Anti-apoptotic treatment of warm ischemic male rat livers in machine perfusion improves symptoms of ischemia-reperfusion injury
Mohammadreza Mojoudi,
McLean S. Taggart,
Anil Kharga,
Huyun Chen,
Antonia T. Dinicu,
Benjamin T. Wilks,
James F. Markmann,
Mehmet Toner,
Shannon N. Tessier,
Heidi Yeh,
Korkut Uygun
Affiliations
Mohammadreza Mojoudi
Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Shriners Children's, Boston, MA, USA
McLean S. Taggart
Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Shriners Children's, Boston, MA, USA
Anil Kharga
Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Shriners Children's, Boston, MA, USA
Huyun Chen
Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Shriners Children's, Boston, MA, USA
Antonia T. Dinicu
Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Shriners Children's, Boston, MA, USA
Benjamin T. Wilks
Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Shriners Children's, Boston, MA, USA
James F. Markmann
Harvard Medical School, Boston, MA, USA; Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
Mehmet Toner
Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Shriners Children's, Boston, MA, USA
Shannon N. Tessier
Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Shriners Children's, Boston, MA, USA
Heidi Yeh
Harvard Medical School, Boston, MA, USA; Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
Korkut Uygun
Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Shriners Children's, Boston, MA, USA; Corresponding author. 51 Blossom Street, Boston, MA, 02114, USA.
Background: Liver donation after cardiac death (DCD) makes up a small percentage of the organs used in transplantation and poses a higher risk of graft loss compared to donation after brain death (DBD); this is a result of ischemia reperfusion for which the exact injury mechanisms are currently not fully understood. However, reperfusion injury has been shown to lead to necrosis as well as apoptosis through oxidative stress and mitochondrial dysfunction. In this work, we propose that use of the pro-survival, anti-apoptotic CEPT cocktail in post-ischemia normothermic machine perfusion (NMP) may improve recovery in rat livers subjected to extended durations of warm ischemia. Materials and Methods: Livers procured from male Lewis rats were subjected to 90 min of warm ischemia, followed by 6 h of NMP where they were treated either with the survival-enhancing anti-apoptotic cocktail (CEPT), the vehicle (DMSO) or the base media with no additives. Results: The CEPT-treated group exhibited lower expression of hepatic injury biomarkers, and improvement in a range of hepatocellular symptoms associated with the hepatic parenchyma, biliary epithelium and the sinusoidal endothelium, including recovery of bile secretion and lowered vascular resistance. Conclusions: This study's findings suggest apoptosis plays a more significant role in ischemia-reperfusion injury than previously understood, and provide useful insight for further investigation of the specific underlying mechanisms and development of novel treatment methods.
