TNF alpha and Fas mediate tissue damage and functional outcome after traumatic brain injury in mice
TNF alpha and Fas mediate tissue damage and functional outcome after traumatic brain injury in mice
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DOI：
10.1038/sj.jcbfm.9600487
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发表时间：
2007-11-01
影响因子：
6.3
通讯作者：
Whalen, Michael J.
中科院分区：
文献类型：
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作者：
Bermpohl, Daniela;You, Zerong;Whalen, Michael J.
肿瘤坏死因子-α（TNF α）和Fas在创伤性脑损伤（TBI）后被诱导;然而，它们的功能作用还不完全清楚。使用受控皮质撞击（CCI）和TNF α、Fas或两者（TNF α/ Fas -/-）缺陷的小鼠，我们假设TNF α和Fas受体以冗余方式介导继发性TBI。与野生型（WT）相比，CCI后1 - 4天TNF α/ Fas -/-小鼠的运动能力得到改善（P < 0.05），8 - 14天空间记忆获得得到改善（P < 0.05），2周和6周脑损伤面积减小（P < 0.05）。在CCI之前用重组TNF α重建TNF α/Fas -/-小鼠免于组织病理学和运动缺陷的保护被逆转，并且施用抗Fas配体抗体的TNF α-/-小鼠与类似处理的WT小鼠相比具有改善的空间记忆获得（P < 0.05）。肿瘤坏死因子-α/Fas -/-小鼠CCI后6 h皮层细胞质膜损伤明显减少（P< 0.05），48和72 h损伤脑组织基质金属蛋白酶-9活性明显降低。在CCI的未成熟小鼠中，TNF α和Fas的遗传抑制对成年期的组织病理学和空间记忆获得产生有益作用（与WT相比均P < 0.05），表明TNF α/ Fas抑制的有益作用可能是永久性的。这些数据表明，TNF α和Fas启动的冗余信号通路在TBI的发病机制中起着关键作用，TNF α/ Fas下游的生化机制可能是限制儿童和成人严重TBI神经系统后遗症的新治疗靶点。
Tumor necrosis factor-alpha (TNF alpha) 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 TNF alpha, Fas, or both (TNF alpha/ Fas -/-), we hypothesized that TNF alpha and Fas receptor mediate secondary TBI in a redundant manner. Compared with wild type (WT), TNF alpha/ 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 TNF alpha/Fas -/- mice from histopathological and motor deficits was reversed by reconstitution with recombinant TNF alpha before CCI, and TNF alpha -/- 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 6h ( 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 TNF alpha 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 TNF alpha/ Fas inhibition may be permanent. The data suggest that redundant signaling pathways initiated by TNF alpha and Fas play pivotal roles in the pathogenesis of TBI, and that biochemical mechanisms downstream of TNF alpha/ Fas may be novel therapeutic targets to limit neurological sequelae in children and adults with severe TBI.