Bone fracture exacerbates murine ischemic cerebral injury.
Bone fracture exacerbates murine ischemic cerebral injury.
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DOI：
10.1097/aln.0b013e31828c23f8
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发表时间：
2013-06
期刊：
影响因子：
8.8
通讯作者：
Su H
中科院分区：
文献类型：
--
作者：
Degos V;Maze M;Vacas S;Hirsch J;Guo Y;Shen F;Jun K;van Rooijen N;Gressens P;Young WL;Su H
骨折增加血液中的警报和促炎细胞因子，并刺激巨噬细胞在海马区的渗透和促炎细胞因子的表达。我们最近报道，卒中是骨手术后不良结局的独立危险因素，骨折对卒中结局的影响尚不清楚。我们测试了这一假说，即缺血性中风后不久的骨折通过增强神经炎性反应来增强与中风相关的损伤。建立小鼠大脑中动脉远端永久性闭塞(卒中)后1天的胫骨骨折模型。用高迁移率族盒染色体蛋白-1(HMGB1)模拟骨折效应。检测HMGB1中和抗体和封闭脂蛋白(巨噬细胞耗竭)以减轻骨折效应。3天后分析神经行为功能(n=10)、脑梗塞体积、神经元死亡、巨噬细胞/小胶质细胞浸润(n=6~7)。我们发现，卒中合并骨折的小鼠比单纯卒中的小鼠有更大的梗塞体积(同侧大脑半球平均百分比±SD：30±7%比12±3%，n=6，P<；0.001)，更严重的神经行为障碍，以及梗塞周围区更多的巨噬细胞/小胶质细胞。腹腔注射HMGB1可模拟骨折，而中和HMGB1可减轻骨折效应和巨噬细胞/小胶质细胞的浸润。用闭锁嘴唇消耗巨噬细胞也可以减轻骨折对卒中损伤和行为功能障碍的加重作用。这些新的发现表明，中风后不久的骨折通过HMGB1和巨噬细胞/小胶质细胞的渗透而增加炎症，从而增强了中风损伤。干预早期巨噬细胞/小胶质细胞的激活可能是限制中风后骨折的不良后果的治疗目标。
Bone fracture increases alarmins and pro-inflammatory cytokines in the blood, and provokes macrophage infiltration and pro-inflammatory cytokine expression in the hippocampus. We recently reported that stroke is an independent risk factor after bone surgery for adverse outcome, the impact of bone fracture on stroke outcome is unknown. We tested the hypothesis that bone fracture, shortly after ischemic stroke, enhances stroke-related injuries by augmenting the neuroinflammatory response. Tibia fracture (bone fracture) was induced in mice one day after permanent occlusion of the distal middle cerebral artery (stroke). High-mobility-group box chromosomal protein-1 (HMGB1) was tested to mimic the bone fracture effects. HMGB1 neutralizing antibody and clodrolip (macrophage depletion) were tested to attenuate the bone fracture effects. Neurobehavioral function (n=10), infarct volume, neuronal death, and macrophages/microglia-infiltration (n=6–7) were analyzed three days after. We found that mice with both stroke and bone fracture had larger infarct volumes (mean percentage of ipsilateral hemisphere±SD: 30±7% vs. 12±3%, n=6, P<0.001) more severe neurobehavioral dysfunction, and more macrophages/microglia in the peri-infarct region than mice with stroke only. Intraperitoneal injection of HMGB1 mimicked, whereas neutralizing HMGB1 attenuated, the bone fracture effects and the macrophage/microglia infiltration. Depleting macrophages with clodrolip also attenuated the aggravating effects of bone fracture on stroke lesion and behavioral dysfunction. These novel findings suggest that bone fracture shortly after stroke enhances stroke injury via augmented inflammation through HMGB1 and macrophage/microglia infiltration. Interventions to modulate early macrophage/microglia activation could be therapeutic goals to limit the adverse consequences of bone fracture after stroke.