右美托咪定通过PKCγ下调七氟醚麻醉导致的TRPV1通路敏化减轻小儿急性呼吸道不良事件

Airway hyperresponsiveness (AHR) triggered adverse respiratory events remain one of commonly complications in pediatric anesthesia with sevoflurane, the most favorable volatile anesthetic. It should be noted that adverse respiratory events induced by AHR can result in severe hypoxia even death in case of inappropriate treatment. Previous study found that sevoflurane is highly associated with up-regulated transient receptor potential vanilloid 1 (TRPV1) and PKCγ expressions, moreover, our previous study has demonstrated that dexmedetomidine can attenuate the incidences of AREs, further, we also found that dexmedetomidine can down-regulate PKCγ and inhibit calcium influx in vitro, unfortunately, the underlying biological mechanism by which dexmedetomidine prevent AREs during the period of sevoflurane anesthesia remains largely unknown. Based on the above results, we hypothesized that dexmedetomidine could prevent AREs through inhibiting PKCγ-TRPV1 signal pathway to reduce substance P and calcium influx during sevoflurane anesthesia. In order to testify the hypothesis, we will confirm the distinct roles of TRPV1 and the underlying mechanism in AHR through in vivo studies, furthermore, we will explore the mechanisms by which PKCγ-TRPV1 activation triggers AHR disruption by specially knocking down or inhibit TRPV1 or PKCγ in vitro or using TRPV1 knockout mice ex vivo or in vivo, meanwhile, we will observe the synergistic effects of substance P and calcium influx on AHR and the precise mechanisms using in vitro, ex vivo and in vivo studies, and we will also explore the preventive effects of dexmedetomidine on AHR. The results will provide novel therapeutic benefits of dexmedetomidine against perioperative AHR induced adverse respiratory events under sevoflurane anesthesia.

因气道高反应性（AHR）导致的急性呼吸道不良事件（AREs）是小儿麻醉期间常见的并发症，处理不慎可危及生命。既往研究发现七氟醚与瞬时受体电位香草酸亚型1（TRPV1）与PKCγ表达的上调有重要因果关系；我们前期研究证实右美托咪定可有效预防AREs的发生，并在体外初步发现与其抑制呼吸道黏膜PKCγ及Ca2+内流有关，但具体机制不明。据此提出“右美托咪定通过抑制PKCγ-TRPV1通路减少Ca2+内流与P物质释放预防AREs的发生”这一科学假说。本项目将通过体外细胞、离体及动物AHR模型论证上述假设，阐明七氟醚上调TRPV1与PKCγ在AHR进程中的作用及机制；特异性沉默SP作用受体及抑制Ca2+内流解析P物质协同Ca2+内流在AHR进程中的作用；最后论证右美托咪定在AHR中的防治作用及机制，以期为七氟醚诱发小儿AHR的机理提供新的理论根据，并为右美托咪定用于小儿AHR的防治奠定实验依据

围术期急性呼吸不良事件（AREs）是小儿全身麻醉的急危并发症，本课题组前期研究已证实，右美托咪定可有效降低七氟醚麻醉围术期气道不良事件。阿片类药物相关气道不良事件例如呛咳、胸部肌肉僵直可给部分眼科病人带来灾难性后果。巨噬细胞是肺泡对抗有害刺激的主要免疫细胞之一，巨噬细胞极化为M1表型，分泌TNF-α，可诱发外周神经元敏化，可诱发痛觉过敏、咳嗽等不良事件。瑞芬太尼诱发组织巨噬细胞的募集和极化可能是OIC的重要机制。. 本项目从通过临床研究，寻找小儿眼科日间手术术前焦虑高危因素，早期识别AREs相关高危人群；探索全凭七氟醚麻醉在小儿门诊眼底血管荧光素钠造影检查应用的安全模式；研究阿片类药物相关呛咳（OIC）的防治，扩大气道不良事件研究范围。通过流式细胞检测、动物实验，追踪外周血单核细胞组织间隙巨噬细胞的变化。. 独生子女、较低的体重、较低的父母教育程度是小儿眼科日间手术术前焦虑的高危因素，是早期药物干预对象，可避免该特征患儿术前哭闹、气道分泌物增多进一步诱发AREs。七氟醚深度麻醉可安全应用于小儿眼科门诊检查。小剂量纳布啡可有效预防OIC。瑞芬太尼可诱发外周血单核细胞迁移和组织间隙巨噬细胞聚集，可能是气道高反应的基础。. 巨噬细胞在阿片类药物所致的气道不良事件中起关键作用，可能与外周血单核细胞迁移极化有关。

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