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

doi:10.1016/j.jhep.2008.11.016

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

Dipartimento di Scienze della Salute

Risultato della ricerca: Contributo su rivista › Articolo in rivista › peer 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/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.

Lingua originale	Inglese
pagine (da-a)	937-947
Numero di pagine	11
Rivista	Journal of Hepatology
Volume	50
Numero di pubblicazione	5
DOI	https://doi.org/10.1016/j.jhep.2008.11.016
Stato di pubblicazione	Pubblicato - mag 2009

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10.1016/j.jhep.2008.11.016

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Cescon, M., Carini, R., Grazi, G., Caraceni, P., Alchera, E., Gasloli, G., Ravaioli, M., Tuci, F., Imarisio, C., Ponte, C. D., Pertosa, A. M., Bernardi, M., Pinna, A. D., & Albano, E. (2009). Variable activation of phosphoinositide 3-kinase influences the response of liver grafts to ischemic preconditioning. Journal of Hepatology, 50(5), 937-947. https://doi.org/10.1016/j.jhep.2008.11.016

@article{d78bd7c918aa45bca05e23407ae28f65,

title = "Variable activation of phosphoinositide 3-kinase influences the response of liver grafts to ischemic preconditioning",

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 T2h/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). T2h/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.",

keywords = "Hepatoprotection, Ischemia-reperfusion, Liver transplantation, PKB/Akt, PTEN",

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

note = "Funding Information: Financial Support: This work has been supported by the Regional Government of Piedmont (Fondi Ricerca Sanitaria Finalizzata, 2006), the Italian Ministry of Instruction, University and Research (PRIN 2004), the University “Amedeo Avogadro” and by an unrestricted research grant from Alma Medicina Foundation, Bologna, Italy.",

year = "2009",

month = may,

doi = "10.1016/j.jhep.2008.11.016",

language = "English",

volume = "50",

pages = "937--947",

journal = "Journal of Hepatology",

issn = "0168-8278",

publisher = "Elsevier B.V.",

number = "5",

}

Cescon, M, Carini, R, Grazi, G, Caraceni, P, Alchera, E, Gasloli, G, Ravaioli, M, Tuci, F, Imarisio, C, Ponte, CD, Pertosa, AM, Bernardi, M, Pinna, AD & Albano, E 2009, 'Variable activation of phosphoinositide 3-kinase influences the response of liver grafts to ischemic preconditioning', Journal of Hepatology, vol. 50, n. 5, pagg. 937-947. https://doi.org/10.1016/j.jhep.2008.11.016

TY - JOUR

T1 - Variable activation of phosphoinositide 3-kinase influences the response of liver grafts to ischemic preconditioning

AU - Cescon, Matteo

AU - Carini, Rita

AU - Grazi, Gianluca

AU - Caraceni, Paolo

AU - Alchera, Elisa

AU - Gasloli, Giorgio

AU - Ravaioli, Matteo

AU - Tuci, Francesco

AU - Imarisio, Chiara

AU - Ponte, Caterina Dal

AU - Pertosa, Anna Maria

AU - Bernardi, Mauro

AU - Pinna, Antonio D.

AU - Albano, Emanuele

N1 - Funding Information: Financial Support: This work has been supported by the Regional Government of Piedmont (Fondi Ricerca Sanitaria Finalizzata, 2006), the Italian Ministry of Instruction, University and Research (PRIN 2004), the University “Amedeo Avogadro” and by an unrestricted research grant from Alma Medicina Foundation, Bologna, Italy.

PY - 2009/5

Y1 - 2009/5

N2 - 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 T2h/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). T2h/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.

AB - 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 T2h/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). T2h/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.

KW - Hepatoprotection

KW - Ischemia-reperfusion

KW - Liver transplantation

KW - PKB/Akt

KW - PTEN

UR - http://www.scopus.com/inward/record.url?scp=64549134597&partnerID=8YFLogxK

U2 - 10.1016/j.jhep.2008.11.016

DO - 10.1016/j.jhep.2008.11.016

M3 - Article

SN - 0168-8278

VL - 50

SP - 937

EP - 947

JO - Journal of Hepatology

JF - Journal of Hepatology

IS - 5

ER -

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

Abstract

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