Gujral Jaspreet S, Farhood Anwar, Jaeschke Hartmut
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Toxicol Appl Pharmacol. 2003 Jul 1;190(1):37-46. doi: 10.1016/s0041-008x(03)00154-6.
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.
半乳糖胺（Gal）诱导的肝损伤过程中的细胞死亡方式最初被认为是胀亡性坏死，但最近有人提出是凋亡。因此，目的是评估在病理生理学中凋亡和胀亡是相继发生的事件还是独立的事件。此外，还研究了半胱天冬酶在Gal诱导的凋亡信号传导中的作用。500mg/kg的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小时：430±122U/L）。这伴随着前半胱天冬酶-3的加工以及肝脏和血浆中半胱天冬酶-3活性的显著增加。使用形态学和TUNEL染色对凋亡细胞和胀亡细胞进行定量。凋亡肝细胞的数量从对照组的0.14%增加到Gal处理后24小时的5.4±1.0%。此外，具有胀亡形态的细胞数量从0增加到占总肝细胞的6.9%。用泛半胱天冬酶抑制剂IDN-7314（10mg/kg）处理或用尿苷（1g/kg）预处理可将凋亡的所有参数降至基线水平。然而，给予IDN-7314在6小时时不影响血浆ALT活性和胀亡细胞数量，仅在24小时时适度降低这些参数。另一方面，尿苷可防止血浆ALT水平升高，并使凋亡细胞和胀亡细胞数量减少>80%。总之，大鼠中半乳糖胺诱导的肝细胞凋亡是半胱天冬酶依赖性的。虽然一些凋亡细胞可能会发生继发性坏死，但大量肝细胞通过胀亡性坏死作为一种独立的细胞死亡机制而死亡。
