RETRACTED: Molecular forms of HMGB1 and keratin-18 as mechanistic biomarkers for mode of cell death and prognosis during clinical acetaminophen hepatotoxicity.
RETRACTED: Molecular forms of HMGB1 and keratin-18 as mechanistic biomarkers for mode of cell death and prognosis during clinical acetaminophen hepatotoxicity.
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DOI：
10.1016/j.jhep.2011.12.019
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发表时间：
2012-05
影响因子：
25.7
通讯作者：
Park, B. Kevin
中科院分区：
文献类型：
--
作者：
Antoine, Daniel J.;Jenkins, Rosalind E.;Dear, James W.;Williams, Dominic P.;McGill, Mitchell R.;Sharpe, Matthew R.;Craig, Darren G.;Simpson, Kenneth J.;Jaeschke, Hartmut;Park, B. Kevin
全长角蛋白-18（FL-K18）和高迁移率族蛋白盒-1（HMGB 1）代表体内对乙酰氨基酚（APAP）肝毒性期间坏死的循环指标。此外，半胱天冬酶切割的K18片段（cK 18）和超乙酰化HMGB 1分别代表细胞凋亡和免疫细胞活化的血清指标。本研究的目的是评估它们在临床APAP肝毒性的整个时间过程中建立细胞凋亡、坏死和免疫细胞活化之间平衡的机制效用。在APAP过量患者（n=78）中，通过新型LC-MS/MS测定法鉴定和定量HMGB 1（总，乙酰化）和K18（凋亡，坏死）。HMGB 1（总计;与无肝损伤的过量患者和健康志愿者相比，在APAP过量患者中肝损伤的血清中cK 18（5649.8±721.0U/l，p<0.01）和FL-K18（54770.2±6717.0U/l，p<0.005）升高。HMGB 1和FL-K18与丙氨酸氨基转移酶（ALT）活性（R2分别为0.60和0.58，p<0.0001）和凝血酶原时间（R2分别为0.62和0.71，p<0.0001）相关。总HMGB 1和乙酰化HMGB 1和FL-K18的增加与更差的预后（国王学院标准）或与自发存活者相比死亡/需要肝移植的患者相关（所有p<0.05-0.001），这一发现未被ALT反映，并得到ROC分析的支持。乙酰化HMGB 1是一个更好的预测结果比其他标志物的细胞死亡。K18和HMGB 1代表了研究细胞死亡平衡临床APAP肝毒性的血液工具。如乙酰化HMGB 1的独特特征所示，免疫应答的激活在时间进程中较晚，并且与更差的结局相关。
Full length keratin-18 (FL-K18) and High Mobility Group Box-1 (HMGB1) represent circulating indicators of necrosis during acetaminophen (APAP) hepatotoxicity in vivo. In addition, the caspase-cleaved fragment of K18 (cK18) and hyper-acetylated HMGB1 represent serum indicators of apoptosis and immune cell activation respectively. The study aim was to assess their mechanistic utility to establish the balance between apoptosis, necrosis and immune cell activation throughout the time course of clinical APAP hepatotoxicity. HMGB1 (total, acetylated) and K18 (apoptotic, necrotic) were identified and quantified by novel LC-MS/MS assays in APAP overdose patients (n=78). HMGB1 (total; 15.4±1.9ng/ml, p<0.01, acetylated; 5.4±2.6ng/ml, p<0.001), cK18 (5649.8±721.0U/l, p<0.01) and FL-K18 (54770.2±6717.0U/l, p<0.005) were elevated in the sera of APAP overdose patients with liver injury compared to overdose patients without liver injury and healthy volunteers. HMGB1 and FL-K18 correlated with alanine aminotransferase (ALT) activity (R2=0.60 and 0.58 respectively, p<0.0001) and prothrombin time (R2=0.62 and 0.71 respectively, p<0.0001). Increased total and acetylated HMGB1 and FL-K18 were associated with worse prognosis (King’s College Criteria) or patients that died/required liver transplant compared to spontaneous survivors (all p<0.05-0.001), a finding not reflected by ALT and supported by ROC analysis. Acetylated HMGB1 was a better predictor of outcome than the other markers of cell death. K18 and HMGB1 represent blood-based tools to investigate the cell death balance clinical APAP hepatotoxicity. Activation of the immune response was seen later in the time course as shown by the distinct profile of acetylated HMGB1 and was associated with worse outcome.
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