Concurrent induction of necrosis, apoptosis, and autophagy in ischemic preconditioned human livers formerly treated by chemotherapy

被引：46

作者：

Domart, Marie-Charlotte ^{[1
,2
]}

Degli Esposti, Davide ^{[1
,2
,3
]}

Sebagh, Mylene ^{[4
]}

Olaya, Natalia ^{[1
,2
]}

Harper, Francis ^{[5
]}

Pierron, Gerard ^{[5
]}

Franc, Brigitte ^{[6
]}

Tanabe, Kenneth K. ^{[7
,8
]}

Debuire, Brigitte ^{[1
]}

Azoulay, Daniel ^{[9
]}

Brenner, Catherine ^{[10
]}

Lemoine, Antoinette ^{[1
,3
]}

机构：

[1] Hop Paul Brousse, AP HP, Serv Biochim & Biol Mol, F-94804 Villejuif, France

[2] Univ Paris 11, INSERM, Inst Andre Lwoff IFR89, PRES Universud Paris,U602, Villejuif, France

[3] Univ Paris 11, Fac Pharm, Lab Biochim & Biol Cellulaire, F-92290 Chatenay Malabry, France

[4] Univ Paris 11, AP HP, Hop Paul Brousse, Inst Andre Lwoff,Serv Anat Pathol,Inserm U785, F-94804 Villejuif, France

[5] Inst Andre Lwoff, Lab Replicat ADN & Ultrastruct Noyau, UPR 1983, Villejuif, France

[6] Univ Versailles St Quentin, Hop Ambroise Pare, AP HP, Serv Anat Pathol,PRES Universud Paris, Versailles, France

[7] Massachusetts Gen Hosp, Ctr Canc, Div Surg Oncol, Boston, MA USA

[8] Harvard Univ, Sch Med, Boston, MA USA

[9] Univ Paris 11, Hop Paul Brousse, AP HP, Ctr Hepatobiliaire, Villejuif, France

[10] Univ Versailles St Quentin, CNRS, PRES Univsud Paris, UMR 8159, Versailles, France

来源：

JOURNAL OF HEPATOLOGY | 2009年 / 51卷 / 05期

关键词：

Cell death; Ischemia/reperfusion; Ischemic preconditioning; Chemotherapy; Bcl-2; Beclin-1; Autophagy; Liver; MOUSE-LIVER; PREOPERATIVE CHEMOTHERAPY; REPERFUSION INJURY; COLORECTAL-CANCER; CELL-DEATH; IN-VIVO; BCL-2; METASTASES; OXALIPLATIN; MECHANISMS;

D O I：

10.1016/j.jhep.2009.06.028

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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.

引用

页码：881 / 889

页数：9

共 36 条

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