Dexamethasone protects auditory hair cells against TNFα-initiated apoptosis via activation of PI3K/Akt and NFκB signaling
Dexamethasone protects auditory hair cells against TNFα-initiated apoptosis via activation of PI3K/Akt and NFκB signaling
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DOI：
10.1016/j.heares.2009.05.003
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发表时间：
2009-09-01
期刊：
影响因子：
2.8
通讯作者：
Van De Water, Thomas R.
中科院分区：
文献类型：
--
作者：
Haake, Scott M.;Dinh, Christine T.;Van De Water, Thomas R.
背景：肿瘤坏死因子 α (TNF α) 与创伤引起的听力损失有关。用糖皮质激素对遭受创伤的动物的耳蜗进行局部治疗，可有效降低创伤后发生的听力损失水平（例如，电极插入创伤引起的听力损失/地塞米松治疗）。假设：地塞米松 (Dex) 通过激活促进细胞存活的细胞信号通路，保护听毛细胞 (AHC) 免受创伤引起的听力损失。材料和方法：用使用耳保护药物 Dex 建立耳毒性水平的 TNF α 创伤模型。将一系列抑制剂与 TNF α 暴露的外植体的 Dex 处理结合使用，以研究参与 Dex 介导的耳保护的信号分子。 Dex 针对 TNF α 耳毒性的耳保护能力是通过从用 FITC-鬼笔环肽标记染色的固定外植体中获得的毛细胞计数来确定的，研究人员对样本身份不知情。 结果：通用 caspase 抑制剂 Boc-d-fmk 可以防止 TNF α 诱导的 AHC 死亡。当以下细胞事件被阻断时，Dex 耳保护对 TNF α 耳毒性的功效显着降低 (p < 0.05)：(1) 糖皮质激素受体 (Mif)； (2)PI3K(LY294002)； (3) Akt/PKB (SH-6)； (4) NF kappa B (NF kappa B-I)。 结论：Dex 治疗通过激活 PI3K/Akt 和 NF kappa B 信号传导，在体外保护毛细胞免受 TNF α 凋亡。 (C) 2009 Elsevier B.V. 保留所有权利。
Background: Tumor necrosis factor alpha (TNF alpha) is associated with trauma-induced hearing loss. Local treatment of cochleae of trauma-exposed animals with a glucocorticoid is effective in reducing the level of hearing loss that occurs post-trauma (e.g., electrode insertion trauma-induced hearing loss/dexamethasone treatment).Hypothesis: Dexamethasone (Dex) protects auditory hair cells (AHCs) from trauma-induced loss by activating cellular signal pathways that promote cell survival.Materials and methods: Organ of Corti explants challenged with an ototoxic level of TNF alpha was the trauma model with Dex the otoprotective drug. A series of inhibitors were used in combination with the Dex treatment of TNF alpha-exposed explants to investigate the signal molecules that participate in Dex-mediated otoprotection. The otoprotective capacity of Dex against TNF alpha ototoxicity was determined by hair cell counts obtained from fixed explants stained with FITC-phalloidin labeling with investigators blinded to specimen identity.Results: The general caspase inhibitor Boc-d-fmk prevented TNF alpha-induced AHC death. There was a significant reduction (p < 0.05) in the efficacy of Dex otoprotection against TNF alpha ototoxicity when the following cellular events were blocked: (1) glucocorticoid receptors (Mif); (2) PI3K (LY294002); (3) Akt/PKB (SH-6); and (4) NF kappa B (NF kappa B-I).Conclusion: Dex treatment protects hair cells against TNF alpha apoptosis in vitro by activation of PI3K/Akt and NF kappa B signaling. (C) 2009 Elsevier B.V. All rights reserved.