Abstract：
Traumatic brain injury (TBI) is a common cause of morbidity and mortality in children. We have previously shown that TBI with a concurrent extracranial injury reliably leads to post-injury suppression of the innate and adaptive immune systems. In patients with post-injury immune suppression, if immune function could be preserved, this might represent a therapeutic opportunity. As such, we examined, in an animal injury model, whether systemic administration of granulocyte macrophage colony-stimulating factor (GM-CSF) could reverse post-injury immune suppression and whether treatment was associated with neuroinflammation or functional deficit. Prepubescent male rats were injured using a controlled cortical impact model and then subjected to removal of 25% blood volume (TBI/H). Sham animals underwent surgery without injury induction, and the treatment groups were sham and injured animals treated with either saline vehicle or 50 μg/kg GM-CSF. GM-CSF was administered following injury and then daily until sacrifice at post-injury day (PID) 7. Immune function was measured by assessing tumor necrosis factor-α (TNF-α) levels in whole blood and spleen following ex vivo stimulation with pokeweed mitogen (PWM). Brain samples were assessed by multiplex enzyme-linked immunosorbent assay (ELISA) for cytokine levels and by immunohistochemistry for microglia and astrocyte proliferation. Neuronal cell count was examined using cresyl violet staining. Motor coordination was evaluated using the Rotarod performance test. Treatment with GM-CSF was associated with a significantly increased response to PWM in both whole blood and spleen. GM-CSF in injured animals did not lead to increases in levels of pro-inflammatory cytokines in brain samples but was associated with significant increases in counted astrocytes. Finally, while injured animals treated with saline showed a significant impairment on behavioral testing, injured animals treated with GM-CSF performed similarly to uninjured animals. GM-CSF treatment in animals with combined injury led to increased systemic immune cell response in whole blood and spleen in the acute phase following injury. Improved immune response was not associated with elevated pro-inflammatory cytokine levels in the brain or functional impairment.
摘要：
创伤性脑损伤（TBI）是儿童发病和死亡的常见原因。我们先前已经表明，并发颅外损伤的TBI可靠地导致先天和适应性免疫系统的损伤后抑制。在损伤后免疫抑制的患者中，如果免疫功能可以保留，这可能代表一个治疗机会。因此，我们检查了,在动物损伤模型中，全身给予GM-CSF是否可以逆转损伤后免疫抑制,治疗是否与神经炎症或功能缺陷相关.使用受控的皮质冲击模型对青春期前雄性大鼠进行损伤,然后去除25%的血液体积(TBI/H)。假动物接受了手术，没有受伤诱导，和治疗组是:用盐水媒介物或50μg/kgGM-CSF治疗的假动物和受伤动物。在损伤后给予GM-CSF,然后每天给予,直到在损伤后第7天处死。免疫功能是通过评估用戳杂草丝裂原（PWM）离体刺激后全血和脾脏中的TNF-α水平来测量的。通过多重ELISA评估脑样品的细胞因子水平，并通过免疫组织化学评估小胶质细胞和星形胶质细胞增殖。使用甲酚紫染色检查神经元细胞计数。电机的协调性使用旋转杆性能测试进行评估。GM-CSF治疗与全血和脾脏对PWM的反应显着增加有关。受伤动物中的GM-CSF并未导致脑样品中促炎细胞因子水平的增加，但与计数的星形胶质细胞的显着增加有关。最后,虽然用盐水治疗的受伤动物在行为测试中表现出明显的损害，用GM-CSF治疗的受伤动物的表现与未受伤动物相似。在合并损伤的动物中GM-CSF治疗导致损伤后急性期全血和脾脏中全身免疫细胞应答增加。改善的免疫应答与脑中促炎细胞因子水平升高或功能障碍无关。
