Variable activation of phosphoinositide 3-kinase influences the response of liver grafts to ischemic preconditioning

Background/Aims: 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/T₀ 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/T₀ PTEN ratios were also decreased (p ≤ 0.03) only in IPC-responsive grafts. The patients receiving IPC-responsive organs had ameliorated (p ≤ 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.