气道神经源性炎症在慢性间歇性缺氧豚鼠模型咳嗽敏感性增高中的作用及机制研究

Chronic cough is an important clinical manifestation in the patients with obstructive sleep apnea hypopnea syndrome (OSAHS) and needs to be actively faced with since it may involve a huge number of the potential population. We have found the patients with OSAHS presented with an increased cough reflex sensitivity, which had a significant correlation with airway inflammation and may be associated with the pathogenesis of OSAHS-related cough in our early research. However, the underlying mechanisms remain unclear. It is hypothesized that airway inflammation, initiated by chronic intermittent hypoxia of OSAHS, activates and sensitizes C nerve afferents expressing TRPV1 which release tachykinins and induce airway neurogenic inflammation. Then, the resultant plasticity on C nerve afferents expressing TRPV1 causes cough reflex hypersensitivity. We plan to compare the changes in cough reactivity and levels of substance P and CGRP in bronchoalveolar lavage fluid from guinea pigs with chronic intermittent hypoxia which are pretreated with an inhibitor of nonspecific inflammation, an antagonist of TRPV1 or substance P alone or in combination, and to analyze the number and distribution of C nerve afferents expressing TRPV1 in trachea-bronchial mucosa under laser scanning confocal microscope combined with the fluorescent immuno-staining. The purpose of the study is to verify the important role of airway neurogenic inflammation in cough reflex hypersensitivity related to OSAHS, which would provide a theoretical and experimental basis for more effective treatment.

慢性咳嗽是阻塞性睡眠呼吸暂停综合症（OSAHS）的重要临床表现。我们前期研究发现OSAHS患者存在气道炎症并具有咳嗽高敏感性，两者具有明显的相关性，我们推测咳嗽易感性是OSAHS相关咳嗽的发生基础，但机制尚不清楚。假设OSAHS的慢性间歇性缺氧通过启动气道炎症，激活和致敏表达TRPV1的C传入神经纤维，后者释放速激肽诱发气道神经源性炎症，导致C传入神经纤维的可塑性改变，从而促进咳嗽高敏感性的形成。本研究拟单独或组合使用非特异性炎症、TRPV1和P物质抑制剂预处理慢性间歇性缺氧模型豚鼠，比较各组辣椒素咳嗽反应性和BALF中P物质及CGRP浓度差异，荧光免疫染色结合激光共聚焦显微镜分析气管支气管黏膜中表达TRPV1神经纤维数量和分布的变化，证实气道神经源性炎症在OSAHS咳嗽高敏感性形成中的重要地位，为疾病更有效的治疗提供理论和实验依据。

背景：慢性咳嗽是阻塞性睡眠呼吸暂停综合症（OSAHS）的重要临床表现，本研究拟证实慢性间歇性缺氧通过启动气道炎症，激活和致敏表达TRPV1的C传入神经纤维，后者释放速激肽诱发气道神经源性炎症，导致C传入神经纤维的可塑性改变，从而促进OSAHS咳嗽高敏感性的形成。.方法：本研究通过建立慢性间歇性缺氧豚鼠模型，比较其咳嗽反应性、BALF炎症细胞、炎性介质P物质及CGRP浓度变化。长期使用非特异性炎症、TRPV1和P物质抑制剂预处理慢性间歇性缺氧模型豚鼠，比较各组模型豚鼠辣椒素咳嗽反应性和BALF中炎症细胞、炎性介质P物质及CGRP浓度以及气管支气管组织TRPV1mRNA表达差异，并通过荧光免疫染色结合激光共聚焦显微镜分析各组气管支气管黏膜中表达TRPV1神经纤维数量和分布的差异。.结果：慢性间歇性缺氧豚鼠在造模14天出现咳嗽高敏感性，咳嗽次数较对照组明显升高（P＜0.05），BALF中中性粒细胞和淋巴细胞比例、炎性介质P物质和CGRP浓度较对照组均显著升高（P＜0.05），停止造模后豚鼠咳嗽反应性、肺泡灌洗液中中性粒细胞和淋巴细胞比例、炎性介质P物质和CGRP浓度逐渐恢复正常（P＜0.05）。长期使用TRPV1抑制剂及P物质拮抗剂预处理模型豚鼠咳嗽次数、肺泡灌洗液细胞分类中中性粒细胞和淋巴细胞比例、炎性介质P物质浓度水平、气管支气管组织TRPV1mRNA表达较慢性间歇性缺氧模型豚鼠组明显下降（P＜0.05），气管支气管黏膜中表达TRPV1神经纤维数量和分布的表达受到明显抑制。.结论：慢性间歇性缺氧能导致豚鼠咳嗽高敏感性，其机制与气道TRPV1神经纤维发生可塑性改变和气道炎症尤其是气道神经源性炎症有关。