长期使用鼻用糖皮质激素在变应性鼻炎中对嗅觉功能影响的病理机制研究和临床初探

Intranasal glucocorticoids (IGC) have been administered extensively and even over an extended period in the anti-inflammatory treatment of allergic rhinitis (AR). There are few clinical reports that mentioned the impact of short-term used IGC on olfactory function. While research on the effect of long-term use of IGC for over 12 weeks on olfactory function have never been performed so far. Our clinical follow-up demonstrates that short-term use of IGC may improve olfaction, but the efficacy of long-term use was limited with unknown mechanism. Further preliminary research has shown that long-term use of IGC may induce considerable apoptosis of olfactory sensory neurons (OSN) in AR mice, resulting in hyposmia. Accordingly, we initiate that IGC may have not only anti-inflammatory properties but also apoptosis-promoting capabilities. Short-term use of IGC can improve the olfaction by inhibiting inflammation, whereas long-term use may promote apoptosis of OSN, resulting in hyposmia. By conducting prospective randomized double-blind controlled trials at both in vivo and clinical levels, and also with application of subjective and objective tests, neuroimaging technique, molecular biology techniques and methods for detecting the expression of classical biomarkers in both OSN apoptosis and AR inflammation, this study will probe into the influence of time and dosage gradient of IGC on AR olfaction as well as the relationship between olfactory change and AR inflammatory status or OSN apoptosis, in order to reveal the pathologic mechanisms and action rules of long-term use of IGC affecting olfaction in AR.

鼻用糖皮质激素（IGC）被大量甚至长期用于变应性鼻炎（AR）的抗炎治疗，目前仅有极少的短期使用IGC对嗅觉影响的临床报道，未见超过12周应用对嗅觉影响的研究。我们临床随访观察到短期使用IGC可改善嗅觉功能，长期使用效果欠佳，其机制未明。进一步的前期实验发现长期应用IGC可诱导AR小鼠嗅感觉神经元（OSN）大量凋亡，导致嗅觉减退。据此，我们首次提出IGC在AR中可能同时发挥着抗炎和促OSN凋亡两种作用，短期使用可通过抑制炎症改善嗅觉，长期则可能促进OSN凋亡，导致嗅觉减退。本研究拟在动物实验和临床研究两个水平上，采用前瞻性随机双盲对照的方法，以嗅觉主、客观检测、神经影像学技术及检测OSN凋亡和AR炎症的经典标记物表达的分子生物学技术及方法，探讨梯度时间和剂量的IGC对AR嗅觉的影响及该嗅觉变化与AR炎症状态及OSN凋亡之间的关系，以期揭示长期使用IGC在AR中对嗅觉影响的病理机制和作用规律。

嗅觉障碍是变应性鼻炎（AR）的主要症状之一，20-40%患者受此影响。虽然鼻腔炎症被公认是AR导致嗅觉功能的主要原因，但临床证据表明使用鼻用糖皮质激素（INGS）进行局部抗炎治疗不能确切地改善AR患者的嗅觉障碍症状。另一方面，动物实验已经提示糖皮质激素（GS）能够直接损伤嗅觉，但其机制尚不清楚。本研究拟探索连续经鼻滴入GC对于正常小鼠及AR模型小鼠嗅觉功能的潜在作用。通过嗅觉相关行为学实验判断小鼠嗅觉功能。通过免疫组化和Western Blot评估鼻腔嗅黏膜内嗅觉神经细胞(OSN)数量，OSN轴突投射及嗅觉信号传入嗅球的程度。研究结果显示：正常小鼠反复经鼻滴入GC能够呈时间依赖性诱导嗅黏膜内OSN退化，其病理机制与非成熟OSN成熟障碍有关。伴随嗅上皮OSN退化，GC治疗小鼠出现了嗅球萎缩及外周嗅觉信号通路破坏。经鼻长期滴入GC导致的上述形态及功能改变可在停药后完全恢复。长期经鼻滴入GC有效抑制AR小鼠鼻腔炎症反应，却无法恢复OSN数量。综上所述，本次研究结果提示了长期经鼻使用GC通过介导OSN退化损伤嗅觉。AR状态下长期使用INGC调控嗅觉可能具有双向性，因此需要密切关注患者嗅觉功能。