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

Matteo Cescon, Rita Carini, Gianluca Grazi, Paolo Caraceni, Elisa Alchera, Giorgio Gasloli, Matteo Ravaioli, Francesco Tuci, Chiara Imarisio, Caterina Dal Ponte, Anna Maria Pertosa, Mauro Bernardi, Antonio D. Pinna, Emanuele Albano

Research output: Contribution to journalArticlepeer-review

Abstract

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/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 ≤ 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.

Original languageEnglish
Pages (from-to)937-947
Number of pages11
JournalJournal of Hepatology
Volume50
Issue number5
DOIs
Publication statusPublished - May 2009

Keywords

  • Hepatoprotection
  • Ischemia-reperfusion
  • Liver transplantation
  • PKB/Akt
  • PTEN

ASJC Scopus subject areas

  • Hepatology

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