延髓中枢对胃食道反流诱发的气道神经源性炎症的调控作用

Gastro-esophageal reflux is one of the common causes of chronic cough. Previous studies showed that airway neurogenic inflammation mediated by esophageal-bronchial reflex played an important role in the gastro-esophageal reflux-related cough. Dorsal vagal complex including the nucleus of the solitary tract and dorsal motor nucleus of the vagus is the center of cough regulation, also the terminal of sensory afferent nerves innervating airway. We hypothesis that dorsal vagal complex is involved in the regulation of airway neurogenic inflammation induced by gastro-esophageal reflux. By using the guinea pig model of gastro-esophageal reflux which we established previously, the changes of neurons activities, the expressions of neuropeptides and receptors, and activations of TRP channels will be investigated with functional magnetic resonance imaging, immunofluorescence. Combining stereotaxic technique and nuclei microinjection is used to activate or inhibit neurons of dorsal vagal complex, then the changes of airway neurogenic inflammation, microvascular leakage, and TRP channels expressions and function are observed respectively. In the further study, DiI anterograde tracing and PRV retrograde tracing will be adopted to confirm the pathway from esophagus-medulla-airway anatomically. This study will clarify the regulation pathway of airway neurogenic inflammation induced by gastro-esophageal via dorsal vagal complex, and provide the new target for therapy of gastro-esophageal reflux-related cough, even reflux-related severe asthma.

胃食道反流是慢性咳嗽的常见原因。前期研究发现食管-支气管反射介导的气道神经源性炎症具有重要作用，但其是否涉及神经中枢的调控尚不明确。孤束核、迷走背核在内的延髓迷走复合体等核团是重要的咳嗽调控中枢，也是支配气道感觉神经传入的终末区域，我们推测其参与胃食道反流诱发的气道神经源性炎症的调控。本课题拟采用前期建立的胃食道反流豚鼠模型，通过脑功能成像、免疫荧光等技术，观察酸灌注食道后延髓核团神经元活动、神经肽及受体、瞬时受体电位（TRP）通道表达等变化。进而采用脑立体定位核团微量注射术，分别研究延髓核团神经元激活或抑制时，对气道神经源性炎症、TRP通道表达及功能的调节作用。最后通过DiI顺行和PRV逆行示踪技术，从解剖学上证实食道-延髓-气道的神经通路。本研究对阐明胃食道反流所诱发的气道神经源性炎症的中枢调控作用和途径具有重要意义，可望为胃食道反流性咳嗽乃至反流相关的重症哮喘的治疗提供新的靶点。

胃食道反流是慢性咳嗽的常见原因,前期研究发现食管-支气管反射介导的气道神经源性炎症具有重要作用，但其是否涉及神经中枢的调控尚不明确。孤束核、迷走背核在内的延髓迷走复合体等核团是重要的咳嗽调控中枢，也是支配气道感觉神经传入的终末区域，我们推测其参与胃食道反流诱发的气道神经源性炎症的调控。本课题采用胃食道反流豚鼠模型，通过脑功能成像、免疫荧光等技术，证实酸灌注食道后延髓核团神经元活动激活，神经肽P物质表达增加。采用脑立体定位核团微量注射术，延髓核团神经元被激活或抑制时，可调节气道神经源性炎症和血浆微渗漏。最后通过示踪技术，从解剖学上证实食道-延髓-气道的神经通路。本研究对阐明胃食道反流所诱发的气道神经源性炎症的中枢调控作用和途径具有重要意义，为胃食道反流性咳嗽乃至反流相关的重症哮喘治疗提供新的靶点。