Transforming growth factor-β1-mediated neuroprotection against excitotoxic injury in vivo
Transforming growth factor-β1-mediated neuroprotection against excitotoxic injury in vivo
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DOI：
10.1097/01.wcb.0000090080.64176.44
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发表时间：
2003-10-01
影响因子：
6.3
通讯作者：
Perry, VH
中科院分区：
文献类型：
--
作者：
Boche, D;Cunningham, C;Perry, VH
缺血预处理是一种描述亚致死性缺血损伤如何诱导对后续缺血耐受的现象。在不同的动物模型中，局灶性或全局性缺血后观察到这种现象。然而，细菌感染可能导致神经元对损伤耐受的假设尚未得到研究。为了模拟大脑细菌感染，我们在小鼠右背海马注射细菌脂多糖（LPS）， 24小时后用kainic酸对小鼠模型进行兴奋毒性损伤。甲酚紫反染后的损伤大小定量显示LPS预处理对CA3神经元具有抗KA攻击的神经保护作用。为了研究这种保护背后的事件，我们研究了LPS注射后诱导的细胞因子谱。白细胞介素(IL)-1 β和转化生长因子β 1 （tgf - β 1）是注射LPS后24小时主要表达的细胞因子。由于il -1 β在急性损伤中被描述为有害的，我们决定研究tgf - β的功能。在诱导兴奋毒性病变前1周向脑内注射一种表达tgf - β 1组成活性形式的腺病毒，观察到神经元保护作用。为了证实TGF-beta1的神经保护作用，我们用重组人TGF-beta1蛋白代替TGF-beta1腺病毒，观察总的神经保护作用。此外，抗体介导的tgf - β 1作用阻断了LPS预处理的保护作用。我们已经在体内证明了LPS预处理诱导的脑耐受现象是由tgf - β 1细胞因子介导的。
Ischemic preconditioning is a phenomenon that describes how a sublethal ischemic insult can induce tolerance to subsequent ischemia. This phenomenon has been observed after focal or global ischemia in different animal models. However, the hypothesis that bacterial infection might lead to neuronal tolerance to injury has not been investigated. To mimic cerebral bacterial infection, we injected bacterial lipopolysaccharide (LPS) in the right dorsal hippocampus, followed 24 hours later by an excitotoxic lesion using kainic acid in the mouse model. Quantification of lesion size after cresyl violet counterstaining revealed that LPS pretreatment afforded neuroprotection to CA3 neurons against KA challenge. To investigate the events underlying this protection, we studied the cytokine profile induced after LPS injection. Interleukin (IL)-1beta and transforming growth factor beta 1 (TGF-beta1) were the main cytokines expressed at 24 hours after LPS injection. Because IL-1beta has been described as deleterious in acute injury, we decided to investigate the function of TGF-beta1. An adenovirus expressing a constitutively active form of TGF-beta1 was injected intracerebrally 1 week before the induction of excitotoxic lesion, and neuronal protection was observed. To confirm the neuroprotective role of TGF-beta1, the TGF-beta1 adenovirus was replaced by recombinant human TGF-beta1 protein and total neuroprotection was observed. Furthermore, the antibody-mediated blocking of TGF-beta1 action prevented the protective effect of pretreatment with LPS. We have demonstrated in vivo that the cerebral tolerance phenomenon induced by LPS pretreatment is mediated by TGF-beta1 cytokine.