Concurrent induction of necrosis, apoptosis, and autophagy in ischemic preconditioned human livers formerly treated by chemotherapy
Concurrent induction of necrosis, apoptosis, and autophagy in ischemic preconditioned human livers formerly treated by chemotherapy
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DOI：
10.1016/j.jhep.2009.06.028
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发表时间：
2009-11-01
影响因子：
25.7
通讯作者：
Lemoine, Antoinette
中科院分区：
文献类型：
--
作者：
Domart, Marie-Charlotte;Degli Esposti, Davide;Lemoine, Antoinette
背景/目标：已知化疗诱导的肝脏病理学（脂肪变性或血管损伤）会增加肝脏对缺血/再灌注（I/R）损伤的敏感性，从而增加肝切除术后的发病率和死亡率。我们的目的是评估是否缺血预处理（IP）减少I/R损伤的肝脏化疗诱导pathology.Methods：我们分析了一系列的肝脏化疗结直肠癌患者接受IP（n = 30）或不（n = 31）肝切除术前。除了一个肝脏表现出化疗诱导的脂肪变性和/或紫癜之前的I/R insult.Results：坏死是不太常见的（p = 0.038），在肝脏与IP比其他。通过末端转移酶尿苷酸缺口末端标记（TUNEL）分析或caspase-3、-8和-9表达评估，IP对细胞凋亡无影响。IP诱导B细胞白血病/淋巴瘤2（Bcl-2; p < 0.05）增加两倍，其定位于小叶中心和肾盂区的肝细胞，并与IP肝脏中的自噬蛋白beclin-1共定位，表明它们在自噬中的协调作用。在预处理的肝脏中观察到磷酸化Bcl-2的表达增加，并且与beclin-1的免疫沉淀减少和轻链3 II型（LC 3-II）的表达增加相关。通过电子显微镜观察到的自噬空泡的数量增加证实了自噬在化疗损伤的肝脏后IP的关联。然而，蛋白质表达的差异并没有反映在切除术后肝损伤的测试或测量patient morbidity.Conclusions：IP是与减少坏死的肝细胞已经被化疗和自噬的激活损坏。Bcl-2和Beclin-1可能是I/R损伤过程中细胞死亡调控的主要靶点。(C)2009年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background/Aims: Liver pathology induced by chemotherapy (steatosis or vascular injury) is known to increase the liver's sensitivity to ischemia/reperfusion (I/R) injury, thereby increasing morbidity and mortality after liver resection. Our aim was to assess whether ischemic preconditioning (IP) reduces I/R injury to livers with chemotherapy-induced pathology.Methods: We analyzed a series of livers from patients treated with chemotherapy for colorectal cancer who underwent IP (n = 30) or not (n = 31) before hepatectomy. All but one of the livers exhibited chemotherapy-induced steatosis and/or peliosis before the I/R insult.Results: Necrosis was less frequent (p = 0.038) in livers with IP than in the others. IP had no influence on apoptosis as assessed by terminal transferase uridyl nick-end labeling (TUNEL) assay or caspase-3, -8 and -9 expression. I P induced a twofold increase in B-cell leukemia/lymphoma 2 (Bcl-2; p < 0.05), which was localized to hepatocytes of centrolobular and peliotic areas and colocalized with the autophagy protein beclin-1 in livers with IP, suggesting their coordinated role in autophagy. Increased expression of the phosphorylated Bcl-2 was observed in preconditioned livers and was associated with a decreased immunoprecipitation of beclin-1 and the increased expression of light chain 3 type II (LC3-II). The increased number of autophagic vacuoles seen by electron microscopy confirmed an association of autophagy in chemotherapy-injured livers following I P. However, the differences in protein expression were not reflected in postresection liver-injury tests or measure of patient morbidity.Conclusions: IP is associated with a reduction in necrosis of hepatocytes already damaged by chemotherapy and an activation of autophagy. Bcl-2 and beclin-1 could be major targets in the regulation of cell death during I/R injury. (C) 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.