Campbell Sandra J, Anthony Daniel C, Oakley Fiona, Carlsen Harald, Elsharkawy Ahmed M, Blomhoff Rune, Mann Derek A
Experimental Neuropathology, Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
J Neuropathol Exp Neurol. 2008 Mar;67(3):223-30. doi: 10.1097/NEN.0b013e3181654957.
Acute brain injury is associated with induction of hepatic chemokine expression, which is an essential element in the subsequent recruitment of leukocytes to the damaged brain. To further understand the significance of the hepatic inflammatory response, we focused on nuclear factor (NF)-kappa B, a pivotal regulator of inflammation. Nondestructive real-time whole-body imaging was undertaken in the 3XNF-kappa B-luciferase mouse to monitor NF-kappa B activation. Acute brain injury induced by intracerebral injection of interleukin-1 provoked rapid activation of hepatic and CNS NF-kappa B, with only minimal changes in other organs. Elevated NF-kappa B in the brain was limited to the site of the lesion, whereas hepatic NF-kappa B was widespread. The function of NF-kappa B in this model was determined by monitoring leukocyte recruitment to the liver and brain of nf kappa b1 mice, which lack the anti-inflammatory p50:p50 NF-kappa B homodimer. Brain injury in the nf kappa b1 mice was associated with increased neutrophil recruitment to the liver and brain compared with wild-type mice, thereby confirming a regulatory role for the NF-kappa B system. To determine the role of hepatic NF-kappa B, it was selectively inhibited by intravenous adenoviral-mediated delivery of an I kappa B alpha super-repressor. This treatment significantly reduced the numbers of neutrophils recruited to the brain. In conclusion, acute brain injury is associated with rapid and robust activation of hepatic NF-kappa B, which is required for efficient mobilization of circulating leukocytes to the brain.
急性脑损伤与肝脏趋化因子表达的诱导有关，而趋化因子是随后白细胞向受损脑募集的关键因素。为了进一步了解肝脏炎症反应的意义，我们聚焦于炎症的关键调节因子核因子（NF）-κB。利用3XNF-κB荧光素酶小鼠进行非侵入性实时全身成像，以监测NF-κB的激活情况。脑室内注射白细胞介素-1诱导的急性脑损伤可迅速激活肝脏和中枢神经系统的NF-κB，而其他器官仅有微小变化。脑中NF-κB的升高局限于损伤部位，而肝脏中的NF-κB则广泛存在。通过监测nf kappa b1小鼠（缺乏抗炎性p50:p50 NF-κB同型二聚体）肝脏和脑中白细胞的募集情况，确定了该模型中NF-κB的功能。与野生型小鼠相比，nf kappa b1小鼠的脑损伤与肝脏和脑中嗜中性粒细胞募集增加有关，从而证实了NF-κB系统的调节作用。为了确定肝脏NF-κB的作用，通过静脉注射腺病毒介导的IκBα超级抑制剂对其进行选择性抑制。该治疗显著减少了募集到脑中的嗜中性粒细胞数量。总之，急性脑损伤与肝脏NF-κB迅速而强烈的激活有关，这是循环白细胞有效动员至脑所必需的。
