Joohyun Kim1, Michael A Zimmerman, Woo Young Shin, Brent T Boettcher, Ju-Seog Lee, Jong-In Park, Muhammed Ali, Meiying Yang, Jyotsna Mishra, Catherine E Hagen, Joseph E McGraw, Angela Mathison, Harvey J Woehlck, Gwen Lomberk, Amadou K S Camara, Raul A Urrutia, David F Stowe, Johnny C Hong. 1. Division of Transplant Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee WI, USA Transplant Center, Froedtert & the Medical College of Wisconsin, and Children's Wisconsin, Milwaukee, WI, USA Department of Surgery, Inha University School of Medicine, Incheon, South Korea Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA Department of Pathology, Mayo Clinic, Rochester, MN, USA Department of Pharmacology, Concordia University, Mequon, WI, USA Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI, USA Division of Research, Department of Surgery, Medical College of Wisconsin, Milwaukee WI, USA.
Abstract
OBJECTIVE: We sought to investigate the biological effects of pre-reperfusion treatments of the liver after warm and cold ischemic injuries in a porcine donation after circulatory death (DCD) model. SUMMARY OF BACKGROUND DATA: DCD represents a severe form of liver ischemia and reperfusion injury that has a profound impact on graft function after liver transplantation. METHODS: Twenty donor pig livers underwent 60 minutes of in situ warm ischemia after circulatory arrest and 120 minutes of cold static preservation prior to simulated transplantation using an ex vivo perfusion machine. Four reperfusion treatments were compared: Control-Normothermic (N), Control-Subnormothermic (S), regulated hepatic reperfusion (RHR)-N, and RHR-S (n = 5 each). The biochemical, metabolic, and transcriptomic profiles, as well as mitochondrial function were analyzed. RESULTS: Compared to the other groups, RHR-S treated group showed significantly lower post-reperfusion aspartate aminotransferase levels in the reperfusion effluent and histologic findings of hepatocyte viability and lesser degree of congestion and necrosis. RHR-S resulted in a significantly higher mitochondrial respiratory control index and calcium retention capacity. Transcriptomic profile analysis showed that treatment with RHR-S activated cell survival and viability, cellular homeostasis as well as other biological functions involved in tissue repair such as cytoskeleton or cytoplasm organization, cell migration, transcription, and microtubule dynamics. Furthermore, RHR-S inhibited organismal death, morbidity and mortality, necrosis, and apoptosis. CONCLUSION: Subnormothermic RHR mitigates IRI and preserves hepatic mitochondrial function after warm and cold hepatic ischemia. This organ resuscitative therapy may also trigger the activation of protective genes against IRI. Subnormothermic RHR has potential applicability to clinical liver transplantation.
OBJECTIVE: We sought to investigate the biological effects of pre-reperfusion treatments of the liver after warm and cold ischemic injuries in a porcine donation after circulatory death (DCD) model. SUMMARY OF BACKGROUND DATA: DCD represents a severe form of liver ischemia and reperfusion injury that has a profound impact on graft function after liver transplantation. METHODS: Twenty donor pig livers underwent 60 minutes of in situ warm ischemia after circulatory arrest and 120 minutes of cold static preservation prior to simulated transplantation using an ex vivo perfusion machine. Four reperfusion treatments were compared: Control-Normothermic (N), Control-Subnormothermic (S), regulated hepatic reperfusion (RHR)-N, and RHR-S (n = 5 each). The biochemical, metabolic, and transcriptomic profiles, as well as mitochondrial function were analyzed. RESULTS: Compared to the other groups, RHR-S treated group showed significantly lower post-reperfusion aspartate aminotransferase levels in the reperfusion effluent and histologic findings of hepatocyte viability and lesser degree of congestion and necrosis. RHR-S resulted in a significantly higher mitochondrial respiratory control index and calcium retention capacity. Transcriptomic profile analysis showed that treatment with RHR-S activated cell survival and viability, cellular homeostasis as well as other biological functions involved in tissue repair such as cytoskeleton or cytoplasm organization, cell migration, transcription, and microtubule dynamics. Furthermore, RHR-S inhibited organismal death, morbidity and mortality, necrosis, and apoptosis. CONCLUSION: Subnormothermic RHR mitigates IRI and preserves hepatic mitochondrial function after warm and cold hepatic ischemia. This organ resuscitative therapy may also trigger the activation of protective genes against IRI. Subnormothermic RHR has potential applicability to clinical liver transplantation.
Authors: T Sakai; K J Johnson; M Murozono; K Sakai; M A Magnuson; T Wieloch; T Cronberg; A Isshiki; H P Erickson; R Fässler Journal: Nat Med Date: 2001-03 Impact factor: 53.440
Authors: MeiYing Yang; Amadou K S Camara; Mohammed Aldakkak; Wai-Meng Kwok; David F Stowe Journal: Biochim Biophys Acta Bioenerg Date: 2017-03-22 Impact factor: 3.991
Authors: Johnny C Hong; Dimitri Koroleff; Victor Xia; Chun Ming Chang; Sergio M Duarte; Junming Xu; Charles Lassman; Jerzy Kupiec-Weglinski; Ana J Coito; Ronald W Busuttil Journal: J Am Coll Surg Date: 2012-02-07 Impact factor: 6.113
Authors: Isabel M A Brüggenwirth; Willemijn S van der Plas; Otto B van Leeuwen; Adam M Thorne; Michel Rayar; Vincent E de Meijer; Robert J Porte Journal: Artif Organs Date: 2021-12-16 Impact factor: 2.663