Pharmacological inhibition of cochlear mitochondrial respiratory chain induces secondary inflammation in the lateral wall: a potential therapeutic target for sensorineural hearing loss.
Pharmacological inhibition of cochlear mitochondrial respiratory chain induces secondary inflammation in the lateral wall: a potential therapeutic target for sensorineural hearing loss.
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DOI：
10.1371/journal.pone.0090089
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Matsunaga T
中科院分区：
文献类型：
--
作者：
Fujioka M;Okamoto Y;Shinden S;Okano HJ;Okano H;Ogawa K;Matsunaga T
最近有报道称，髋关节外侧壁是一个常见的炎症部位，但炎症反应的确切分子机制尚未阐明。本研究检测了由线粒体毒素3-硝基丙酸（3-NP）诱导的急性线粒体功能障碍后外侧壁的炎症反应。逆转录（RT）-PCR显示促炎细胞因子白细胞介素（IL）-1β和IL-6的表达增加。免疫组织化学显示，在激活的耳蜗巨噬细胞的数量增加的侧壁，这是在接近IL-6表达细胞。外侧壁的全基因组DNA微阵列分析显示，在3-NP施用后1天和3天分别显示>2倍上调的基因中有35%和60%是炎性基因，包括CC型和CXC型趋化因子基因。CCL-1、2和3在1 d时高表达，CCL-1、2、3、4和5、CCR-2和5以及CX 3CR 1在3-NP给药后3 d时高表达，加上CX 3CL 1表达水平无变化，表明巨噬细胞和单核细胞可能参与了对3-NP介导的损伤的炎症反应。定量（q）RT-PCR显示在3-NP介导的损伤的24 h内瞬时诱导IL-1β和IL-6表达，随后持续表达趋化因子CCL-2、4和5，直至损伤后7 d。CCL-2和IL-6的表达在显示永久性听力损伤的动物中高于显示暂时性听力损伤的动物，这表明这些炎症反应可能不利于听力恢复。目前的研究结果表明，急性线粒体功能障碍诱导耳蜗侧壁的继发性炎症反应，IL-6/CCL-2炎症通路参与单核细胞活化。因此，这些继发性炎症反应可能是潜在的损伤后治疗靶点，用于旨在预防耳蜗外侧壁急性线粒体功能障碍引起的损伤。
Cochlear lateral wall has recently been reported as a common site of inflammation, yet precise molecular mechanisms of the inflammatory responses remain elucidated. The present study examined the inflammatory responses in the lateral wall following acute mitochondrial dysfunction induced by a mitochondrial toxin, 3-nitropropionic acid (3-NP). Reverse-transcription (RT)-PCR revealed increases in the expression of the proinflammatory cytokines interleukin (IL)-1β and IL-6. Immunohistochemistry showed an increase in the number of activated cochlear macrophages in the lateral wall, which were in close proximity to IL-6-expressing cells. A genome-wide DNA microarray analysis of the lateral wall revealed that 35% and 60% of the genes showing >2-fold upregulation at 1 d and 3 d post-3-NP administration, respectively, were inflammatory genes, including CC- and CXC-type chemokine genes. High expression of CCL-1, 2, and 3 at 1 d, and of CCL-1, 2, 3, 4, and 5, CCR-2 and 5, and CX3CR1 at 3 d post-3-NP administration, coupled with no change in the level of CX3CL1 expression suggested that macrophages and monocytes may be involved in the inflammatory response to 3-NP-mediated injury. Quantitative (q)RT-PCR showed a transient induction of IL-1β and IL-6 expression within 24 h of 3-NP-mediated injury, followed by sustained expression of the chemoattractants, CCL-2, 4 and 5, up until 7 d after injury. The expression of CCL-2 and IL-6 was higher in animals showing permanent hearing impairment than in those showing temporary hearing impairment, suggesting that these inflammatory responses may be detrimental to hearing recovery. The present findings suggest that acute mitochondrial dysfunction induces secondary inflammatory responses in the lateral wall of the cochlear and that the IL-6/CCL-2 inflammatory pathway is involved in monocyte activation. Therefore, these secondary inflammatory responses may be a potential post-insult therapeutic target for treatments aimed at preventing the damage caused by acute mitochondrial dysfunction in the cochlear lateral wall.
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DOI：
10.1007/s101620020028
发表时间：
2002-09-01
期刊：
JARO
影响因子：
--
作者：
Wang, Y;Hirose, K;Liberman, MC
通讯作者：
Liberman, MC
影响因子：
1.6
作者：
Okamoto, Y;Hoya, N;Matsunaga, T
通讯作者：
Matsunaga, T
影响因子：
4.4
作者：
Yamasoba, T;Kikuchi, S;Higo, R
通讯作者：
Higo, R
影响因子：
2.5
作者：
Lang, HN;Ebihara, Y;Schulte, BA
通讯作者：
Schulte, BA
影响因子：
23.9
作者：
Belema-Bedada, Fikru;Uchida, Shizuka;Braun, Thomas
通讯作者：
Braun, Thomas