Jia H, François F, Bourien J, Eybalin M, Lloyd R V, Van De Water T R, Puel J-L, Venail F
INSERM - UMR 1051, Institute for Neurosciences of Montpellier, Montpellier, France; University Montpellier 1 & 2, Montpellier, France; Department of ORL H&N Surgery, Xinhua Hospital - Ear Institute, Shanghai Jiaotong University School of Medicine, China.
INSERM - UMR 1051, Institute for Neurosciences of Montpellier, Montpellier, France; University Montpellier 1 & 2, Montpellier, France.
Neuroscience. 2016 Mar 1;316:261-78. doi: 10.1016/j.neuroscience.2015.12.031. Epub 2015 Dec 21.
Cochlear fibrosis is a common finding following cochlear implantation. Evidence suggests that cochlear fibrosis could be triggered by inflammation and epithelial-to-mesenchymal cell transition (EMT). In this study, we investigate the mechanisms of cochlear fibrosis and the risk/benefit ratio of local administration of the anti-inflammatory drug dexamethasone (DEX) and antimitotic drug aracytine (Ara-C). Cochlear fibrosis was evaluated in cochlear fibrosis models of rat cochlear slices in vitro and in KLH-induced immune labyrinthitis and platinum wire cochlear implantation-induced fibrosis in vivo. Cochleae were invaded with tissue containing fibroblastic cells expressing α-SMA (alpha smooth muscle actin), which along with collagen I, fibronectin, and laminin in the extracellular matrix, suggests the involvement of a fibrotic process triggered by EMT in vitro and in vivo. After perilymphatic injection of an adenoviral vector expressing GFP in vivo, we demonstrated that the fibroblastic cells derived from the mesothelial cells of the scalae tympani and vestibuli. Activation of inflammatory and EMT pathways was further assessed by ELISA analysis of the expression of IL-1β and TGF-β1. Both markers were elevated in vitro and in vivo, and DEX and Ara-C were able to reduce IL-1β and TGF-β1 production. After 5days of culture in vitro, quantification of calcein-positive cells revealed that Ara-C was 30-fold more efficient in preventing fibrosis, and provoked less sensory hair cell loss, than DEX. In KLH-induced immune labyrinthitis and platinum wire-implanted models, Ara-C was more efficient in preventing proliferation of fibrosis with less side effects on hair cells and neurons than DEX. In conclusion, DEX and Ara-C both prevent fibrosis in the cochlea. Analysis of the risk/benefit ratio favors the use of Ara-C for preventing cochlear fibrosis.
耳蜗纤维化是人工耳蜗植入术后常见的现象。有证据表明，耳蜗纤维化可能由炎症和上皮-间充质细胞转化（EMT）引发。在本研究中，我们探究了耳蜗纤维化的机制以及局部应用抗炎药物地塞米松（DEX）和抗有丝分裂药物阿糖胞苷（Ara-C）的风险/效益比。在体外大鼠耳蜗切片的耳蜗纤维化模型以及体内钥孔戚血蓝蛋白（KLH）诱导的免疫性迷路炎和铂丝耳蜗植入诱导的纤维化模型中评估耳蜗纤维化情况。耳蜗被含有表达α-平滑肌肌动蛋白（α-SMA）的成纤维细胞的组织侵入，这与细胞外基质中的I型胶原蛋白、纤连蛋白和层粘连蛋白一起，表明在体外和体内均有由EMT触发的纤维化过程参与。在体内经外淋巴注射表达绿色荧光蛋白（GFP）的腺病毒载体后，我们证明成纤维细胞来源于鼓阶和前庭阶的间皮细胞。通过ELISA分析白细胞介素-1β（IL-1β）和转化生长因子-β1（TGF-β1）的表达进一步评估炎症和EMT途径的激活情况。这两种标志物在体外和体内均升高，并且DEX和Ara-C能够降低IL-1β和TGF-β1的产生。体外培养5天后，钙黄绿素阳性细胞的定量分析显示，与DEX相比，Ara-C在预防纤维化方面的效率高30倍，并且引起的感觉毛细胞损失更少。在KLH诱导的免疫性迷路炎和铂丝植入模型中，与DEX相比，Ara-C在预防纤维化增殖方面更有效，对毛细胞和神经元的副作用更小。总之，DEX和Ara-C均能预防耳蜗纤维化。风险/效益比分析表明，使用Ara-C预防耳蜗纤维化更为有利。
