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Peer-reviewedCC BYPLOS One

MIF inhibitor ISO-1 attenuates ischemia-reperfusion injury in a rat model of donation after circulatory death liver transplantation

  • Deniz Uluk1
  • Wenjia Liu2
  • Decan Jiang1
  • Christian Stoppe3,4,5
  • Franziska Alexandra Meister6
  • Sandra Kraemer7,8
  • Christian Beckers9
  • Alexander Theissen9
  • Christian Bleilevens9
  • Jan Bednarsch10
  • Ulf Peter Neumann10
  • Rene Hany Tolba2
1 more authors
  • Zoltan Czigany10,11
11 affiliations
  1. 1Department of General Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria.
  2. 2Institute for Laboratory Animal Science and Experimental Surgery, Faculty of Medicine, University Hospital RWTH Aachen, Aachen, Germany.
  3. 3Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital, Würzburg, Germany.
  4. 4Department of Cardiac Anaesthesiology and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Berlin, Germany.
  5. 5Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
  6. 6Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany.
  7. 7Department of Thoracic and Cardiovascular Surgery, University Hospital RWTH Aachen, Aachen, Germany.
  8. 8Cardiovascular Critical Care & Anesthesia research and evaluation (3CARE), University Hospital RWTH Aachen, Aachen, Germany.
  9. 9Department of Intensive Care Medicine, RWTH Aachen University, Aachen, Germany.
  10. 10Department of General, Visceral, Vascular, and Transplantation Surgery, University Hospital Essen, Essen, Germany.
  11. 11Faculty of Medicine, University Duisburg-Essen, Essen, Germany.
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Abstract

Macrophage migration inhibitory factor (MIF) is an early mediator of ischemia–reperfusion injury (IRI), however, the evidence on its role in orthotopic liver transplantation (OLT), particularly with donation after circulatory death (DCD) grafts is limited. Given its key regulatory function, this study investigated the effects of IRI on graft injury and assessed whether the use of ISO-1, a small-molecule MIF-inhibitor, affect IRI in a rat DCD-OLT model. 196 male Lewis rats were randomized into DBD control, DCD-30 min, DCD-60 min, DCD-30 + ISO-1, and DCD-30 + vehicle groups (n = 7/group/time-point). ISO-1 was administered before controlled cardiac arrest (0–60 min) and 3 h cold preservation before arterialized OLT. Animals were sacrificed at 1, 3, 24, and 168 h post-reperfusion. DCD grafts showed marked injury, with the DCD-60 group exhibiting lethal IRI. ISO-1 significantly reduced early hepatocellular injury compared with vehicle (AST:294 ± 63 vs 867 ± 211 IU/L, p = 0.017) and resulted in values comparable to DBD controls. Serum HMGB-1 (11 ± 2.8 vs 26 ± 6.2 pg/mL, p = 0.045) and MIF (45 ± 5.3 vs 144 ± 27.5 ng/mL, p = 0.034) levels were similarly decreased following ISO-1 application. ISO-1 improved graft microcirculation at 24 h, attenuated histological injury, and was associated with an altered time course of CD163 + macrophage infiltration. ISO-1 pre-treatment attenuated hepatocellular injury and was associated with improved graft microcirculation and reduced DAMP release, supporting further mechanistic and translational evaluation in DCD liver transplantation.

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Cite

BibTeXRIS
BibTeX
@article{uluk2026inhibitor,
  title = {{MIF inhibitor ISO-1 attenuates ischemia-reperfusion injury in a rat model of donation after circulatory death liver transplantation}},
  author = {Deniz Uluk and Wenjia Liu and Decan Jiang and Christian Stoppe and Franziska Alexandra Meister and Sandra Kraemer and Christian Beckers and Alexander Theissen and Christian Bleilevens and Jan Bednarsch and Ulf Peter Neumann and Rene Hany Tolba and Zoltan Czigany},
  journal = {PLOS One},
  year = {2026},
  month = oct,
  doi = {10.1371/journal.pone.0361214},
  url = {https://doi.org/10.1371/journal.pone.0361214},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - MIF inhibitor ISO-1 attenuates ischemia-reperfusion injury in a rat model of donation after circulatory death liver transplantation
AU  - Deniz Uluk
AU  - Wenjia Liu
AU  - Decan Jiang
AU  - Christian Stoppe
AU  - Franziska Alexandra Meister
AU  - Sandra Kraemer
AU  - Christian Beckers
AU  - Alexander Theissen
AU  - Christian Bleilevens
AU  - Jan Bednarsch
AU  - Ulf Peter Neumann
AU  - Rene Hany Tolba
AU  - Zoltan Czigany
PY  - 2026
DA  - 2026/10/26
JO  - PLOS One
DO  - 10.1371/journal.pone.0361214
UR  - https://doi.org/10.1371/journal.pone.0361214
AB  - Macrophage migration inhibitory factor (MIF) is an early mediator of ischemia–reperfusion injury (IRI), however, the evidence on its role in orthotopic liver transplantation (OLT), particularly with donation after circulatory death (DCD) grafts is limited. Given its key regulatory function, this study investigated the effects of IRI on graft injury and assessed whether the use of ISO-1, a small-molecule MIF-inhibitor, affect IRI in a rat DCD-OLT model. 196 male Lewis rats were randomized into DBD control, DCD-30 min, DCD-60 min, DCD-30 + ISO-1, and DCD-30 + vehicle groups (n = 7/group/time-point). ISO-1 was administered before controlled cardiac arrest (0–60 min) and 3 h cold preservation before arterialized OLT. Animals were sacrificed at 1, 3, 24, and 168 h post-reperfusion. DCD grafts showed marked injury, with the DCD-60 group exhibiting lethal IRI. ISO-1 significantly reduced early hepatocellular injury compared with vehicle (AST:294 ± 63 vs 867 ± 211 IU/L, p = 0.017) and resulted in values comparable to DBD controls. Serum HMGB-1 (11 ± 2.8 vs 26 ± 6.2 pg/mL, p = 0.045) and MIF (45 ± 5.3 vs 144 ± 27.5 ng/mL, p = 0.034) levels were similarly decreased following ISO-1 application. ISO-1 improved graft microcirculation at 24 h, attenuated histological injury, and was associated with an altered time course of CD163 + macrophage infiltration. ISO-1 pre-treatment attenuated hepatocellular injury and was associated with improved graft microcirculation and reduced DAMP release, supporting further mechanistic and translational evaluation in DCD liver transplantation.
SN  - 1932-6203
ER  -