Yan Bin, Xie Daoli, Wu Yuancheng, Wang Shuli, Zhang Xiaolin, Zhao Tong, Liu Luying, Ma Peng, Li Guqiang, Yang Ying, Zhao Yucheng, Zheng Tihua, Geng Ruishuang, Li Bo, Zheng Qingyin
Hearing and Speech Rehabilitation Institute, College of Special Education, Binzhou Medical University, Yantai, China.
Rehabilitation Medicine & Physical Therapy, School of Rehabilitation Medicine, Binzhou Medical University, Yantai, China.
Cell Death Discov. 2022 Apr 21;8(1):217. doi: 10.1038/s41420-022-01025-1.
Otitis media (OM) is a common disease that can cause hearing loss in children. Currently, the main clinical treatment for OM is antibiotics, but the overuse of antibiotics might lead to bacterial resistance, which is a worldwide public health challenge. Studying the pathogenesis of OM will help us develop new effective treatments. Ferroptosis is one type of programmed cell death characterized by the occurrence of lipid peroxidation driven by iron ions. Many studies have shown that ferroptosis is associated with infectious diseases. It is presently unclear whether ferroptosis is involved in the pathogenesis of OM. In this study, we explored the relationship between ferroptosis and OM by PGPS-induced OM in C57BL/6 mice and treating the induced OM with ferroptosis inhibitors deferoxamine (DFO), Ferrostatin-1 (Fer-1), and Liperoxstatin-1 (Lip-1). We examined the expression of ferroptosis-related proteins acyl-CoA synthetase long chain family member 4 (ACSL4) and prostaglandin-endoperoxide synthase 2 (Cox2), glutathione peroxidase 4 (GPX4) protein as well as lipid peroxidation markers 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA). The results showed that in PGPS-induced OM model mice, several ferroptosis-related proteins including ACSL4 and Cox2 were up-regulated compared to mice treated with saline. Meanwhile, a ferroptosis-related protein GPX4 was down-regulated upon PGPS treatment. The DFO treatment in PGPS-inoculated mice effectively inhibited the development of OM. The inhibitors treatment caused a significant decrease in the expression of ACSL4, Cox2, 4 HNE, MDA, reduction in free iron. Meanwhile, the ferroptosis inhibitors treatment caused increase in the expression of inflammation-related factors tumor necrosis factor-α (TNF-α) and antioxidant protein GPX4. Our results suggest that there is a crosstalk between ferroptosis signaling pathway and the pathogenesis of OM. Ferroptosis inhibition can alleviate PGPS-induced OM.
中耳炎（OM）是一种常见疾病，可导致儿童听力丧失。目前，OM的主要临床治疗方法是使用抗生素，但抗生素的过度使用可能导致细菌耐药性，这是一个全球性的公共卫生挑战。研究OM的发病机制将有助于我们开发新的有效治疗方法。铁死亡是一种程序性细胞死亡，其特征是由铁离子驱动的脂质过氧化的发生。许多研究表明，铁死亡与传染病有关。目前尚不清楚铁死亡是否参与OM的发病机制。在本研究中，我们通过在C57BL/6小鼠中用PGPS诱导OM并用铁死亡抑制剂去铁胺（DFO）、铁抑素-1（Fer-1）和脂氧素-1（Lip-1）治疗诱导的OM，探讨了铁死亡与OM之间的关系。我们检测了铁死亡相关蛋白酰基辅酶A合成酶长链家族成员4（ACSL4）和前列腺素内过氧化物合酶2（Cox2）、谷胱甘肽过氧化物酶4（GPX4）蛋白以及脂质过氧化标志物4-羟基壬烯醛（4-HNE）和丙二醛（MDA）的表达。结果表明，在PGPS诱导的OM模型小鼠中，与用生理盐水处理的小鼠相比，包括ACSL4和Cox2在内的几种铁死亡相关蛋白上调。同时，PGPS处理后铁死亡相关蛋白GPX4下调。PGPS接种小鼠中的DFO治疗有效抑制了OM的发展。抑制剂治疗导致ACSL4、Cox2、4-HNE、MDA的表达显著降低，游离铁减少。同时，铁死亡抑制剂治疗导致炎症相关因子肿瘤坏死因子-α（TNF-α）和抗氧化蛋白GPX4的表达增加。我们的结果表明，铁死亡信号通路与OM的发病机制之间存在相互作用。抑制铁死亡可以减轻PGPS诱导的OM。
