title: The use of a reversible proteasome inhibitor in a model of Reduced-Size Orthotopic Liver transplantation in rats.
abstract: Ischemia/reperfusion injury (IRI), inherent in liver transplantation (LT), is the main cause of initial deficiencies and primary non-function of liver allografts. Living-related LT was developed to alleviate the mortality resulting from the scarcity of suitable deceased grafts. The main problem in using living-related LT for adults is graft size disparity. In this study we propose for the first time that the use of a proteasome inhibitor (Bortezomib) treatment could improve liver regeneration and reduce IRI after Reduced-Size Orthotopic Liver transplantation (ROLT). Rat liver grafts were reduced by removing the left lateral lobe and the two caudate lobes and preserved in UW or IGL-1 preservation solution for 1h liver and then subjected to ROLT with or without Bortezomib treatment. Our results show that Bortezomib reduces IRI after LT and is correlated with a reduction in mitochondrial damage, oxidative stress and endoplasmic reticulum stress. Furthermore, Bortezomib also increased liver regeneration after reduced-size LT and increased the expression of well-known ischemia/reperfusion protective proteins such as nitric oxide synthase, heme oxigenase 1 (HO-1) and Heat Shock Protein 70. Our results open new possibilities for the study of alternative therapeutic strategies aimed at reducing IRI and increasing liver regeneration after LT. It is hoped that the results of our study will contribute towards improving the understanding of the molecular processes involved in IRI and liver regeneration, and therefore help to improve the outcome of this type of LT in the future.
authors.affiliation: Experimental Hepatic Ischemia-Reperfusion Unit, Institut d´Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones Científicas, Barcelona, Spain.
authors.forename: Susagna
authors.initials: S
authors.lastname: Padrissa-Altés
authors.forename: Mohamed Amine
authors.initials: MA
authors.lastname: Zaouali
authors.forename: Eleonora
authors.initials: E
authors.lastname: Boncompagni
authors.forename: Eliano
authors.initials: E
authors.lastname: Bonaccorsi-Riani
authors.forename: Teresa
authors.initials: T
authors.lastname: Carbonell
authors.forename: Fawzia
authors.initials: F
authors.lastname: Bardag-Gorce
authors.forename: Joan
authors.initials: J
authors.lastname: Oliva
authors.forename: Samuel W
authors.initials: SW
authors.lastname: French
authors.forename: Ramon
authors.initials: R
authors.lastname: Bartrons
authors.forename: Joan
authors.initials: J
authors.lastname: Roselló-Catafau
mesh_terms: D000818:Animals; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis*; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis; D008115:Liver Regeneration / Q000187:drug effects; D016031:Liver Transplantation / Q000379:methods*; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis; D009929:Organ Size; D018384:Oxidative Stress / Q000187:drug effects; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy
chemical_list: D001897:Boronic Acids; D004791:Enzyme Inhibitors; D018840:HSP70 Heat-Shock Proteins; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat