NF-κB pathway protects cochlear hair cells from aminoglycoside-induced ototoxicity
NF-κB pathway protects cochlear hair cells from aminoglycoside-induced ototoxicity
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DOI：
10.1002/jnr.20392
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发表时间：
2005-03-01
影响因子：
4.2
通讯作者：
Schacht, J
中科院分区：
文献类型：
--
作者：
Jiang, HY;Sha, SH;Schacht, J
氨基糖苷类抗生素诱导的哺乳动物内耳外毛细胞的细胞死亡是由活性氧（ROS）介导的，可以通过抗氧化剂预防。本研究探讨了核因子（NF）-kappaB通路在成年CBA小鼠细胞死亡或存活中的作用。卡那霉素（700 mg/kg皮下注射，每天两次）逐渐破坏毛细胞，但给药7天后，听觉功能和形态尚未受到显著影响，允许研究药物诱导的细胞死亡的早期事件。4-羟基壬烯醛的免疫染色，脂质过氧化的指示，在耳蜗升高，但没有影响硝基酪氨酸，过氧亚硝酸盐的标志物。NF-κ B在治疗3小时、3天和7天时增加，p50和p65蛋白是其最丰富的亚基。p50的免疫反应性存在于药物治疗后存活的内毛细胞和支持细胞的细胞核中。与此相反，外毛细胞的细胞核没有标记。然而，同时注射抗氧化剂，如2，3-二羟基苯甲酸或水杨酸（防止卡那霉素诱导的细胞死亡），促进NF-κ B易位到外毛细胞的细胞核中。此外，卡那霉素治疗减少抑制性IkappaB α蛋白的酪氨酸磷酸化，导致耳蜗中IkappaB α水平增加;与抗氧化剂共同治疗可逆转该效应。这些结果表明，耳蜗氧化还原状态的变化刺激NF-κ B的激活，这种激活是细胞保护。(C)2005 Wiley-Liss，Inc.
Cell death in outer hair cells of the mammalian inner ear induced by aminoglycoside antibiotics is mediated by reactive oxygen species (ROS) and can be prevented by antioxiclants. The current study investigates the role of the nuclear factor (NF)-kappaB pathway in cell death or survival in adult CBA mice. Kanamycin (700 mg/kg subcutaneously, twice per day) progressively destroys hair cells but after 7 days of treatment auditory function and morphology are not yet affected significantly, permitting investigations of early events in drug-induced cell death. Immunostaining for 4-hydroxynonenal, indicative of lipid peroxiclation, was elevated in the cochlea, but there was no effect on nitrotyrosine, a marker for peroxynitrite. NF-kappaB was increased at 3 hr, 3 days, and 7 days of treatment, with p50 and p65 proteins as its most abundant subunits. Immunoreactivity for p50 was present in nuclei of inner hair cells and supporting cells that survive the drug treatment. In contrast, nuclei of outer hair cells were devoid of label. Concomitant injections of antioxiclants, however, such as 2,3-dihydroxybenzoic acid or salicylate (which prevent cell death induced by kanamycin), promoted the translocation of NF-kappaB into the nuclei of outer hair cells. In addition, kanamycin treatment decreased tyrosine phosphorylation of the inhibitory IkappaBalpha protein, leading to increased IkappaBalpha levels in the cochlea; the effect was reversed by cotreatment with antioxiclants. These results suggest that changes in the redox state of the cochlea stimulate the activation of NF-kappaB and that this activation is cell protective. (C) 2005 Wiley-Liss, Inc.