Variable activation of phosphoinositide 3-kinase influences the response of liver grafts to ischemic preconditioning.
OBJECTIVE
The efficacy of ischemic preconditioning (IPC) in preventing reperfusion injury in human liver transplants is still questioned. Phosphoinositide-3-kinase (PI3K) is essential for IPC development in rodent livers. This work investigates whether PI3K-dependent signals might account for the inconsistent responses to IPC of transplanted human livers.


METHODS
Forty livers from deceased donors were randomized to receive or not IPC before recovery. PI3K activation was evaluated in biopsies obtained immediately before IPC and 2 h after reperfusion by measuring the phosphorylation of the PI3K downstream kinase PKB/Akt and the levels of the PI3K antagonist phosphatase tensin-homologue deleted from chromosome 10 (PTEN).


RESULTS
IPC increased PKB/Akt phosphorylation (p = 0.01) and decreased PTEN levels (p = 0.03) in grafts, but did not significantly ameliorate post-transplant reperfusion injury. By calculating T(2h)/T(0) PKB/Akt phosphorylation ratios, 10/19 (53%) of the preconditioned grafts had ratios above the control threshold (IPC-responsive), while the remaining nine grafts showed ratios comparable to controls (IPC-non-responsive). T(2h)/T(0) PTEN ratios were also decreased (p < or = 0.03) only in IPC-responsive grafts. The patients receiving IPC-responsive organs had ameliorated (p < or = 0.05) post-transplant aminotransferase and bilirubin levels, while prothrombin activity was unchanged.


CONCLUSIONS
Impaired PI3K signaling might account for the variability in the responses to IPC of human grafts from deceased donors.
Cescon
Matteo
M
Department of General Surgery and Organ Transplantation, Liver and Multiorgan Transplant Unit, Alma Mater Studiorum University of Bologna, Bologna, Italy.
Carini
Rita
R
Grazi
Gianluca
G
Caraceni
Paolo
P
Alchera
Elisa
E
Gasloli
Giorgio
G
Ravaioli
Matteo
M
Tuci
Francesco
F
Imarisio
Chiara
C
Dal Ponte
Caterina
C
Pertosa
Anna Maria
AM
Bernardi
Mauro
M
Pinna
Antonio D
AD
Albano
Emanuele
E
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D005260:Female; D006801:Humans; D019194:Ischemic Preconditioning; D008099:Liver / Q000201:enzymology / Q000473:pathology; D016031:Liver Transplantation / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000378:metabolism / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015427:Reperfusion Injury / Q000517:prevention & control*; D015398:Signal Transduction / Q000502:physiology; D023001:Transplantation Tolerance / Q000502:physiology
D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase