TRAIL enhances paracetamol-induced liver sinusoidal endothelial cell death in a Bim- and Bid-dependent manner
TRAIL enhances paracetamol-induced liver sinusoidal endothelial cell death in a Bim- and Bid-dependent manner
复制标题
DOI：
10.1038/cddis.2012.185
复制
发表时间：
2012-12-01
影响因子：
9
通讯作者：
Corazza, N.
中科院分区：
文献类型：
--
作者：
Badmann, A.;Langsch, S.;Corazza, N.
扑热息痛(对乙酰氨基酚，APAP)是一种常用的止痛药和退热药。在治疗剂量下，过量被认为是安全的，会导致急性肝损伤，其特征是小叶中心肝坏死。扑热息痛所致肝病的主要临床问题之一是发生出血性改变。虽然肝细胞是过量扑热息痛细胞毒性作用的主要靶点，但在扑热息痛诱导的肝病中，也描述了涉及肝窦内皮细胞(LSECs)形态变化的内皮内扰动。最近，我们发现TRAIL信号通路协同增强了扑热息痛诱导的肝损伤。由于LSEC持续暴露于包括TRAIL在内的表达死亡配体的活化免疫细胞中，我们研究了TRAIL在扑热息痛诱导的LSEC死亡中的作用。我们在这里首次证明TRAIL强烈地增强了扑热息痛介导的LSEC死亡，具有典型的细胞凋亡特征。使用特定的抑制剂抑制半胱氨酸氨基转移酶可显著减少细胞死亡。TRAIL似乎通过激活促凋亡的BH3-Only蛋白Bid和Bim来增强扑热息痛诱导的LSEC死亡，Bid和Bim启动了线粒体凋亡途径。综上所述，本研究表明，肝脏内皮层，主要是LSECs，是扑热息痛细胞毒性作用的直接靶点，TRAIL受体的激活通过线粒体凋亡途径协同增强了扑热息痛诱导的LSEC死亡。TRAIL介导的对乙酰氨基酚诱导的细胞死亡的加速可能参与了对乙酰氨基酚诱导的肝损伤的发病机制。《细胞死亡与疾病》(2012年)3，e447；doi：10.1038/cddis.2012.185；2012年12月20日在线发布
Paracetamol (acetaminophen, APAP) is a universally used analgesic and antipyretic agent. Considered safe at therapeutic doses, overdoses cause acute liver damage characterized by centrilobular hepatic necrosis. One of the major clinical problems of paracetamol-induced liver disease is the development of hemorrhagic alterations. Although hepatocytes represent the main target of the cytotoxic effect of paracetamol overdose, perturbations within the endothelium involving morphological changes of liver sinusoidal endothelial cells (LSECs) have also been described in paracetamol-induced liver disease. Recently, we have shown that paracetamol-induced liver damage is synergistically enhanced by the TRAIL signaling pathway. As LSECs are constantly exposed to activated immune cells expressing death ligands, including TRAIL, we investigated the effect of TRAIL on paracetamol-induced LSEC death. We here demonstrate for the first time that TRAIL strongly enhances paracetamol-mediated LSEC death with typical features of apoptosis. Inhibition of caspases using specific inhibitors resulted in a strong reduction of cell death. TRAIL appears to enhance paracetamol-induced LSEC death via the activation of the pro-apoptotic BH3-only proteins Bid and Bim, which initiate the mitochondrial apoptotic pathway. Taken together this study shows that the liver endothelial layer, mainly LSECs, represent a direct target of the cytotoxic effect of paracetamol and that activation of TRAIL receptor synergistically enhances paracetamol-induced LSEC death via the mitochondrial apoptotic pathway. TRAIL-mediated acceleration of paracetamol-induced cell death may thus contribute to the pathogenesis of paracetamol-induced liver damage. Cell Death and Disease (2012) 3, e447; doi:10.1038/cddis.2012.185; published online 20 December 2012