Medical Research Council Centre for Drug Safety Science Department of Pharmacology and Therapeutics, Institute for Translational Medicine, University of Liverpool, Liverpool, UK.
Mol Med. 2010 Nov-Dec;16(11-12):479-90. doi: 10.2119/molmed.2010.00126. Epub 2010 Aug 27.
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 ATP, 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.
对乙酰氨基酚（APAP）过量是急性肝衰竭的主要原因，它为阐明机制、易患因素和治疗干预提供了范例。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 24 小时是否可以通过耗尽基础 ATP 来抑制 APAP 诱导的半胱氨酸蛋白酶激活和细胞凋亡。我们还在禁食小鼠中研究了抑制依赖半胱氨酸蛋白酶的 HMGB1 中第 106 位半胱氨酸氧化在细胞死亡时由于 ATP 耗竭释放的 HMGB1 中作为免疫激活机制的关键作用。在给予 APAP 的进食小鼠中，坏死是肝细胞死亡的主要形式。然而，也观察到了凋亡，这表明 K18 切割、DNA 梯状和前半胱氨酸蛋白酶-3 处理。在给予 APAP 的禁食小鼠中，仅观察到坏死。仅在给予 APAP 的禁食小鼠或给予 caspase 抑制剂的进食小鼠中观察到了由于肝细胞死亡引起的炎症细胞募集。肝炎症也与血清氧化 HMGB1 检测的丧失有关。HMGB1 中和抗体证实了 HMGB1 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由于基础肝 ATP 显著减少所致，这阻止了半胱氨酸蛋白酶的处理，而不是谷胱甘肽耗竭或改变 APAP 代谢。因此，禁食导致的 ATP 耗竭抑制半胱氨酸蛋白酶驱动的细胞凋亡和 HMGB1 氧化促进了药物诱导的肝毒性/肝病理过程中的炎症反应。
