Melatonin protects steatotic and nonsteatotic liver grafts against cold ischemia and reperfusion injury

Authors

  • Mohamed Amine Zaoualí,

    1. Experimental Hepatic Ischemia-Reperfusion Unit, Institut d’Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas, Barcelona, Spain
    2. Unitat de Transplantament de Fetge i Viabilitat de l’Empelt, Institut d’Investigacions Biomèdiques August Pi i Sunyer(IDIBAPS), Barcelona, Spain
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  • Russel J. Reiter,

    1. Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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  • Susagna Padrissa-Altés,

    1. Experimental Hepatic Ischemia-Reperfusion Unit, Institut d’Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas, Barcelona, Spain
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  • Eleonora Boncompagni,

    1. Department of Animal Biology and IGM-CNR, University of Pavia, Italy
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  • Joaquín J. García,

    1. Department of Pharmacology and Physiology, Universidad de Zaragoza, Zaragoza, Spain
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  • Hassen ben Abnennebi,

    1. Laboratory of Human Physiology, Faculty of Pharmacy, University of Monastir, Monastir, Tunisia
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  • Isabel Freitas,

    1. Department of Animal Biology and IGM-CNR, University of Pavia, Italy
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  • Francisco A. García-Gil,

    1. Department of Surgery, Universidad de Zaragoza, Zaragoza, Spain
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  • Joan Rosello-Catafau

    1. Experimental Hepatic Ischemia-Reperfusion Unit, Institut d’Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas, Barcelona, Spain
    2. Unitat de Transplantament de Fetge i Viabilitat de l’Empelt, Institut d’Investigacions Biomèdiques August Pi i Sunyer(IDIBAPS), Barcelona, Spain
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Address reprint requests to Joan Roselló-Catafau, Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona, Spanish National Research Council, 7a Planta, C/Rosselló 161, 7th Floor, 08036 Barcelona, Spain.
E-mail: jrcbam@iibb.csic.es

Abstract

Abstract:  Chronic organ-donor shortage has required the acceptance of steatotic livers for transplantation purposes despite the higher risk of graft dysfunction or nonfunction associated with the cold ischemia–reperfusion injury. This study evaluated the use of melatonin as an additive to Institute Georges Lopez (IGL-1) solution for protecting nonsteatotic and steatotic liver grafts against cold ischemia–reperfusion injury. In the current investigation, we used an ex vivo isolated perfused rat liver model. Steatotic and nonsteatotic livers were preserved for 24 hr (4°C) in University of Wisconsin or IGL-1 solutions with or without melatonin, as well as in University of Wisconsin solution alone. Thereafter, livers were subjected to 2-hr reperfusion (37°C). We assessed hepatic injury (transaminases) and function [bile production and sulfobromophthalein (BSP) clearance, vascular resistance], as well as other factors potentially implicated in the high vulnerability of steatotic livers against ischemia–reperfusion injury (oxidative stress and related inflammatory mediators including nitric oxide and cytokines). We also evaluated well-known cytoprotective factors as hemeoxygenase 1 (HO-1). Fatty livers preserved in IGL-1 solution enriched with melatonin showed lower transaminase levels and higher bile production and BSP clearance when compared to those obtained for livers maintained in IGL-1 solution alone. A significant diminution of vascular resistance was also observed when melatonin was added to the IGL-1 solution. The melatonin benefits correlated with the generation of nitric oxide (through constitutive e-NOS activation) and the prevention of oxidative stress and inflammatory cytokine release including tumor necrosis factor and adiponectin, respectively. The addition of melatonin to IGL-1 solution improved nonsteatotic and steatotic liver graft preservation, limiting their risk against cold ischemia–reperfusion injury.

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