TY - JOUR
T1 - Advancing Perfusion Models
T2 - Dual-Vessel Ex Vivo Rat Liver Perfusion Based on a Clinical Setup
AU - Strobl, Felix
AU - Michelotto, Julian
AU - Muth, Vanessa
AU - Moosburner, Simon
AU - Knaub, Kristina
AU - Zimmer, Maximilian
AU - Patel, Madhukar S.
AU - Pratschke, Johann
AU - Sauer, Igor M.
AU - Raschzok, Nathanael
AU - Gassner, Joseph M.G.V.
N1 - Publisher Copyright:
© 2023 Mary Ann Liebert Inc.. All rights reserved.
PY - 2023/10/1
Y1 - 2023/10/1
N2 - Normothermic ex vivo liver machine perfusion (NEVLP) has been developed to address the increasing organ shortage in liver transplantation, through optimal preservation, assessment, and conditioning of grafts from extended criteria donors. There remains a need to establish simple and standardized animal models that simulate clinical NEVLP to test novel therapies. Liver grafts from 36 Sprague-Dawley rats were perfused for 6 h in a dual-vessel NEVLP system with a Dulbecco’s modified Eagles medium-based perfusate supplemented with rat plasma and erythrocytes. Varying doses of the clinically used vasodilator epoprostenol, Kupffer cell inhibitor glycine, and a SteenTM-based perfusate were assessed. Perfusion pressures and bile production were recorded, and perfusate was analyzed for transaminase secretion. Tissue samples were evaluated histologically, and levels of cytokines and 8-Isoprostane were measured. Increasing levels of epoprostenol and the addition of glycine resulted in a stepwise decrease of transaminase secretion and improved bile production. Steen further decreased transaminase release and interleukin 1 beta levels. Liver grafts perfused with the optimized Steen-based protocol exhibited lowest levels of oxidative stress and best-preserved liver integrity. In conclusion, epoprostenol seemed to ameliorate liver function and prevent cellular damage beyond its vasodilatory effect, with glycine acting synergistically. The anti-inflammatory and antioxidative properties of Steen further improved the outcome of perfusion. Our rodent NEVLP system may be used to rapidly test new agents for the pharmacologic conditioning of livers and help translate findings from bench-to-bedside.
AB - Normothermic ex vivo liver machine perfusion (NEVLP) has been developed to address the increasing organ shortage in liver transplantation, through optimal preservation, assessment, and conditioning of grafts from extended criteria donors. There remains a need to establish simple and standardized animal models that simulate clinical NEVLP to test novel therapies. Liver grafts from 36 Sprague-Dawley rats were perfused for 6 h in a dual-vessel NEVLP system with a Dulbecco’s modified Eagles medium-based perfusate supplemented with rat plasma and erythrocytes. Varying doses of the clinically used vasodilator epoprostenol, Kupffer cell inhibitor glycine, and a SteenTM-based perfusate were assessed. Perfusion pressures and bile production were recorded, and perfusate was analyzed for transaminase secretion. Tissue samples were evaluated histologically, and levels of cytokines and 8-Isoprostane were measured. Increasing levels of epoprostenol and the addition of glycine resulted in a stepwise decrease of transaminase secretion and improved bile production. Steen further decreased transaminase release and interleukin 1 beta levels. Liver grafts perfused with the optimized Steen-based protocol exhibited lowest levels of oxidative stress and best-preserved liver integrity. In conclusion, epoprostenol seemed to ameliorate liver function and prevent cellular damage beyond its vasodilatory effect, with glycine acting synergistically. The anti-inflammatory and antioxidative properties of Steen further improved the outcome of perfusion. Our rodent NEVLP system may be used to rapidly test new agents for the pharmacologic conditioning of livers and help translate findings from bench-to-bedside.
KW - extended criteria donor
KW - ischemia reperfusion injury
KW - liver transplantation
KW - normothermic machine perfusion
KW - organ shortage
KW - rat model
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U2 - 10.1089/ten.tea.2023.0014
DO - 10.1089/ten.tea.2023.0014
M3 - Article
C2 - 37498780
AN - SCOPUS:85172131974
SN - 1937-3341
VL - 29
SP - 518
EP - 528
JO - Tissue Engineering - Part A
JF - Tissue Engineering - Part A
IS - 19-20
ER -