N-Acetylcysteine attenuates tumor necrosis factor alpha levels in autoimmune inner ear disease patients.
N-Acetylcysteine attenuates tumor necrosis factor alpha levels in autoimmune inner ear disease patients.
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DOI：
10.1007/s12026-015-8696-3
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发表时间：
2015-12
影响因子：
4.4
通讯作者：
Vambutas A
中科院分区：
文献类型：
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作者：
Pathak S;Stern C;Vambutas A
自身免疫性内耳疾病 (AIED) 是一种人们知之甚少的疾病，其特点是由未知刺激引发的双侧快速进行性听力损失，60% 的患者对皮质类固醇有反应。尽管该疾病的机制尚不清楚，但据信细胞因子的复杂相互作用会导致炎症性疾病过程和听力损失。之前我们展示了 TNF-α 在类固醇敏感性中的作用，以及 IL-1β 在类固醇抵抗性免疫介导的听力损失中的作用。 N-乙酰半胱氨酸 (NAC) 是一种广谱抗氧化剂，对其他自身免疫性疾病有效。其他研究表明，NAC 对人类特发性突发性听力损失具有保护性辅助作用，其中添加 NAC 比单独使用类固醇能更好地恢复听力，尽管这种保护机制尚未阐明。在本研究中，我们观察到与正常健康对照相比，AIED 患者的 PBMC 表现出更高的基线 TNF-α 和 MPO 水平。 NAC 可有效消除 AIED 患者和对照者 PBMC 中 LPS 介导的 TNF-α 释放。我们证明，在 AIED 患者中，TNF-α 下游信号通路似乎受到异常调节，影响 MPO 和 IL-8 的表达。鉴于NAC有效地消除了LPS介导的TNF-α释放，并且对该通路的下游靶点影响最小，我们认为NAC可能是这种神秘疾病的合理辅助疗法，值得临床探索。
Autoimmune Inner Ear Disease (AIED) is a poorly understood disease marked by bilateral, rapidly progressive hearing loss triggered by unknown stimuli, which is corticosteroid responsive in 60% of patients. Although the mechanism of the disease is not precisely understood, a complex interaction of cytokines is believed to contribute towards the inflammatory disease process and hearing loss. Previously we showed the role of TNF-α in steroid-sensitive, and IL-1β in steroid-resistant immune mediated hearing loss. N-acetylcysteine (NAC), a broad spectrum antioxidant, has been effective in other autoimmune disorders. Other studies have shown NAC to have a protective adjunct role in human idiopathic sudden hearing loss, where the addition of NAC resulted in better hearing recovery than with steroids alone, although the mechanism of this protection was not elucidated. In the present study, we observed PBMCs from AIED patients exhibited higher baseline TNF-α and MPO levels compared to normal healthy controls. NAC effectively abrogates LPS-mediated TNF-α release from PBMC of both AIED patients and controls. We demonstrated that in AIED patients, the TNF-α down-stream signaling pathway appears aberrantly regulated, influencing both MPO and IL-8 expression. Given that NAC effectively abrogated LPS mediated TNF-α release and exerted minimal effects on the downstream targets of this pathway, we feel NAC may be a rational adjunct therapy for this enigmatic disease, worthy of clinical exploration.