Aminophylline restores glucocorticoid sensitivity in a guinea pig model of sudden sensorineural hearing loss induced by lipopolysaccharide.
Aminophylline restores glucocorticoid sensitivity in a guinea pig model of sudden sensorineural hearing loss induced by lipopolysaccharide.
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DOI：
10.1038/s41598-017-02956-x
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发表时间：
2017-06-02
影响因子：
4.6
通讯作者：
She WD
中科院分区：
文献类型：
--
作者：
Zhou QQ;Dai YH;Du XP;Hou J;Qi H;She WD
糖皮质激素已被用于治疗听力损失和前庭功能障碍多年。然而，一些报告表明，这些疾病的患者的子集表现出糖皮质激素不敏感或抵抗。组蛋白去乙酰化酶2（HDAC 2）活性和表达的减少已被报道在糖皮质激素抵抗中起关键作用。在此，我们研究了氨茶碱对脂多糖（LPS）诱导的豚鼠突发性感音神经性耳聋中HDAC 2表达和糖皮质激素敏感性的保护作用。我们评估了应用LPS的豚鼠的听力恢复情况，这些豚鼠要么不接受治疗，要么接受地塞米松、氨茶碱或两者联合全身治疗。我们利用荧光显微镜和酶联免疫吸附试验来分析HDAC 2的分布模式，并检测其在耳蜗中的水平。用苏木精-伊红染色法观察耳蜗组织病理学改变。在不存在处理的情况下，在暴露于LPS的动物中检测到显著的听力损失。氨茶碱和地塞米松在维持HDAC 2表达水平、预防LPS暴露动物的听力损失和减少耳蜗损伤方面观察到协同效应。提示氨茶碱可恢复糖皮质激素的敏感性，为糖皮质激素治疗无效的听力障碍患者提供了新的治疗途径。
Glucocorticoids have been used to treat hearing loss and vestibular dysfunction for many years. However, some reports have indicated that a subset of patients with these disorders exhibit glucocorticoid insensitivity or resistance. A reduction in histone deacetylase 2 (HDAC2) activity and expression has been reported to play a critical role in glucocorticoid resistance. Here, we investigated the protective effects of aminophylline on HDAC2 expression and glucocorticoid sensitivity in lipopolysaccharide (LPS)-induced sudden sensorineural hearing loss in guinea pigs. We assessed hearing recovery in LPS-applied guinea pigs, which were either left untreated or were systemically treated with either dexamethasone, aminophylline, or a combination of the two. We utilized fluorescence microscopy and enzyme-linked immunosorbent assay to analyze the distribution patterns of HDAC2 and detect its levels in the cochlea. We used hematoxylin-eosin staining to examine cochlear histopathological changes. In the absence of treatment, significant hearing loss was detected in LPS-exposed animals. A synergistic effect was observed between aminophylline and dexamethasone in maintaining HDAC2 expression levels, preventing hearing loss in LPS-exposed animals and reducing cochlear damage. This study indicates that aminophylline can restore glucocorticoid sensitivity, which provides a new approach to treating patients with hearing disorders who are refractory to glucocorticoids.