Department of Rehabilitation, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, PR China.
Chongqing Mental Health Center, Chongqing, 4001147, PR China.
Neurosci Lett. 2020 Jul 13;731:135011. doi: 10.1016/j.neulet.2020.135011. Epub 2020 Jun 1.
Urokinase-type plasminogen activator (uPA) was demonstrated to alleviate kaolin-induced communicating hydrocephalus via inhibiting subarachnoid space fibrosis, but the exact mechanism remains elusive. Thus, this study was designed to investigate if hepatocyte growth factor (HGF), which plays a vital role in uPA-triggered inhibiting of fibrosis in multiple systems, is involved in this process in hydrocephalus. There were 2 parts in this study. First, hydrocephalus was induced in rats by basal cistern injection of kaolin. Then rats were treated with saline or uPA and brain tissue and CSF were collected for Western blot and enzyme-linked immuno sorbent assay (ELISA) four days later. Second, kaolin-induced hydrocephalus rats were treated with saline, uPA, uPA + PHA665752 (antagonist of HGF) or PHA665752. Some animals received MRI four weeks later and brains were used for immunofluorescence. The others were euthanized four days later for ELISA. Both levels of total and activated HGF in the CSF was increased after uPA injections, but related mRNA expression of HGF showed no statistical significance when compared with the control group. Further, the effects of uPA that alleviating ventricular enlargement, subarachnoid fibrosis and reactive astrocytosis were partially reversed by PHA665752. Moreover, PHA665752 partially abolished uPA-induced reduction of transforming growth factor- β1(TGF- β1) level in CSF. Our data suggest that uPA effectively inhibited subarachnoid fibrosis and restricted the development of communicating hydrocephalus in rats in part by promoting HGF release and activation, which may further regulate the TGF-β1 expression in CSF.
尿激酶型纤溶酶原激活物（uPA）被证明可通过抑制蛛网膜下腔纤维化来减轻高岭土诱导的交通性脑积水，但确切的机制仍不清楚。因此，本研究旨在探讨在脑积水过程中是否涉及多系统纤维化中起重要作用的肝细胞生长因子（HGF）。本研究分为两部分。首先，通过向基底池注射高岭土在大鼠中诱导脑积水。然后，用生理盐水或 uPA 处理大鼠，四天后收集脑组织和 CSF 进行 Western blot 和酶联免疫吸附试验（ELISA）。其次，用生理盐水、uPA、uPA+PHA665752（HGF 拮抗剂）或 PHA665752 处理高岭土诱导的脑积水大鼠。一些动物在四周后接受 MRI 检查，并用免疫荧光法检查大脑。其余动物在四天后安乐死进行 ELISA。uPA 注射后 CSF 中总 HGF 和激活型 HGF 的水平均增加，但与对照组相比，HGF 的相关 mRNA 表达无统计学意义。此外，PHA665752 部分逆转了 uPA 减轻脑室扩大、蛛网膜下腔纤维化和反应性星形胶质细胞增生的作用。此外，PHA665752 部分消除了 uPA 诱导的 CSF 中转化生长因子-β1（TGF-β1）水平降低。我们的数据表明，uPA 通过促进 HGF 释放和激活，有效地抑制了大鼠蛛网膜下腔纤维化，并限制了交通性脑积水的发展，这可能进一步调节 CSF 中的 TGF-β1 表达。
