Inhibition of caspases prevents ototoxic and ongoing hair cell death
Inhibition of caspases prevents ototoxic and ongoing hair cell death
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DOI：
10.1523/jneurosci.22-04-01218.2002
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发表时间：
2002-02-15
影响因子：
5.3
通讯作者：
Warchol, ME
中科院分区：
文献类型：
--
作者：
Matsui, JI;Ogilvie, JM;Warchol, ME
感觉毛细胞在听觉创伤或耳毒性侮辱后死亡，但介导毛细胞死亡的信号转导途径尚不清楚。在这里，我们确定了几个重要的信号事件，调节前庭毛细胞的死亡。在添加耳毒性抗生素新霉素和影响细胞死亡途径中的信号分子的选定药理物质的基础上，培养鸡卵圆囊。用新霉素处理的毛细胞表现出典型的凋亡形态，如核浓缩和DNA片段化。抑制蛋白质合成(通过环己亚胺治疗)可增加新霉素治疗后毛细胞的存活率，这表明毛细胞死亡需要从头合成蛋白质。最后，抑制半胱氨酸氨基转移酶促进了新霉素处理后毛细胞的存活。鸟类前庭器官中的感觉毛细胞在整个成熟生命过程中也会经历不断的细胞死亡和更替。目前尚不清楚毛细胞的丧失是否刺激了支持细胞的增殖，或者新细胞的产生是否触发了毛细胞的死亡。我们研究了半胱氨酸天冬氨酸氨基转移酶抑制对鸡卵圆囊毛细胞自发性死亡的影响。Caspase抑制剂以剂量依赖的方式减少正在进行的毛细胞死亡和正在进行的支持细胞增殖的数量。然而，在分离的感觉上皮细胞中，半胱氨酸氨基转移酶抑制剂并不直接影响支持细胞的增殖。我们的数据表明，正在进行的毛细胞死亡刺激成熟椭圆形中的支持细胞增殖。
Sensory hair cells die after acoustic trauma or ototoxic insults, but the signal transduction pathways that mediate hair cell death are not known. Here we identify several important signaling events that regulate the death of vestibular hair cells. Chick utricles were cultured in media supplemented with the ototoxic antibiotic neomycin and selected pharmacological agents that influence signaling molecules in cell death pathways. Hair cells that were treated with neomycin exhibited classically defined apoptotic morphologies such as condensed nuclei and fragmented DNA. Inhibition of protein synthesis (via treatment with cycloheximide) increased hair cell survival after treatment with neomycin, suggesting that hair cell death requires de novo protein synthesis. Finally, the inhibition of caspases promoted hair cell survival after neomycin treatment. Sensory hair cells in avian vestibular organs also undergo continual cell death and replacement throughout mature life. It is unclear whether the loss of hair cells stimulates the proliferation of supporting cells or whether the production of new cells triggers the death of hair cells. We examined the effects of caspase inhibition on spontaneous hair cell death in the chick utricle. Caspase inhibitors reduced the amount of ongoing hair cell death and ongoing supporting cell proliferation in a dose-dependent manner. In isolated sensory epithelia, however, caspase inhibitors did not affect supporting cell proliferation directly. Our data indicate that ongoing hair cell death stimulates supporting cell proliferation in the mature utricle.