Neutrophil extracellular traps as a unique target in the treatment of chemotherapy-induced peripheral neuropathy.
Neutrophil extracellular traps as a unique target in the treatment of chemotherapy-induced peripheral neuropathy.
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DOI：
10.1016/j.ebiom.2023.104499
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发表时间：
2023-04
期刊：
影响因子：
11.1
通讯作者：
Liu, Wen-Tao
中科院分区：
文献类型：
--
作者：
Wang, Chao-Yu;Lin, Tong-Tong;Hu, Liang;Xu, Chen-Jie;Hu, Fan;Wan, Li;Yang, Xing;Wu, Xue-Feng;Zhang, Xiao-Tao;Li, Yan;Yin, Hao-Yuan;Jiang, Chun-Yi;Xin, Hong-Liang;Liu, Wen-Tao
关键词：
化疗引起的周围神经病变（CIPN）是化疗的严重剂量限制性副作用，仍然是一个巨大的临床挑战。在这里，我们探讨的作用，微循环缺氧诱导的中性粒细胞胞外陷阱（NETs）在CIPN的发展，并寻找潜在的治疗。采用ELISA、免疫组化、免疫荧光和Western blotting等方法检测血浆和背根神经节（DRG）内神经干细胞的表达。应用IVIS频谱成像技术和激光多普勒血流测量技术，探讨了NETs在CIPN形成过程中引起的微循环缺氧。中风归巢肽（SHp）引导的脱氧核糖核酸酶1（DNase 1）用于降解NET。接受化疗的患者NET水平显著升高。NET在CIPN小鼠的DRG和肢体中积累。它导致奥沙利铂（L-OHP）治疗的肢体和坐骨神经微循环障碍和缺血状态。此外，用DNase 1靶向NET显著降低了化疗诱导的机械性痛觉过敏。对髓过氧化物酶（MPO）或肽基精氨酸脱亚胺酶-4（PAD 4）的药理学或遗传学抑制显著改善L-OHP引起的小鼠微循环障碍，并防止CIPN的发展。除了揭示NET作为CIPN发展中的关键因素的作用外，我们的发现还提供了一种潜在的治疗策略，即通过SHp引导的DNase 1靶向降解NET可能是CIPN的有效治疗方法。本研究由81870870、81971047、81773798、82271252; BK 20191253; 2017 NJMUCX 004; BE 2019732; YKK 19170资助。
Chemotherapy-induced peripheral neuropathy (CIPN) is a severe dose-limiting side effect of chemotherapy and remains a huge clinical challenge. Here, we explore the role of microcirculation hypoxia induced by neutrophil extracellular traps (NETs) in the development of CIPN and look for potential treatment. The expression of NETs in plasma and dorsal root ganglion (DRG) are examined by ELISA, IHC, IF and Western blotting. IVIS Spectrum imaging and Laser Doppler Flow Metry are applied to explore the microcirculation hypoxia induced by NETs in the development of CIPN. Stroke Homing peptide (SHp)-guided deoxyribonuclease 1 (DNase1) is used to degrade NETs. The level of NETs in patients received chemotherapy increases significantly. And NETs accumulate in the DRG and limbs in CIPN mice. It leads to disturbed microcirculation and ischemic status in limbs and sciatic nerves treated with oxaliplatin (L-OHP). Furthermore, targeting NETs with DNase1 significantly reduces the chemotherapy-induced mechanical hyperalgesia. The pharmacological or genetic inhibition on myeloperoxidase (MPO) or peptidyl arginine deiminase-4 (PAD4) dramatically improves microcirculation disturbance caused by L-OHP and prevents the development of CIPN in mice. In addition to uncovering the role of NETs as a key element in the development of CIPN, our finding provides a potential therapeutic strategy that targeted degradation of NETs by SHp-guided DNase1 could be an effective treatment for CIPN. This study was funded by the 81870870, 81971047, 81773798, 82271252; BK20191253; 2017NJMUCX004; BE2019732; YKK19170.
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DOI：
10.1084/jem.20100239
发表时间：
2010-08-30
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Li P;Li M;Lindberg MR;Kennett MJ;Xiong N;Wang Y
通讯作者：
Wang Y
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影响因子：
17.1
作者：
Lv, Wei;Xu, Jianpei;Xin, Hongliang
通讯作者：
Xin, Hongliang
影响因子：
2.8
作者：
Loegters, Tim;Paunel-Goerguelue, Adnana;Jaeger, Marcus
通讯作者：
Jaeger, Marcus
影响因子：
--
作者：
Addington, James;Freimer, Miriam
通讯作者：
Freimer, Miriam
影响因子：
16.6
作者：
Kolaczkowska, Elzbieta;Jenne, Craig N.;Surewaard, Bas G. J.;Thanabalasuriar, Ajitha;Lee, Woo-Yong;Sanz, Maria-Jesus;Mowen, Kerri;Opdenakker, Ghislain;Kubes, Paul
通讯作者：
Kubes, Paul