Immunomodulation of Trauma Program, US Army Institute of Surgical Research, 3650 Chambers Pass, BHT2/Building 3610, Fort Sam Houston, TX 78234, USA.
Acta Neuropathol Commun. 2013 Aug 16;1:52. doi: 10.1186/2051-5960-1-52.
Blast-induced neurotrauma (BINT) is the signature life threatening injury of current military casualties. Neuroinflammation is a key pathological occurrence of secondary injury contributing to brain damage after blast injury. We have recently demonstrated that blast-triggered complement activation and cytokine release are associated with BINT. Here, we evaluated if administration of the complement inhibitor recombinant human decay-accelerating factor (rhDAF) is beneficial on neuroinflammation and neurodegeneration in a rat model of moderate BINT. Administration of rhDAF after exposure to moderate blast overpressure (BOP, 120 kPa) mitigated brain injury characterized by neuronal degeneration. rhDAF treatment reduced complement hemolytic activity at 3 hours and tissue complement deposition at 3, 24, and 48 hours as well as systemic and local cytokine release at 24 hours post BOP. Furthermore, rhDAF protected blood-brain barrier (BBB) integrity and reduced cytotoxic edema. Interaction between complement cleavage component, C3a and C3a receptor and tau phosphorylation were also attenuated in rhDAF treated animals at 3 and 24 hours after BOP. These novel findings suggest early complement targeted inhibition as a new therapeutic strategy to decrease neuroinflammation and neurodegeneration after blast TBI.
Administration of rhDAF after exposure to moderate blast overpressure (BOP, 120 kPa) mitigated brain injury characterized by neuronal degeneration. rhDAF treatment reduced complement hemolytic activity at 3 hours and tissue complement deposition at 3, 24, and 48 hours as well as systemic and local cytokine release at 24 hours post BOP. Furthermore, rhDAF protected blood-brain barrier (BBB) integrity and reduced cytotoxic edema. Interaction between complement cleavage component, C3a and C3a receptor and tau phosphorylation were also attenuated in rhDAF treated animals at 3 and 24 hours after BOP.
These novel findings suggest early complement targeted inhibition as a new therapeutic strategy to decrease neuroinflammation and neurodegeneration after blast TBI.
爆炸诱导的神经创伤（BINT）是当前军事伤亡的标志性致命伤。神经炎症是继发性损伤的关键病理事件，导致爆炸伤后的脑损伤。我们最近证明，爆炸引发的补体激活和细胞因子释放与 BINT 有关。在这里，我们评估了在中度 BINT 大鼠模型中，给予补体抑制剂重组人衰变加速因子（rhDAF）是否对神经炎症和神经退行性变有益。在暴露于中度爆炸超压（BOP，120 kPa）后给予 rhDAF 可减轻以神经元变性为特征的脑损伤。rhDAF 治疗可降低 3 小时的补体溶血活性和 3、24 和 48 小时的组织补体沉积以及 BOP 后 24 小时的全身和局部细胞因子释放。此外，rhDAF 可保护血脑屏障（BBB）的完整性并减少细胞毒性水肿。在 BOP 后 3 和 24 小时，rhDAF 处理的动物中补体裂解成分 C3a 和 C3a 受体与 tau 磷酸化之间的相互作用也减弱。这些新发现表明，早期针对补体的靶向抑制可能是减少爆炸性颅脑损伤后神经炎症和神经退行性变的新治疗策略。
在暴露于中度爆炸超压（BOP，120 kPa）后给予 rhDAF 可减轻以神经元变性为特征的脑损伤。rhDAF 治疗可降低 3 小时的补体溶血活性和 3、24 和 48 小时的组织补体沉积以及 BOP 后 24 小时的全身和局部细胞因子释放。此外，rhDAF 可保护血脑屏障（BBB）的完整性并减少细胞毒性水肿。在 BOP 后 3 和 24 小时，rhDAF 处理的动物中补体裂解成分 C3a 和 C3a 受体与 tau 磷酸化之间的相互作用也减弱。
这些新发现表明，早期针对补体的靶向抑制可能是减少爆炸性颅脑损伤后神经炎症和神经退行性变的新治疗策略。
