Activation of caspase 3 (CPP32)-like proteases is essential for TNF-alpha-induced hepatic parenchymal cell apoptosis and neutrophil-mediated necrosis in a murine endotoxin shock model.
Activation of caspase 3 (CPP32)-like proteases is essential for TNF-alpha-induced hepatic parenchymal cell apoptosis and neutrophil-mediated necrosis in a murine endotoxin shock model.
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DOI：
10.4049/jimmunol.160.7.3480
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发表时间：
1998-04
影响因子：
4.4
通讯作者：
H. Jaeschke;M. A. Fisher;J. A. Lawson;C. Simmons;A. Farhood;D. A. Jones
中科院分区：
文献类型：
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作者：
H. Jaeschke;M. A. Fisher;J. A. Lawson;C. Simmons;A. Farhood;D. A. Jones
内毒素（ET）诱导的肝功能衰竭以肝实质细胞凋亡和炎症导致肝细胞坏死为特征。半胱天冬酶家族的成员参与细胞凋亡的信号转导途径。本研究的目的是表征ET诱导的肝caspase激活和凋亡，并探讨其对嗜铬细胞瘤介导的肝损伤的影响。用700 mg/kg半乳糖胺（Gal）和100 μ g/kg马流产沙门氏菌ET处理C3 Heb/FeJ小鼠，6 h后半胱天冬酶3样蛋白酶活性（Asp-Val-Glu-Asp-底物）增加1730 +/- 140%。有一个平行的增强细胞凋亡（DNA片段化ELISA和末端脱氧核苷酸转移酶介导的dUTP缺口末端标记测定评估）。相反，胱天蛋白酶1（IL-1 β-转化酶）样蛋白酶（Tyr-Val-Ala-Asp-底物）的活性在整个实验中没有变化。Gal/ET不能诱导ET抵抗小鼠（C3 H/HeJ）Caspase 3样蛋白酶活性和细胞凋亡。此外，只有小鼠TNF-α，而不是IL-1 α增加caspase活性和细胞凋亡。Gal/ET在7小时引起嗜中性粒细胞依赖性肝细胞坏死（坏死面积，45 ± 3%）。半胱天冬酶3样蛋白酶抑制剂Z-Val-Ala-Asp-CH 2F（Z-VAD）（10 mg/kg，3 h）延迟处理可使细胞凋亡减少81%至88%，并防止肝细胞坏死（≤ 5%）。Z-VAD对初始炎症反应没有影响，包括中性粒细胞在窦状隙中的隔离。然而，Z-VAD阻止中性粒细胞的迁移和坏死。我们的数据表明，半胱氨酸蛋白酶的半胱天冬酶3亚家族的激活是实质细胞凋亡的发展的关键。此外，过度的肝细胞凋亡可能是隔离在血窦中的致敏中性粒细胞迁移的重要信号。
Endotoxin (ET)-induced liver failure is characterized by parenchymal cell apoptosis and inflammation leading to liver cell necrosis. Members of the caspase family have been implicated in the signal transduction pathway of apoptosis. The aim of this study was to characterize ET-induced hepatic caspase activation and apoptosis and to investigate their effect on neutrophil-mediated liver injury. Treatment of C3Heb/FeJ mice with 700 mg/kg galactosamine (Gal) and 100 microg/kg Salmonella abortus equi ET increased caspase 3-like protease activity (Asp-Val-Glu-Asp-substrate) by 1730 +/- 140% at 6 h. There was a parallel enhancement of apoptosis (assessed by DNA fragmentation ELISA and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay). In contrast, activity of caspase 1 (IL-1beta-converting enzyme)-like proteases (Tyr-Val-Ala-Asp-substrate) did not change throughout the experiment. Caspase 3-like protease activity and apoptosis was not induced by Gal/ET in ET-resistant mice (C3H/HeJ). Furthermore, only murine TNF-alpha but not IL-1alphabeta increased caspase activity and apoptosis. Gal/ET caused neutrophil-dependent hepatocellular necrosis at 7 h (area of necrosis, 45 +/- 3%). Delayed treatment with the caspase 3-like protease inhibitor Z-Val-Ala-Asp-CH2F (Z-VAD) (10 mg/kg at 3 h) attenuated apoptosis by 81 to 88% and prevented liver cell necrosis (< or = 5%). Z-VAD had no effect on the initial inflammatory response, including the sequestration of neutrophils in sinusoids. However, Z-VAD prevented neutrophil transmigration and necrosis. Our data indicate that activation of the caspase 3 subfamily of cysteine proteases is critical for the development of parenchymal cell apoptosis. In addition, excessive hepatocellular apoptosis can be an important signal for transmigration of primed neutrophils sequestered in sinusoids.