Oncotic necrosis and caspase-dependent apoptosis during galactosamine-induced liver injury in rats
Oncotic necrosis and caspase-dependent apoptosis during galactosamine-induced liver injury in rats
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DOI：
10.1016/s0041-008x(03)00154-6
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发表时间：
2003-07-01
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;Farhood, A;Jaeschke, H
半乳糖胺（Gal）诱导的肝损伤的细胞死亡方式最初被认为是肿瘤坏死，但最近提出是凋亡。因此，目的是评估细胞凋亡和胀亡在病理生理学中是连续的还是独立的事件。此外，半胱天冬酶在半乳糖诱导的细胞凋亡信号中的作用进行了研究。500 mg/kg Gal剂量导致雌性Sprague-Dawley大鼠血浆丙氨酸转氨酶（ALT）水平呈时间依赖性升高（24 h：430 +/- 122 U/L）。这伴随着半胱天冬酶原-3的加工以及肝脏和血浆半胱天冬酶-3活性的显著增加。采用形态学和TUNEL染色，对凋亡和凋亡细胞进行定量。Gal处理后24 h，凋亡肝细胞的数量从对照组的0.14%增加至5.4 +/- 1.0%。此外，具有Ontario形态的细胞数量从0增加到总肝细胞的6.9%。用泛半胱天冬酶抑制剂IDN-7314（10 mg/kg）处理或用尿苷（1 g/kg）预处理，将细胞凋亡的所有参数降低至基线。然而，IDN-7314给药在6 h时不影响血浆ALT活性和肿瘤细胞数量，在24 h时仅适度降低这些参数。另一方面，尿苷可防止血浆ALT水平的升高，并使凋亡和凋亡细胞的数量减少> 80%。结论：半乳糖胺诱导的大鼠肝细胞凋亡是caspase依赖性的。虽然一些凋亡细胞可能发生继发性坏死，但大量肝细胞通过坏死性坏死作为细胞死亡的独立机制而死亡。(C)2003 Elsevier Science（美国）。All rights reserved.
The mode of cell death during galactosamine (Gal)-induced liver injury was originally thought to be oncotic necrosis but recently it was suggested to be apoptosis. Thus, the objective was to assess whether apoptosis and oncosis are sequential or independent events in the pathophysiology. In addition, the role of caspases in Gal-induced apoptotic signaling was investigated. A dose of 500 mg/kg Gal caused a time-dependent increase in plasma alanine transaminase (ALT) levels (24 h: 430 +/- 122 U/L) in female Sprague-Dawley rats. This was accompanied by processing of procaspase-3 and significant increases in hepatic and plasma caspase-3 activities. Using morphology and TUNEL staining, apoptotic and oncotic cells were quantitated. The number of apoptotic hepatocytes increased from 0.14% in controls to 5.4 +/- 1.0% 24 h after Gal treatment. In addition, the number of cells with oncotic morphology increased from 0 to 6.9% of total hepatocytes. Treatment with the pan-caspase inhibitor IDN-7314 (10 mg/kg) or pretreatment with uridine (1 g/kg), reduced all parameters of apoptosis to baseline. However, IDN-7314 administration did not affect plasma ALT activities and the number of oncotic cells at 6 h and only modestly reduced these parameters at 24 h. Uridine, on the other hand, prevented the increase of plasma ALT levels and reduced the number of apoptotic and oncotic cells by >80%. In conclusion, galactosamine-induced hepatocellular apoptosis in rats is caspase dependent. Although some of the apoptotic cells may undergo secondary necrosis, a significant number of hepatocytes die through oncotic necrosis as an independent mechanism of cell death. (C) 2003 Elsevier Science (USA). All rights reserved.