The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, Jiangsu 210009, China.
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 210029, China.
Biomed Res Int. 2019 Jul 10;2019:5347804. doi: 10.1155/2019/5347804. eCollection 2019.
Chemotherapy induced peripheral neuropathy (CIPN) is a serious adverse effect of chemotherapeutics with limited pathogenetic mechanism been known. Whether microcirculatory disturbance is involved in CIPN has not been reported. Considering that tissue factor (TF) is an endogenous coagulation factor, we hypothesize CIPN may be induced by the high expression of TF in macrophages and sciatic nerve, which induces the molecular signal related to ischemia and hypoxia. Oxaliplatin (L-OHP) was used to establish CIPN model. Von Frey Hairs was used to measure nociception. The murine macrophage cell line Raw 264.7 was used for cell experiments. Gelatin zymography and western blotting were used to measure the activity or expression of protein. TF expression and MMP-9/2 activity in sciatic nerve and blood are significantly increased by L-OHP. L-OHP increased the release of HSP70 from macrophage and enhanced the expression of p-p38 and HIF-1 in vivo and in vitro. Hirudin significantly suppressed the overexpression of p38, HIF-1 and activation of MMP-9/2 induced by L-OHP and attenuated CIPN in mice. This study suggests that a novel HSP70-TLR-4-p38-TF-HIF-1a axis may play a pivotal role in the pathological process of CIPN. It is also shown that the use of anticoagulant Hirudin can inhibit the above mechanisms and improve CIPN.
化疗引起的周围神经病（CIPN）是一种严重的化疗药物不良反应，其发病机制尚不清楚。微血管紊乱是否与 CIPN 有关尚未报道。鉴于组织因子（TF）是一种内源性凝血因子，我们假设 CIPN 可能是由巨噬细胞和坐骨神经中 TF 的高表达引起的，这会引发与缺血和缺氧相关的分子信号。奥沙利铂（L-OHP）用于建立 CIPN 模型。使用 von Frey 毛发测量疼痛。使用鼠巨噬细胞系 Raw 264.7 进行细胞实验。明胶酶谱和 Western blot 用于测量蛋白的活性或表达。L-OHP 使坐骨神经和血液中的 TF 表达和 MMP-9/2 活性明显增加。L-OHP 增加了巨噬细胞中 HSP70 的释放，并增强了体内和体外 p-p38 和 HIF-1 的表达。水蛭素显著抑制了 L-OHP 诱导的 p38、HIF-1 和 MMP-9/2 激活的过表达，并减轻了小鼠的 CIPN。本研究表明，一种新的 HSP70-TLR-4-p38-TF-HIF-1a 轴可能在 CIPN 的病理过程中发挥关键作用。还表明，抗凝剂水蛭素的使用可以抑制上述机制并改善 CIPN。
