Department of Neurology, the Second Hospital Affiliated to Shanxi Medical University, 382 Wuyi Road, Taiyuan, Shanxi 030000, China.
Shanxi Medical University, 56 new south road, Taiyuan, Shanxi 030000, China.
Neuroscience. 2019 May 15;406:369-375. doi: 10.1016/j.neuroscience.2019.03.032. Epub 2019 Mar 23.
Early brain injury (EBI) mainly leads to the poor outcome of subarachnoid hemorrhage (SAH), with which inflammation is closely associated. It was reported that triggering receptor expressed on myeloid cells-1 (TREM-1), a critical inflammatory amplifier, increased in cerebrospinal fluid of SAH patients in our recent research. This study was conducted to examine the effects of TREM-1 inhibition on EBI after experimental SAH (eSAH). The endovascular perforation model of SAH was produced and 120 rats were randomly divided into four groups as sham, SAH + vehicle and SAH + LP17 (1.0 mg/kg and 3.5 mg/kg). The LP17, a selective inhibitor of TREM-1, or vehicle was administered by an intraperitoneal injection 1 h post-modeling. Western blot analysis for TREM-1, p38 mitogen-activated protein kinase (p38MAPK), matrix metalloproteinase-9 (MMP-9) and zonula occludens-1 (ZO-1) was conducted at 24 h post-modeling. EBI was assessed in terms of mortality, neuroscore, brain edema, blood-brain barrier (BBB) disruption in 24 and 72 h. The results showed that TREM-1 was induced in brain after eSAH. Both high dose (3.5 mg/kg) and low dose (1.0 mg/kg) of Lp17 significantly inhibited the induction of TREM-1, but only high dose of LP17 improved neuroscore, brain edema, and BBB disruption which are associated with downregulation of p38MAPK/MMP-9 and subsequent preservation of ZO-1. Overall, the current study provides new evidence that TREM-1 may participate in the pathogenesis of SAH-induced EBI via promoting p38MAPK/MMP-9 activation and ZO-1 degradation, while TREM-1 inhibition attenuated the EBI severity obviously, providing a novel approach for the treatment of EBI.
早期脑损伤（EBI）主要导致蛛网膜下腔出血（SAH）的预后不良，炎症与之密切相关。我们最近的研究报道，触发髓系细胞表达的受体-1（TREM-1），一种关键的炎症放大器，在 SAH 患者的脑脊液中增加。这项研究旨在研究 TREM-1 抑制对实验性 SAH（eSAH）后 EBI 的影响。制作了 SAH 的血管内穿孔模型，将 120 只大鼠随机分为 4 组：假手术组、SAH+载体组和 SAH+LP17（1.0mg/kg 和 3.5mg/kg）组。模型制作后 1h 通过腹腔注射给予 LP17，一种 TREM-1 的选择性抑制剂或载体。在模型制作后 24h 进行 TREM-1、p38 丝裂原活化蛋白激酶（p38MAPK）、基质金属蛋白酶-9（MMP-9）和紧密连接蛋白-1（ZO-1）的 Western blot 分析。在 24 和 72h 评估 EBI 的死亡率、神经评分、脑水肿和血脑屏障（BBB）破坏。结果显示，eSAH 后脑组织中诱导了 TREM-1。高剂量（3.5mg/kg）和低剂量（1.0mg/kg）的 LP17 均显著抑制了 TREM-1 的诱导，但只有高剂量的 LP17 改善了神经评分、脑水肿和 BBB 破坏，这与 p38MAPK/MMP-9 的下调和随后 ZO-1 的保存有关。总之，本研究提供了新的证据，表明 TREM-1 可能通过促进 p38MAPK/MMP-9 的激活和 ZO-1 的降解参与 SAH 诱导的 EBI 的发病机制，而 TREM-1 抑制明显减轻了 EBI 的严重程度，为 EBI 的治疗提供了一种新的方法。
