title: Concurrent induction of necrosis, apoptosis, and autophagy in ischemic preconditioned human livers formerly treated by chemotherapy.
abstract: OBJECTIVE
  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. IP 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 IP. 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.
authors.affiliation: AP-HP, Hôpital Paul Brousse, Service de Biochimie et Biologie Moléculaire, Villejuif, France.
authors.forename: Marie-Charlotte
authors.initials: MC
authors.lastname: Domart
authors.forename: Davide Degli
authors.initials: DD
authors.lastname: Esposti
authors.forename: Mylène
authors.initials: M
authors.lastname: Sebagh
authors.forename: Natalia
authors.initials: N
authors.lastname: Olaya
authors.forename: Francis
authors.initials: F
authors.lastname: Harper
authors.forename: Gérard
authors.initials: G
authors.lastname: Pierron
authors.forename: Brigitte
authors.initials: B
authors.lastname: Franc
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Tanabe
authors.forename: Brigitte
authors.initials: B
authors.lastname: Debuire
authors.forename: Daniel
authors.initials: D
authors.lastname: Azoulay
authors.forename: Catherine
authors.initials: C
authors.lastname: Brenner
authors.forename: Antoinette
authors.initials: A
authors.lastname: Lemoine
mesh_terms: D000368:Aged; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D000071186:Beclin-1; D015179:Colorectal Neoplasms / Q000188:drug therapy; D005260:Female; D006801:Humans; D019194:Ischemic Preconditioning; D008099:Liver / Q000098:blood supply* / Q000293:injuries / Q000378:metabolism / Q000473:pathology*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000556:secondary / Q000601:surgery; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D009336:Necrosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015427:Reperfusion Injury / Q000517:prevention & control
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2