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首页> 外文期刊>Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism >TNF alpha and Fas mediate tissue damage and functional outcome after traumatic brain injury in mice.
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TNF alpha and Fas mediate tissue damage and functional outcome after traumatic brain injury in mice.

机译：TNFα和Fas介导小鼠颅脑损伤后的组织损伤和功能结果。

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摘要

Tumor necrosis factor-alpha (TNFalpha) and Fas are induced after traumatic brain injury (TBI); however, their functional roles are incompletely understood. Using controlled cortical impact (CCI) and mice deficient in TNFalpha, Fas, or both (TNFalpha/Fas-/-), we hypothesized that TNFalpha and Fas receptor mediate secondary TBI in a redundant manner. Compared with wild type (WT), TNFalpha/Fas-/- mice had improved motor performance from 1 to 4 days (P<0.05), improved spatial memory acquisition at 8 to 14 days (P<0.05), and decreased brain lesion size at 2 and 6 weeks after CCI (P<0.05). Protection in TNFalpha/Fas-/- mice from histopathological and motor deficits was reversed by reconstitution with recombinant TNFalpha before CCI, and TNFalpha-/- mice administered anti-Fas ligand antibodies had improved spatial memory acquisition versus similarly treated WT mice (P<0.05). Tumor necrosis factor-alpha/Fas-/- mice had decreased the numbers of cortical cells with plasmalemma damage at 6 h (P<0.05 versus WT), and reduced matrix metalloproteinase-9 activity in injured brain at 48 and 72 h after CCI. In immature mice subjected to CCI, genetic inhibition of TNFalpha and Fas conferred beneficial effects on histopathology and spatial memory acquisition in adulthood (both P<0.05 versus WT), suggesting that the beneficial effects of TNFalpha/Fas inhibition may be permanent. The data suggest that redundant signaling pathways initiated by TNFalpha and Fas play pivotal roles in the pathogenesis of TBI, and that biochemical mechanisms downstream of TNFalpha/Fas may be novel therapeutic targets to limit neurological sequelae in children and adults with severe TBI.
机译：创伤性脑损伤（TBI）后诱发肿瘤坏死因子-α（TNFalpha）和Fas。但是，它们的功能角色尚不完全清楚。我们使用可控的皮层撞击（CCI）和TNFalpha，Fas或两者均缺乏的小鼠（TNFalpha / Fas-/-），我们假设TNFalpha和Fas受体以多余的方式介导继发性TBI。与野生型（WT）相比，TNFalpha / Fas-/-小鼠在1到4天时具有更好的运动表现（P <0.05），在8到14天时具有更好的空间记忆获得能力（P <0.05），并且脑病变大小减小CCI后2周和6周时（P <0.05）。在CCI之前，通过重组TNFalpha重建了TNFalpha / Fas-/-小鼠免受组织病理学和运动缺陷的保护，并且与相似治疗的WT小鼠相比，给予抗Fas配体抗体的TNFalpha-/-小鼠改善了空间记忆获取（P <0.05 ）。肿瘤坏死因子-α/ Fas-/-小鼠在CCI后48h和72h减少了受损血浆皮质细胞的数量（P <0.05 vs WT），并降低了受损脑中基质金属蛋白酶9的活性。在接受CCI的未成熟小鼠中，TNFα和Fas的遗传抑制对成年后的组织病理学和空间记忆获得具有有益作用（P <0.05与WT相比），这表明TNFα/ Fas抑制的有益作用可能是永久的。数据表明，TNFα和Fas引发的冗余信号通路在TBI的发病机理中起着关键作用，而TNFalpha / Fas下游的生化机制可能是限制严重TBI儿童和成人神经系统后遗症的新型治疗靶点。

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