NF-κB in the mechanism of brain edema in acute liver failure: studies in transgenic mice.
NF-κB in the mechanism of brain edema in acute liver failure: studies in transgenic mice.
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DOI：
10.1016/j.nbd.2010.10.021
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发表时间：
2011-02
影响因子：
6.1
通讯作者：
Norenberg, M. D.
中科院分区：
文献类型：
--
作者：
Jayakumar, A. R.;Bethea, J. R.;Tong, X. Y.;Gomez, J.;Norenberg, M. D.
星形胶质细胞肿胀和脑水肿是急性肝性脑病（急性肝功能衰竭，ALF）的主要并发症。虽然脑氨水平升高是ALF的一个众所周知的病因学因素，但氨引起星形胶质细胞肿胀的机制尚不清楚。我们最近发现，星形胶质细胞培养物暴露于氨激活核因子-κ B（NF-κB），这种激活的药理学抑制导致星形胶质细胞肿胀减少。虽然这些发现表明NF-κB参与了体外星形胶质细胞肿胀，但NF-κB是否参与了体内ALF脑水肿的发展尚不清楚。此外，用于抑制NF-κB的药物可能具有非特异性作用。因此，我们使用了星形胶质细胞NF-κB功能性失活的转基因（Tg）小鼠，并检查这些小鼠是否对ALF相关脑水肿具有抗性。用肝毒素硫代乙酰胺（TAA）处理小鼠诱导ALF。用TAA处理的野生型（WT）小鼠显示脑含水量显著增加（1.65%），沿着显著的星形胶质细胞肿胀和神经胶质细胞海绵状增生，与细胞毒性水肿的存在一致。在用TAA处理的Tg小鼠中未观察到这些变化。此外，患有ALF的WT小鼠显示，TAA处理的WT小鼠星形胶质细胞中的诱导型一氧化氮合酶（iNOS）免疫反应性增加（已知iNOS被NF-κB激活并导致细胞肿胀）。相比之下，用TAA处理的Tg小鼠没有表现出脑水肿、组织学变化，也没有iNOS免疫反应性的增加。我们还检查了来自Tg小鼠的星形胶质细胞培养物，以确定这些细胞暴露于氨后是否表现出较低程度的肿胀和细胞病理学变化。当暴露于氨24 h时，来自Tg小鼠的星形胶质细胞培养物未显示细胞肿胀或形态异常。相比之下，氨显着增加细胞肿胀（31.7%），在培养的星形胶质细胞从WT小鼠和显示细胞学异常。此外，我们观察到，与氨处理的WT小鼠星形胶质细胞相比，氨处理的Tg小鼠星形胶质细胞培养物中诱导型一氧化氮合酶和NADPH氧化酶活性（两者也已知被NF-κB激活并有助于星形胶质细胞肿胀）的增量较小。这些发现强烈提示NF-κB的活化是ALF中星形胶质细胞肿胀/脑水肿发展的关键因素。
Astrocyte swelling and brain edema are major complications of the acute form of hepatic encephalopathy (acute liver failure, ALF). While elevated brain ammonia level is a well-known etiological factor in ALF, the mechanism by which ammonia brings about astrocyte swelling is not well understood. We recently found that astrocyte cultures exposed to ammonia activated nuclear factor-kappaB (NF-κB), and that pharmacological inhibition of such activation led to a reduction in astrocyte swelling. Although these findings suggest the involvement of NF-κB in astrocyte swelling in vitro, it is not known whether NF-κB contributes to the development of brain edema in ALF in vivo. Furthermore, pharmacological agents used to inhibit NF-κB may have non-specific effects. Accordingly, we used transgenic (Tg) mice that have a functional inactivation of astrocytic NF-κB and examined whether these mice are resistant to ALF-associated brain edema. ALF was induced in mice by treatment with the hepatotoxin thioacetamide (TAA). Wild type (WT) mice treated with TAA showed a significant increase in brain water content (1.65%) along with prominent astrocyte swelling and spongiosis of the neuropil, consistent with the presence of cytotoxic edema. These changes were not observed in Tg mice treated with TAA. Additionally, WT mice with ALF showed an increase in inducible nitric oxide synthase (iNOS) immunoreactivity in astrocytes from WT mice treated with TAA (iNOS is known to be activated by NF-κB and to contribute to cell swelling). By contrast, Tg mice treated with TAA did not exhibit brain edema, histological changes nor an increase in iNOS immunoreactivity. We also examined astrocytes cultures derived from Tg mice to determine whether these cells exhibit a lesser degree of swelling and cytopathological changes following exposure to ammonia. Astrocyte cultures derived from Tg mice showed no cell swelling nor morphological abnormalities when exposed to ammonia for 24 h. By contrast, ammonia significantly increased cell swelling (31.7%) in cultured astrocytes from WT mice and displayed cytological abnormalities. Moreover, we observed a lesser increment in inducible nitric oxide synthase and NADPH oxidase activity (both are also known to be activated by NF-κB and to contribute to astrocyte swelling) in astrocyte cultures from Tg mice treated with ammonia, as compared to ammonia-treated WT mice astrocytes. These findings strongly suggest that activation of NF-κB is a critical factor in the development of astrocyte swelling/brain edema in ALF.
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影响因子：
7.4
作者：
Fu ES;Zhang YP;Sagen J;Candiotti KA;Morton PD;Liebl DJ;Bethea JR;Brambilla R
通讯作者：
Brambilla R
影响因子：
15.3
作者：
Brambilla, R;Bracchi-Ricard, V;Hu, WH;Frydel, B;Bramwell, A;Karmally, S;Green, EJ;Bethea, JR
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13.5
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12.7
作者：
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通讯作者：
BUDKA, H
影响因子：
4.7
作者：
Brambilla R;Hurtado A;Persaud T;Esham K;Pearse DD;Oudega M;Bethea JR
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