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Autophagic Punctum

Autophagy is induced by ischemic preconditioning in human livers formerly treated by chemotherapy to limit necrosis

Davide Degli Esposti, Marie-Charlotte Domart, Mylène Sebagh, Francis Harper, Gérard Pierron, Catherine Brenner and Antoinette Lemoine

The effectiveness of ischemic preconditioning (IP) against hepatic ischemia/reperfusion injury during human liver surgery is linked to decreased apoptotic cell death as well as preservation of the ATP content in liver tissue. Overproduction of Bcl-2 is reported in preconditioned organs. In human liver biopsies exhibiting steatosis and/or vascular injuries (mainly peliosis) induced by chemotherapy, we find that the expression of Bcl-2 in centrolobular and peliotic areas colocalizes with the autophagy protein Beclin 1 in IP livers. Increased expression of phosphorylated Bcl-2 in preconditioned livers is associated with a decreased immunoprecipitation of Beclin 1 and increased expression of LC3-II. The increased number of autophagic vacuoles seen by electron microscopy confirmed that IP could trigger autophagy in chemotherapy-injured livers, probably to reduce the pro-inflammatory necrotic cell death of hepatocytes or endothelial cells and to increase ATP levels. Indeed, necrosis is less frequent (p = 0.04) in IP livers than in the others although no change in apoptosis as assessed by TUNEL assay or caspase-3, -8 and -9 expressions is observed. In conclusion, Bcl-2 and Beclin 1 could be major targets in the regulation of cell death during ischemia/reperfusion injury modulating autophagy to switch on/off necrosis and/or apoptosis.

Punctum to: Domart MC, Esposti DD, Sebagh M, Olaya N, Harper F, Pierron G, Franc B, Tanabe KK, Debuire B, Azoulay D, Brenner C, Lemoine A. Concurrent induction of necrosis, apoptosis, and autophagy in ischemic preconditioned human livers formerly treated by chemotherapy. J Hepatol 2009; 51:881-9; PMID: 19765849; DOI: 10.1016/j.jhep.2009.06.028.

Authors

Davide Degli Esposti

AP-HP; Hôpital Paul Brousse; Service de Biochimie et Biologie Moléculaire; Villejuif, France; Inserm U602; Institut André Lwoff-IFR89; Université Paris XI; PRES Universud-Paris; Villejuif, France; Laboratoire de Biochimie et Biologie Cellulaire; Faculté de Pharmacie; Châtenay-Malabry, France

Marie-Charlotte Domart

AP-HP; Hôpital Paul Brousse; Service de Biochimie et Biologie Moléculaire; Villejuif, France; Inserm U602; Institut André Lwoff-IFR89; Université Paris XI; PRES Universud-Paris; Villejuif, France

Mylène Sebagh

AP-HP; Hôpital Paul Brousse; Service d’Anatomie Pathologique; Inserm U785; Université Paris XI; Institut André Lwoff; Villejuif, France

Francis Harper

Institut André Lwoff; UPR-1983, Laboratoire Réplication de l'ADN et Ultrastructure du Noyau; Villejuif, France

Gérard Pierron

Institut André Lwoff; UPR-1983, Laboratoire Réplication de l'ADN et Ultrastructure du Noyau; Villejuif, France

Catherine Brenner

CNRS UMR 8159; Université Versailles/St Quentin; PRES Universud-Paris; Versailles, France

Antoinette Lemoine Corresponding author: antoinette.lemoine@pbr.aphp.fr

AP-HP; Hôpital Paul Brousse; Service de Biochimie et Biologie Moléculaire; Villejuif, France; Inserm U602; Institut André Lwoff-IFR89; Université Paris XI; PRES Universud-Paris; Villejuif, France; Laboratoire de Biochimie et Biologie Cellulaire; Faculté de Pharmacie; Châtenay-Malabry, France