清楚。我们通过建立GER和食管C纤维变性动物模型，研究食管酸反流对气道神经源性炎症的影响；明确5-HT-迷走神经C纤维-神经肽分泌途径在GERC中的作用及分子机制，分析相关药物对GERC的防治作用。结果显示，当乙酰甲胆碱（Mch）刺激浓度达到0.25 mMol/L和0.5 mMol/L时，GER模型组肺阻力增加百分比和肺顺应性减少百分比大于对照组和空白组，气道反应性增高，差异具有统计学意义。模型组远端食管黏膜出现溃疡糜烂，炎症表现明显；气管组织和肺组织炎症明显，主要以嗜酸性粒细胞浸润为主，而对照组和空白组远端食管黏膜结构完好，支气管和肺泡结构正常。模型组支气管肺泡灌洗液（BALF）中的白细胞总数和嗜酸性粒细胞百分比，及神经肽A（NKA）和P物质（SP）含量均显著高于对照组和空白组。模型组食管组织中5-HT水平显著高于对照组和空白组，而5-HT转运体（SERT） mRNA表达水平明显降低。经过药物干预，Mch浓度为0.5 mMol/L时，5-HT4R拮抗剂GR113808组和瞬时感受器电位香草酸受体1（TRPV1）拮抗剂辣椒平组的肺阻力增加百分比和肺顺应性减少百分比小于模型组，气道高反应性得到一定程度缓解。两药物干预组食管黏膜、气管黏膜和肺组织的炎症程度比模型组有所减轻。而GR113808组的BALF中白细胞总数和嗜酸性粒细胞计数均比模型组有所下降，辣椒平组的白细胞总数低于模型组, 差异具有统计学意义。两组BALF中SP含量均比模型组有所降低,差异具有统计学意义。结果表明GER可以引起食管黏膜损伤、气道神经源性炎症和气道高反应性，5-HT-迷走神经通路可能在食管酸反流致气道高反应性中发挥作用；5-HT4R拮抗剂GR113808和TRPV1拮抗剂辣椒平可有效降低食管酸反流引起的气道高反应性，并减轻肺部组织炎症，5HT4R和TRPV1有望成为治疗GERC的新靶点。