Autophagy is induced by ischemic preconditioning in human livers formerly treated by chemotherapy to limit necrosis.
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 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.
Esposti
Davide Degli
DD
AP-HP, Hôpital Paul Brousse, Service de Biochimie et Biologie Moléculaire, Villejuif, France.
Domart
Marie-Charlotte
MC
Sebagh
Mylène
M
Harper
Francis
F
Pierron
Gérard
G
Brenner
Catherine
C
Lemoine
Antoinette
A
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D006801:Humans; D019194:Ischemic Preconditioning / Q000379:methods; D008099:Liver / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology* / Q000601:surgery; D008954:Models, Biological; D009336:Necrosis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D011300:Preoperative Care / Q000379:methods; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control