Mode of cell death after acetaminophen overdose in mice: Apoptosis or oncotic necrosis?
Mode of cell death after acetaminophen overdose in mice: Apoptosis or oncotic necrosis?
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DOI：
10.1093/toxsci/67.2.322
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发表时间：
2002-06-01
影响因子：
3.8
通讯作者：
Jaeschke, H
中科院分区：
文献类型：
--
作者：
Gujral, JS;Knight, TR;Jaeschke, H
对乙酰氨基酚（AAP）过量可导致实验动物和人类严重的肝损伤和肝功能衰竭。最近，一些作者提出凋亡可能是AAP处理后细胞死亡的主要机制。为了解决这个有争议的问题，我们评估了禁食C3 Heb/FeJ小鼠AAP（300 mg/kg）后肝损伤的详细时间过程。使用形态学标准（细胞收缩、染色质凝聚和边集以及凋亡小体）在H& E染色的肝切片中定量凋亡肝细胞。AAP给药后2小时内，细胞凋亡的肝细胞数量保持在基线水平（0.2+/-0.1个细胞/10个高倍视野[HPF]）。然而，在3和24小时之间，凋亡性细胞死亡显著增加，例如，6 h时为6.3+/-0.8个细胞/10 HPF。尽管符合凋亡形态学标准的肝细胞数量增加，但该细胞分数仍远低于所有实质细胞的1%。在任何时间均未检测到半胱天冬酶-3加工或酶活性增加的证据。将这些结果与肝脏切片中坏死细胞的总体百分比进行比较。AAP给药后3 - 24 h，小叶中心坏死的融合区域估计涉及所有肝细胞的40-60%。这些数字与血浆丙氨酸氨基转移酶活性的增加，达到峰值水平5900 - 1350 U/L，在24小时。使用较高剂量的AAP和使用喂养的动物获得了类似的结果。因此，肝细胞坏死而不是凋亡是体内AAP过量后肝细胞死亡的主要机制。
Acetaminophen (AAP) overdose can cause severe liver injury and liver failure in experimental animals and humans. Recently, several authors proposed that apoptosis might be a major mechanism of cell death after AAP treatment. To address this controversial issue, we evaluated a detailed time course of liver injury after AAP (300 mg/kg) in fasted C3Heb/FeJ mice. Apoptotic hepatocytes were quantified in H&E-stained liver sections using morphologic criteria (cell shrinkage, chromatin condensation and margination, and apoptotic bodies). The number of apoptotic hepatocytes remained at baseline (0.2+/-0.1 cells/10 high-power fields [HPF]) up to 2 h after AAP administration. However, between 3 and 24 h, apoptotic cell death increased significantly, e.g., 6.3+/-0.8 cells/10 HPF at 6 h. Despite the increase in the number of hepatocytes meeting the morphological criteria of apoptosis, this cell fraction remained well below 1% of all parenchymal cells. No evidence for caspase-3 processing or increase in enzyme activity was detected at any time. These results were compared to the overall percent of necrotic cells in liver sections. Confluent areas of centrilobular necrosis were estimated to involve 40-60% of all hepatocytes between 3 and 24 h after AAP administration. These numbers correlated with the increase in plasma alanine aminotransferase activities, which reached a peak level of 5900 1350 U/l at 24 h. A similar result was obtained with higher doses of AAP and with the use of fed animals. Thus, oncotic necrosis and not apoptosis is the principal mechanism of liver-cell death after AAP overdose in vivo.