Quantitative Metabolomics of Tissue, Perfusate, and Bile from Rat Livers Subjected to Normothermic Machine Perfusion
Caterina Lonati,
Daniele Dondossola,
Laimdota Zizmare,
Michele Battistin,
Leonie Wüst,
Luigi Vivona,
Margherita Carbonaro,
Alberto Zanella,
Stefano Gatti,
Andrea Schlegel,
Christoph Trautwein
Affiliations
Caterina Lonati
Center for Preclinical Research, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Pace 9, 20100 Milan, Italy
Daniele Dondossola
General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20100 Milan, Italy
Laimdota Zizmare
Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University Hospital Tübingen, Eberhard Karls University of Tübingen, Röntgenweg 13, 72076 Tübingen, Germany
Michele Battistin
Center for Preclinical Research, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Pace 9, 20100 Milan, Italy
Leonie Wüst
Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University Hospital Tübingen, Eberhard Karls University of Tübingen, Röntgenweg 13, 72076 Tübingen, Germany
Luigi Vivona
Department of Pathophysiology and Transplantation, University of Milan, Via Francesco Sforza 35, 20100 Milan, Italy
Margherita Carbonaro
General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20100 Milan, Italy
Alberto Zanella
Department of Pathophysiology and Transplantation, University of Milan, Via Francesco Sforza 35, 20100 Milan, Italy
Stefano Gatti
Center for Preclinical Research, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Pace 9, 20100 Milan, Italy
Andrea Schlegel
Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, 8091 Zürich, Switzerland
Christoph Trautwein
Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University Hospital Tübingen, Eberhard Karls University of Tübingen, Röntgenweg 13, 72076 Tübingen, Germany
Machine perfusion (MP) allows the maintenance of liver cells in a metabolically active state ex vivo and can potentially revert metabolic perturbations caused by donor warm ischemia, procurement, and static cold storage (SCS). The present preclinical research investigated the metabolic outcome of the MP procedure by analyzing rat liver tissue, bile, and perfusate samples by means of high-field (600 MHz) nuclear magnetic resonance (NMR) spectroscopy. An established rat model of normothermic MP (NMP) was used. Experiments were carried out with the addition of an oxygen carrier (OxC) to the perfusion fluid (OxC-NMP, n = 5) or without (h-NMP, n = 5). Bile and perfusate samples were collected throughout the procedure, while biopsies were only taken at the end of NMP. Two additional groups were: (1) Native, in which tissue or bile specimens were collected from rats in resting conditions; and (2) SCS, in which biopsies were taken from cold-stored livers. Generally, NMP groups showed a distinctive metabolomic signature in all the analyzed biological matrices. In particular, many of the differentially expressed metabolites were involved in mitochondrial biochemical pathways. Succinate, acetate, 3-hydroxybutyrate, creatine, and O-phosphocholine were deeply modulated in ex vivo perfused livers compared to both the Native and SCS groups. These novel results demonstrate a broad modulation of mitochondrial metabolism during NMP that exceeds energy production and redox balance maintenance.