Nonselective cation channels as effecters of free radical-induced rat liver cell necrosis
Nonselective cation channels as effecters of free radical-induced rat liver cell necrosis
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DOI：
10.1053/jhep.2001.20530
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发表时间：
2001-01-01
期刊：
影响因子：
13.5
通讯作者：
Hermosilla, T
中科院分区：
文献类型：
--
作者：
Barros, LF;Stutzin, A;Hermosilla, T
坏死是一种非特异性的细胞死亡，它诱导组织炎症，并在细胞水肿之前发生。在非神经元细胞中，后者被解释为由代谢耗竭或通过膜转运蛋白增加的Na+内流引起的Na+向外泵出缺陷。即Na+通过氧化应激激活的非选择性阳离子通道的流入。将肝上皮克隆9细胞暴露于自由基供体calphostin C或甲萘醌诱导约16 pS的非选择性阳离子通道（NSCC）的快速激活。用氟芬那酸阻断这种电导可保护细胞免于肿胀、钙超载和坏死。还通过Gd 3+（牵张激活阳离子通道的抑制剂）或通过用N-甲基-D-葡糖胺等渗置换细胞外Na+来实现保护。提出在健康细胞中普遍存在但大部分无活性的NSCC在严重氧化应激下变得活化。随后的Na+流入引发代谢和电解质紊乱的正反馈，导致细胞坏死死亡。
Necrosis, as opposed to apoptosis, is recognized as a nonspecific cell death that induces tissue inflammation and is preceded by cell edema, In non-neuronal cells, the latter has been explained by defective outward pumping of Na+ caused by metabolic depletion or by increased Na+ influx via membrane transporters, Here we describe a novel mechanism of swelling and necrosis; namely the influx of Na+ through oxidative stress-activated nonselective cation channels. Exposure of liver epithelial Clone 9 cells to the free-radical donors calphostin C or menadione induced the rapid activation of an approximately 16-pS nonselective cation channel (NSCC), Blockage of this conductance with flufenamic acid protected the cells against swelling, calcium overload, and necrosis. Protection was also achieved by Gd3+, an inhibitor of stretch-activated cation channels, or by isosmotic replacement of extracellular Na+ with N-methyl-D-glucamine, It is proposed that NSCCs, which are ubiquitous although largely inactive in healthy cells, become activated under severe oxidative stress, The ensuing influx of Na+ initiates a positive feedback of metabolic and electrolytic disturbances leading cells to their necrotic demise.