Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Toxicol Appl Pharmacol. 2011 Dec 15;257(3):449-58. doi: 10.1016/j.taap.2011.10.006. Epub 2011 Oct 14.
The mechanisms of acetaminophen (APAP)-mediated hepatic oncotic necrosis have been extensively characterized. However, it was recently demonstrated that fed CD-1 mice have a transient caspase activation which initiates apoptosis. To evaluate these findings in more detail, outbred (Swiss Webster, SW) and inbred (C57BL/6) mice were treated with APAP with or without pan-caspase inhibitor and compared to the apoptosis model of galactosamine (GalN)/endotoxin (ET). Fasted or fed APAP-treated C57BL/6 mice showed no evidence of caspase-3 processing or activity. Interestingly, a minor, temporary increase in caspase-3 processing and activity (150% above baseline) was observed after APAP treatment only in fed SW mice. The degree of caspase-3 activation in SW mice after APAP was minor compared to that observed in GalN/ET-treated mice (1600% above baseline). The pancaspase inhibitor attenuated caspase activation and resulted in increased APAP-induced injury (plasma ALT, necrosis scoring). The caspase inhibitor did not affect apoptosis because regardless of treatment only <0.5% of hepatocytes showed consistent apoptotic morphology after APAP. In contrast, >20% apoptotic cells were observed in GalN/ET-treated mice. Presence of the caspase inhibitor altered hepatic glutathione levels in SW mice, which could explain the exacerbation of injury. Additionally, the infiltration of hepatic neutrophils was not altered by the fed state of either mouse strain.
Minor caspase-3 activation without apoptotic cell death can be observed only in fed mice of some outbred strains. These findings suggest that although the severity of APAP-induced liver injury varies between fed and fasted animals, the mechanism of cell death does not fundamentally change.
已广泛描述了对乙酰氨基酚 (APAP) 介导的肝胀性坏死的机制。然而，最近有人证明，给予食物的 CD-1 小鼠会发生短暂的半胱天冬酶激活，从而引发细胞凋亡。为了更详细地评估这些发现，对近交系（C57BL/6）和远交系（瑞士 Webster，SW）小鼠进行了 APAP 治疗，并与半乳糖胺 (GalN)/内毒素 (ET) 的细胞凋亡模型进行了比较。禁食或给予食物的 APAP 处理的 C57BL/6 小鼠没有证据表明存在半胱天冬酶-3 加工或活性。有趣的是，仅在给予食物的 SW 小鼠中观察到 APAP 治疗后，半胱天冬酶-3 加工和活性（比基线高 150%）略有短暂增加。与 GalN/ET 处理的小鼠相比，SW 小鼠在 APAP 后观察到的半胱天冬酶-3 激活程度较小（比基线高 1600%）。全半胱天冬酶抑制剂减弱了半胱天冬酶激活，并导致 APAP 诱导的损伤增加（血浆 ALT、坏死评分）。半胱天冬酶抑制剂不影响细胞凋亡，因为无论治疗如何，仅在 APAP 后 <0.5%的肝细胞表现出一致的凋亡形态。相比之下，在 GalN/ET 处理的小鼠中观察到超过 20%的凋亡细胞。半胱天冬酶抑制剂改变了 SW 小鼠的肝谷胱甘肽水平，这可以解释损伤的加剧。此外，肝中性粒细胞的浸润不受两种小鼠品系的喂养状态的影响。
仅在某些远交系的给予食物的小鼠中可以观察到轻微的半胱天冬酶-3 激活而没有凋亡细胞死亡。这些发现表明，尽管给予食物和禁食动物的 APAP 诱导的肝损伤严重程度不同，但细胞死亡的机制并没有根本改变。
