Echinomycin decreases induction of vascular endothelial growth factor and hepatocyte regeneration in acetaminophen toxicity in mice.
Echinomycin decreases induction of vascular endothelial growth factor and hepatocyte regeneration in acetaminophen toxicity in mice.
复制标题
Echinomycin 可降低小鼠对乙酰氨基酚毒性中血管内皮生长因子的诱导和肝细胞再生。
DOI：
10.1111/j.1742-7843.2011.00812.x
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发表时间：
2012
影响因子：
3.1
通讯作者：
James,LauraP
中科院分区：
文献类型：
--
作者：
Milesi-Hallé,Alessandra;McCullough,Sandra;Hinson,JackA;Kurten,RichardC;Lamps,LauraW;Brown,Aliza;James,LauraP
血管内皮生长因子（VEGF）的上调对小鼠对乙酰氨基酚（APAP）中毒后期肝细胞再生至关重要。本研究利用抑制HIF - 1α DNA结合活性的抑制剂——棘霉素（EC），探讨了缺氧诱导因子1α (HIF - 1α)与APAP毒性中VEGF和肝细胞再生的关系。B6C3F1雄性小鼠先用APAP （200 mg/kg IP）处理，再用EC （0.15 mg IP）处理，4 h处死。APAP/EC和APAP/veh小鼠4小时血清丙氨酸转氨酶（ALT）、坏死、肝谷胱甘肽（GSH）和APAP蛋白加合物相当。其他研究表明，高剂量EC （0.3 mg）降低了肝脏VEGF，但也降低了肝脏GSH。后续研究使用0.15 mg剂量的EC进行。虽然EC 0.15 mg在8小时时对肝脏VEGF水平没有影响，但到24小时时，VEGF水平下降了40%。APAP组和APAP/EC组在24和48小时的毒性（ALT和组织病理学）相当。Western blot分析和免疫组化染色显示APAP/EC小鼠48小时增殖细胞核抗原表达降低。这些数据支持了HIF‐1α的诱导、其与DNA的结合以及随后VEGF的表达是APAP毒性小鼠肝细胞再生的重要因素的假设。
Up‐regulation of vascular endothelial growth factor (VEGF) is important to hepatocyte regeneration in the late stages of acetaminophen (APAP) toxicity in the mouse. This study was conducted to examine the relationship of hypoxia‐inducible factor 1α (HIF‐1α) to VEGF and hepatocyte regeneration in APAP toxicity using an inhibitor of HIF‐1α DNA‐binding activity, echinomycin (EC). B6C3F1 male mice were treated with APAP (200 mg/kg IP), followed by EC (0.15 mg IP) and killed at 4 hr. Serum alanine aminotransferase (ALT), necrosis, hepatic glutathione (GSH) and APAP protein adducts were comparable in the APAP/EC and the APAP/veh mice at 4 hr. Additional studies showed that high dose EC (0.3 mg) reduced hepatic VEGF but also lowered hepatic GSH. Subsequent studies were performed using the 0.15‐mg dose of EC. Although EC 0.15 mg had no effect on hepatic VEGF levels at 8 hr, by 24 hr VEGF levels were decreased by 40%. Toxicity (ALT and histopathology) was comparable in the APAP and APAP/EC groups at 24 and 48 hr. Proliferating cell nuclear antigen expression was reduced by both Western blot analysis and immunohistochemical staining in the APAP/EC mice at 48 hr. The data support the hypothesis that induction of HIF‐1α, its binding to DNA and subsequent expression of VEGF are important factors in hepatocyte regeneration in APAP toxicity in the mouse.