Li Shengjie, Eisenstadt Rachel, Kumasaka Kenichiro, Johnson Victoria E, Marks Joshua, Nagata Katsuhiro, Browne Kevin D, Smith Douglas H, Pascual Jose L
From the Division of Traumatology, Surgical Critical Care and Emergency Surgery (S.L., R.E., K.K., J.M., K.N., J.L.P.), Department of Neurosurgery, Center for Brain Injury, and Repair (V.E.J., K.D.B., D.H.S., J.L.P.), University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; and Department of Neurosurgery (S.L.), Qianfoshan Hospital, Shandong University, Jinan, China.
J Trauma Acute Care Surg. 2016 Mar;80(3):381-7; discussion 387-9. doi: 10.1097/TA.0000000000000935.
Enoxaparin (ENX) has been shown to reduce cerebral edema and improve neurologic recovery after traumatic brain injury (TBI), through blunting of cerebral leukocyte (LEU) recruitment. High mobility group box 1 (HMGB1) protein may induce inflammation through LEU activation. We hypothesized that ENX after TBI reduces LEU-mediated edema through blockade of HMGB1 signaling.
Twenty-three CD1 mice underwent severe TBI by controlled cortical impact and were randomized to one of four groups receiving either monoclonal antibody against HMGB1 (MAb) or isotype (Iso) and either ENX (1 mg/kg) or normal saline (NS): NS + Iso (n = 5), NS + MAb (n = 6), ENX + Iso (n = 6), ENX + MAb (n = 6). ENX or NS was administered 2, 8, 14, 23 and 32 hours after TBI. MAb or Iso (25 μg) was administered 2 hours after TBI. At 48 hours, cerebral intravital microscopy served to visualize live LEU interacting with endothelium and microvascular fluorescein isothiocyanate-albumin leakage. The Neurological Severity Score (NSS) graded neurologic recovery; wet-to-dry ratios determined cerebral/lung edema. Analysis of variance with Bonferroni correction was used for statistical analyses.
ENX and MAb similarly reduced in vivo pial LEU rolling without demonstrating additive effect. In vivo albumin leakage was greatest in vehicle-treated animals but decreased by 25% with either MAb or ENX but by 50% when both were combined. Controlled cortical impact-induced cerebral wet-to-dry ratios were reduced by MAb or ENX without additive effect. Postinjury lung water was reduced by ENX but not by MAb. Neurologic recovery at 24 hours and 48 hours was similarly improved with ENX, MAb, or both treatments combined.
Mirroring ENX, HMGB1 signaling blockade reduces LEU recruitment, cerebrovascular permeability, and cerebral edema following TBI. ENX further reduced lung edema indicating a multifaceted effect beyond HMGB1 blockade. Further study is needed to determine how ENX may play a role in blunting HMGB1 signaling in brain injury patients.
已表明依诺肝素（ENX）通过抑制脑白细胞（LEU）募集，可减轻创伤性脑损伤（TBI）后的脑水肿并改善神经功能恢复。高迁移率族蛋白B1（HMGB1）蛋白可能通过激活LEU诱导炎症。我们推测TBI后ENX通过阻断HMGB1信号传导减轻LEU介导的水肿。
23只CD1小鼠通过控制性皮质撞击造成重度TBI，并随机分为四组之一，分别接受抗HMGB1单克隆抗体（MAb）或同型对照（Iso），以及ENX（1 mg/kg）或生理盐水（NS）：NS + Iso（n = 5），NS + MAb（n = 6），ENX + Iso（n = 6），ENX + MAb（n = 6）。TBI后2、8、14、23和32小时给予ENX或NS。TBI后2小时给予MAb或Iso（25μg）。48小时时，脑活体显微镜用于观察活的LEU与内皮细胞的相互作用以及微血管异硫氰酸荧光素 - 白蛋白渗漏。神经严重程度评分（NSS）对神经功能恢复进行分级；干湿比测定脑/肺水肿情况。采用Bonferroni校正的方差分析进行统计分析。
ENX和MAb同样降低了体内软脑膜LEU滚动，且未显示出相加效应。体内白蛋白渗漏在载体处理的动物中最大，但MAb或ENX均可使其降低25%，两者联合使用时降低50%。控制性皮质撞击诱导的脑干湿比被MAb或ENX降低，且无相加效应。损伤后肺水被ENX降低，但未被MAb降低。ENX、MAb或两者联合治疗在24小时和48小时时同样改善了神经功能恢复。
与ENX类似，HMGB1信号传导阻断可减少TBI后的LEU募集、脑血管通透性和脑水肿。ENX进一步降低了肺水肿，表明其具有超出HMGB1阻断的多方面作用。需要进一步研究以确定ENX在脑损伤患者中如何在抑制HMGB1信号传导方面发挥作用。
