Ma Xiaotang, Cheng Yiming, Garcia Ricardo, Haorah James
Laboratory of Neurovascular Inflammation and Neurodegeneration, Department of Biomedical Engineering, Center for Injury Bio-Mechanics, Materials and Medicine, New Jersey Institute of Technology, Newark, NJ, 07102, USA.
J Neuroimmune Pharmacol. 2020 Jun;15(2):181-195. doi: 10.1007/s11481-019-09882-x. Epub 2019 Nov 26.
Traumatic brain injury (TBI) is a major health problem for over 3.17 million people in the US, attracting increasing public attentions. Understanding the underlying mechanism of TBI is urgent for better diagnosis and treatment. Here, we examined the hypothesis that cerebral hemorrhagic coagulation and subsequent immune cells infiltration causes the progressive mechanisms of brain injury in moderate fluid percussion injury model. This represents a subdural hematoma and hemorrhagic head injury. We found increased hemorrhagic lesions and infarct volume in the injured brain with increment of pressure. The extent of hemorrhage was also validated by the bio-distribution of fluorescent tracer in cerebrospinal fluid (CSF) pathway after the injury. Bio-distribution of tracer was specifically diminished at the site of hemorrhage resulting from coagulation, which blocked the interstitial and CSF movement of the tracer. Increased expression of coagulation factor XII and necrotic cell death in and around the impact site confirmed the reason for this blockade. Different biomarkers, including immune cells accumulation and neuronal death showed that blood-brain barrier disruption played an important role for induction of neuroinflammation and neurodegeneration around the impact site. Our results suggest that instant hemorrhagic injury resulting from rupturing the brain blood vessels intertwined with coagulation causes onsite perivascular inflammation and neurodegeneration. Understanding of this sequential event should be valuable for development of therapeutic treatment in TBI. Graphical Abstract Underlying mechanisms in moderate/severe blunt TBI: hemorrhage following cerebrovascular disruption results in coagulation, thrombotic necrosis, and acute immune cell infiltration.
创伤性脑损伤（TBI）是美国317万多人面临的一个主要健康问题，日益引起公众关注。了解TBI的潜在机制对于更好的诊断和治疗至关重要。在此，我们检验了这样一个假设：在中度液压冲击伤模型中，脑出血凝块形成及随后免疫细胞浸润导致脑损伤的进展机制。这代表硬膜下血肿和出血性头部损伤。我们发现，随着压力升高，受伤大脑中的出血性病变和梗死体积增加。损伤后脑脊液（CSF）通路中荧光示踪剂的生物分布也证实了出血程度。示踪剂的生物分布在凝血导致的出血部位明显减少，这阻碍了示踪剂的间质和脑脊液移动。撞击部位及其周围凝血因子XII表达增加和坏死性细胞死亡证实了这种阻碍的原因。包括免疫细胞聚集和神经元死亡在内的不同生物标志物表明，血脑屏障破坏在撞击部位周围诱导神经炎症和神经退行性变中起重要作用。我们的结果表明，脑血管破裂伴凝血导致的即时出血性损伤会引起局部血管周围炎症和神经退行性变。了解这一连续事件对于TBI治疗方法的开发应该具有重要价值。图形摘要 中度/重度钝性TBI的潜在机制：脑血管破裂后出血导致凝血、血栓性坏死和急性免疫细胞浸润。
