Increased toll-like receptor 4 in cerebral endothelial cells contributes to the astrocyte swelling and brain edema in acute hepatic encephalopathy.
Increased toll-like receptor 4 in cerebral endothelial cells contributes to the astrocyte swelling and brain edema in acute hepatic encephalopathy.
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DOI：
10.1111/jnc.12516
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发表时间：
2014-03
影响因子：
4.7
通讯作者：
Norenberg MD
中科院分区：
文献类型：
--
作者：
Jayakumar AR;Tong XY;Curtis KM;Ruiz-Cordero R;Abreu MT;Norenberg MD
Astrocyte swelling and the subsequent increase in intracranial pressure and brain herniation are major clinical consequences in patients with acute hepatic encephalopathy (AHE). We recently reported that conditioned media (CM) from brain endothelial cells (ECs) exposed to ammonia, a mixture of cytokines (CKs) or lipopolysaccharide (LPS), when added to astrocytes caused cell swelling. In the present study we investigated the possibility that ammonia and inflammatory agents activate the toll-like receptor 4 (TLR4) in ECs, resulting in the release of factors that ultimately cause astrocyte swelling. We found a significant increase in TLR4 protein expression when ECs were exposed to ammonia, CKs or LPS alone, while exposure of ECs to a combination of these agents potentiated such effects. Additionally, astrocytes exposed to CM from TLR4-silenced ECs that were treated with ammonia, CKs or LPS, resulted in a significant reduction in astrocyte swelling. TLR4 protein upregulation was also detected in rat brain ECs after treatment with the liver toxin thioacetamide (TAA), and that TAA-treated TLR4 knock-out mice exhibited a reduction in brain edema. These studies strongly suggest that ECs significantly contribute to the astrocyte swelling/brain edema in AHE, likely as a consequence of increased TLR4 protein expression by blood-borne noxious agents.
