The mechanism of pneumolysin-induced cochlear hair cell death in the rat
The mechanism of pneumolysin-induced cochlear hair cell death in the rat
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DOI：
10.1113/jphysiol.2005.092478
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发表时间：
2005-10-01
影响因子：
5.5
通讯作者：
Dulon, D
中科院分区：
文献类型：
--
作者：
Beurg, M;Hafidi, A;Dulon, D
肺炎链球菌感染可导致局部和全身性疾病，如中耳炎、肺炎和脑膜炎。与这种感染相关的感音神经性听力损失是由一种外毒素溶气素的释放介导的。本研究的目的是表征肺溶素对体外耳蜗毛细胞的毒性机制。溶气血素对耳蜗毛细胞造成严重损伤，从纤毛立体紊乱到全细胞丢失。令人惊讶的是，溶气素诱导的细胞死亡优先针对内毛细胞。溶血素通过钙的流入引发体外细胞死亡。细胞外钙似乎通过毒素形成的孔进入细胞。用BAPTA缓冲细胞内钙可提高毛细胞存活率。使用bongkrekic酸证实了参与溶气素诱导的细胞死亡的线粒体凋亡途径。溶血素与毛细胞细胞膜的结合是诱导细胞死亡的必要条件。增加外源性钙通过阻止溶血素与毛细胞膜的结合而降低细胞毒性。这些结果表明，钙在触发气溶素诱导的毛细胞凋亡和阻止毒素与细胞靶标结合方面具有重要作用。
Streptoccocus pneumoniae infection can result in local and systemic diseases such as otitis media, pneumonia and meningitis. Sensorineural hearing loss associated with this infection is mediated by the release of an exotoxin, pneumolysin. The goal of the present study was to characterize the mechanisms of pneumolysin toxicity in cochlear hair cells in vitro. Pneumolysin induced severe damage in cochlear hair cells, ranging from stereocilia disorganization to total cell loss. Surprisingly, pneumolysin-induced cell death preferentially targeted inner hair cells. Pneumolysin triggered in vitro cell death by an influx of calcium. Extracellular calcium appeared to enter the cell through a pore formed by the toxin. Buffering intracellular calcium with BAPTA improved hair cell survival. The mitochondrial apoptotic pathway involved in pneumolysin-induced cell death was demonstrated by the use of bongkrekic acid. Binding of pneumolysin to the hair cell plasma membrane was required to induce cell death. Increasing external calcium reduced cell toxicity by preventing the binding of pneumolysin to hair cell membranes. These results showed the significant role of calcium both in triggering pneumolysin-induced hair cell apoptosis and in preventing the toxin from binding to its cellular target.