Oregon Hearing Research Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
National Center for Rehabilitative Auditory Research, VA Portland Health Care System, Portland, OR 97239, USA.
Sci Adv. 2019 Jul 17;5(7):eaaw1836. doi: 10.1126/sciadv.aaw1836. eCollection 2019 Jul.
Aminoglycoside antibiotics are essential for treating life-threatening bacterial infections, despite the risk of lifelong hearing loss. Infections induce inflammation and up-regulate expression of candidate aminoglycoside-permeant cation channels, including transient receptor potential vanilloid-1 (TRPV1). Heterologous expression of TRPV1 facilitated cellular uptake of (fluorescently tagged) gentamicin that was enhanced by agonists, and diminished by antagonists, of TRPV1. Cochlear TRPV1 was immunolocalized near the apical membranes of sensory hair cells, adjacent supporting cells, and marginal cells in the stria vascularis. Exposure to immunostimulatory lipopolysaccharides, to simulate of bacterial infections, increased cochlear expression of TRPV1 and hair cell uptake of gentamicin. Lipopolysaccharide exposure exacerbated aminoglycoside-induced auditory threshold shifts and loss of cochlear hair cells in wild-type, but not in heterozygous or knockout, mice. Thus, TRPV1 facilitates cochlear uptake of aminoglycosides, and bacteriogenic stimulation upregulates TRPV1 expression to exacerbate cochleotoxicity. Furthermore, loss-of-function polymorphisms in can protect against immunogenic exacerbation of aminoglycoside-induced cochleotoxicity.
氨基糖苷类抗生素对于治疗危及生命的细菌感染至关重要，尽管存在终身听力损失的风险。感染会引发炎症，并上调候选氨基糖苷类通透阳离子通道的表达，包括瞬时受体电位香草醛 1（TRPV1）。TRPV1 的异源表达促进了（荧光标记的）庆大霉素的细胞摄取，而 TRPV1 的激动剂和拮抗剂则减弱了这种摄取。耳蜗 TRPV1 被免疫定位在感觉毛细胞的顶膜附近，相邻的支持细胞和血管纹的边缘细胞。用免疫刺激性脂多糖（lipopolysaccharides，LPS）模拟细菌感染，会增加耳蜗 TRPV1 的表达和庆大霉素进入毛细胞。脂多糖暴露会加重野生型小鼠，但不会加重杂合子或敲除型小鼠的氨基糖苷类诱导的听觉阈值移位和毛细胞损失。因此，TRPV1 促进了氨基糖苷类在耳蜗中的摄取，而细菌产生的刺激会上调 TRPV1 的表达，从而加重耳蜗毒性。此外， 中的功能丧失性多态性可以防止免疫原性加重氨基糖苷类诱导的耳蜗毒性。
