Diet Restriction Inhibits Apoptosis and HMGB1 Oxidation and Promotes Inflammatory Cell Recruitment during Acetaminophen Hepatotoxicity (Publication with Expression of Concern. See vol. 26, 2020) (Retracted article. See vol. 26, 2020)
Diet Restriction Inhibits Apoptosis and HMGB1 Oxidation and Promotes Inflammatory Cell Recruitment during Acetaminophen Hepatotoxicity (Publication with Expression of Concern. See vol. 26, 2020) (Retracted article. See vol. 26, 2020)
复制标题
DOI：
10.2119/molmed.2010.00126
复制
发表时间：
2010-11-01
影响因子：
5.7
通讯作者：
Park, B. Kevin
中科院分区：
文献类型：
--
作者：
Antoine, Daniel James;Williams, Dominic P.;Park, B. Kevin
对乙酰氨基酚（APAP）过量是急性肝功能衰竭的主要原因，并作为阐明机制，诱发因素和治疗干预的范例。细胞凋亡和炎症在APAP肝毒性中的作用仍存在争议。我们研究了禁食小鼠24 h是否可以通过消耗基础ATP来抑制APAP诱导的caspase激活和凋亡。我们还研究了禁食小鼠中通过抑制caspase依赖性半胱氨酸106氧化在死亡细胞中ATP消耗释放的高迁移率族蛋白B1（HMGB 1）中发挥的关键作用，作为免疫激活的机制。在用APAP处理的进食小鼠中，坏死是肝细胞死亡的主要形式。然而，也观察到细胞凋亡，通过K18切割、DNA梯状化和半胱氨酸蛋白酶原-3加工指示。在用APAP处理的禁食小鼠中，仅观察到坏死。仅在APAP处理的禁食小鼠或与半胱天冬酶抑制剂共处理的进食小鼠中观察到肝细胞死亡导致的炎性细胞募集。肝脏炎症也与血清氧化型HMGB 1检测丢失相关。用HMGB 1中和抗体证实了HMGB 1在诱导炎症中的重要作用。禁食和进食小鼠之间的差异反应是基础肝脏AIR显著减少的结果，这阻止了半胱天冬酶加工，而不是谷胱甘肽耗竭或APAP代谢改变。因此，在药物诱导的肝毒性/肝脏病理学期间，通过禁食ATP耗竭抑制胱天蛋白酶驱动的细胞凋亡和HMGB 1氧化促进炎症反应。(C)2010年费恩斯坦医学研究所，www.feinsteininstitute.org
Acetaminophen (APAP) overdose is a major cause of acute liver failure and serves as a paradigm to elucidate mechanisms, predisposing factors and therapeutic interventions. The roles of apoptosis and inflammation during APAP hepatotoxicity remain controversial. We investigated whether fasting of mice for 24 h can inhibit APAP-induced caspase activation and apoptosis through the depletion of basal ATP We also investigated in fasted mice the critical role played by inhibition of caspase-dependent cysteine 106 oxidation within high mobility group box-1 protein (HMGB1) released by ATP depletion in dying cells as a mechanism of immune activation. In fed mice treated with APAP necrosis was the dominant form of hepatocyte death. However, apoptosis was also observed, indicated by K18 cleavage, DNA laddering and procaspase-3 processing. In fasted mice treated with APAP only necrosis was observed. Inflammatory cell recruitment as a consequence of hepatocyte death was observed only in fasted mice treated with APAP or fed mice cotreated with a caspase inhibitor. Hepatic inflammation was also associated with loss in detection of serum oxidized-HMGB1. A significant role of HMGB1 in the induction of inflammation was confirmed with an HMGB1-neutralizing antibody. The differential response between fasted and fed mice was a consequence of a significant reduction in basal hepatic AIR which prevented caspase processing, rather than glutathione depletion or altered APAP metabolism. Thus, the inhibition of caspase-driven apoptosis and HMGB1 oxidation by ATP depletion from fasting promotes an inflammatory response during drug-induced hepatotoxicity/liver pathology. (C) 2010 The Feinstein Institute for Medical Research, www.feinsteininstitute.org