Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Parkville, Victoria, Australia.
Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Victoria, Australia.
J Comp Neurol. 2019 Apr 15;527(6):1102-1117. doi: 10.1002/cne.24589. Epub 2018 Dec 30.
Accumulating research suggests that children may be more vulnerable to poor long-term outcomes after traumatic brain injury (TBI) compared to adults. The neuroinflammatory response, known to contribute to neuropathology after TBI, appears to differ depending upon age-at-insult, although this response has not been well-characterized. Elevated levels of a key initiator of inflammation, high-mobility group box protein 1 (HMGB1), have been associated with worsened outcomes after TBI in young patients. This study therefore aimed to characterize the acute time course of key mediators of the inflammatory cascade, including HMGB1, after pediatric and adult TBI. Male C57Bl/6 mice were subjected to severe controlled cortical impact or a sham control surgery, at either early adulthood (8-10 weeks) or a pediatric age (3 weeks). Cortical tissue was collected for Western blot detection of astrocyte and microglial activation (GFAP and CD68) and HMGB1 at 2 hr, 6 hr, 24 hr, 3 days, and 7 days postinjury, and serum was collected for enzyme-linked immunoassays to quantify peripheral HMGB1. An additional cohort of brains was harvested at 3 day postinjury for immunofluorescence staining. Results demonstrated a temporal profile of CD68, GFAP, and HMGB1 after TBI relative to sham, which differed between the adult and pediatric cohorts. An increase in peripheral HMGB1 was found in serum from pediatric TBI mice, which was not evident in adult serum. Together, these findings demonstrate that HMGB1 and the downstream cellular inflammatory response are influenced by age-at-insult, which may be an important consideration for treatment strategies aiming to ameliorate this response after TBI.
越来越多的研究表明，与成年人相比，儿童在创伤性脑损伤（TBI）后可能更容易出现长期不良后果。神经炎症反应已知会导致 TBI 后的神经病理学改变，但这种反应的特征尚未得到很好的描述。炎症级联反应中的关键启动子——高迁移率族蛋白 B1（HMGB1）的水平升高与年轻患者 TBI 后的预后恶化有关。因此，本研究旨在描述儿科和成人 TBI 后炎症级联反应中的关键介质（包括 HMGB1）的急性时程。雄性 C57Bl/6 小鼠在成年早期（8-10 周）或儿科年龄（3 周）时接受严重的皮质控制冲击或假手术。在损伤后 2 小时、6 小时、24 小时、3 天和 7 天收集皮质组织，用于 Western blot 检测星形胶质细胞和小胶质细胞激活（GFAP 和 CD68）和 HMGB1，收集血清用于酶联免疫吸附试验以定量外周 HMGB1。另外一组大脑在损伤后 3 天用于免疫荧光染色。结果表明，与假手术相比，TBI 后 CD68、GFAP 和 HMGB1 存在时间依赖性，且在成年和儿科队列之间存在差异。在儿科 TBI 小鼠的血清中发现外周 HMGB1 增加，而在成年血清中则没有。这些发现表明，HMGB1 和下游细胞炎症反应受到损伤时年龄的影响，这可能是治疗策略的一个重要考虑因素，旨在改善 TBI 后的这种反应。
