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

Autores:	Marie-Charlotte Domart, Davide Degli Esposti, Mylène Sebagh, Natalia Olaya, Francis Harper, Gérard Pierron, Brigitte Franc, Kenneth K Tanabe, Brigitte Debuire, Daniel Azoulay, Catherine Brenner, Antoinette Lemoine
Língua:	Eng.
Data:	2009-10-14
Jornal:	Journal of Hepatology (0168-8278)
Release:	J Hepatol. 2009 Nov;51(5):881-9
Abstract:	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. 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.
Copyright:	Journal of Hepatology AP-HP, Hôpital Paul Brousse, Service de Biochimie et Biologie Moléculaire, Villejuif, France.
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Assuntos	Aged, Apoptosis, Apoptosis Regulatory Proteins, Autophagy, Colorectal Neoplasms, Female, Humans, Ischemic Preconditioning, Liver, Liver Neoplasms, Male, Membrane Proteins, Middle Aged, Necrosis, Proto-Oncogene Proteins c-bcl-2, Reperfusion Injury