Effects of Subnormothermic Regulated Hepatic Reperfusion on Mitochondrial and Transcriptomic Profiles in a Porcine Model.
Journal
Annals of surgery
ISSN: 1528-1140
Titre abrégé: Ann Surg
Pays: United States
ID NLM: 0372354
Informations de publication
Date de publication:
01 02 2023
01 02 2023
Historique:
pmc-release:
01
02
2024
pubmed:
14
8
2021
medline:
9
2
2023
entrez:
13
8
2021
Statut:
ppublish
Résumé
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 model. Donation after circulatory death represents a severe form of liver ischemia and reperfusion injury that has a profound impact on graft function after liver transplantation. 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. 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. 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. Sub- normothermic RHR has potential applicability to clinical liver transplantation.
Sections du résumé
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 model.
SUMMARY OF BACKGROUND DATA
Donation after circulatory death 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. Sub- normothermic RHR has potential applicability to clinical liver transplantation.
Identifiants
pubmed: 34387201
doi: 10.1097/SLA.0000000000005156
pii: 00000658-202302000-00046
pmc: PMC8840998
mid: NIHMS1732116
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e366-e375Subventions
Organisme : NCI NIH HHS
ID : P50 CA217674
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA237327
Pays : United States
Informations de copyright
Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
Déclaration de conflit d'intérêts
The authors report no conflicts of interest.
Références
Goto M, Kawano S, Yoshihara H, et al. Hepatic tissue oxygenation as a predictive indicator of ischemia-reperfusion liver injury. Hepatology. 1992;15:432–437.
Tomitsuka E, Kita K, Esumi H. The NADH-fumarate reductase system, a novel mitochondrial energy metabolism, is a new target for anticancer therapy in tumor microenvironments. Ann N Y Acad Sci. 2010;1201:44–49.
Uchida M, Takemoto Y, Nagasue N, et al. Calcium in pig livers following ischemia and reperfusion. J Hepatol. 1994;20:714–719.
Jaeschke H. Reactive oxygen and mechanisms of inflammatory liver injury. J Gastroenterol Hepatol. 2000;15:718–724.
Kim JS, He L, Qian T, et al. Role of the mitochondrial permeability transition in apoptotic and necrotic death after ischemia/reperfusion injury to hepatocytes. Curr Mol Med. 2003;3:527–535.
Hong JC, Koroleff D, Xia V, et al. Regulated hepatic reperfusion mitigates ischemia-reperfusion injury and improves survival after prolonged liver warm ischemia: a pilot study on a novel concept of organ resuscitation in a large animal model. J Am Coll Surg. 2012;214:505–515.
Sosa RA, Zarrinpar A, Rossetti M, et al. Early cytokine signatures of ischemia/reperfusion injury in human orthotopic liver transplantation. JCI Insight. 2016;1:e89679.
Monbaliu D, Libbrecht L, De Vos R, et al. The extent of vacuolation in nonheart-beating porcine donor liver grafts prior to transplantation predicts their viability. Liver Transpl. 2008;14:1256–1265.
Yang M, Camara AKS, Aldakkak M, et al. Identity and function of a cardiac mitochondrial small conductance Ca(2+)-activated K(+) channel splice variant. Biochim Biophys Acta Bioenerg. 2017;1858:442–458.
Qiagen. Regulator Effects in IPA. Available at: https://qiagen.secure.force.-com/KnowledgeBase/KnowledgeIPAPage?id=kA41i000000L65DCAS . Accessed February 24, 2021.
Hoshida Y, Villanueva A, Sangiovanni A, et al. Prognostic gene expression signature for patients with hepatitis C-related early-stage cirrhosis. Gastroenterology. 2013;144:1024–1030.
Kim JH, Sohn BH, Lee HS, et al. Genomic predictors for recurrence patterns of hepatocellular carcinoma: model derivation and validation. PLoS Med. 2014;11:e1001770.
Lee JS, Chu IS, Mikaelyan A, et al. Application of comparative functional genomics to identify best-fit mouse models to study human cancer. Nat Genet. 2004;36:1306–1311.
Lee JS, Heo J, Libbrecht L, et al. A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat Med. 2006;12:410–416.
Sohn BH, Shim JJ, Kim SB, et al. Inactivation of hippo pathway is significantly associated with poor prognosis in hepatocellular carcinoma. Clin Cancer Res. 2016;22:1256–1264.
Sosa RA, Terry AQ, Kaldas FM, et al. Disulfide high-mobility group box 1 drives ischemia-reperfusion injury in human liver transplantation. Hepatology. 2021;73:1158–1175.
Nowak G, Ungerstedt J, Wernerman J, et al. Metabolic changes in the liver graft monitored continuously with microdialysis during liver transplantation in a pig model. Liver Transpl. 2002;8:424–432.
Hansen TN, Wang H, Southard JH. Mitochondrial injury limits salvaging marginal livers by machine perfusion. Transplant Proc. 2001;33:954–955.
Kim JS, Boudjema K, D’Alessandro A, et al. Machine perfusion of the liver: maintenance of mitochondrial function after 48-hour preservation. Transplant Proc. 1997;29:3452–3454.
Agarwal B, Dash RK, Stowe DF, et al. Isoflurane modulates cardiac mitochondrial bioenergetics by selectively attenuating respiratory complexes. Biochim Biophys Acta. 2014;1837:354–365.
Aldakkak M, Camara AK, Heisner JS, et al. Ranolazine reduces Ca2+ overload and oxidative stress and improves mitochondrial integrity to protect against ischemia reperfusion injury in isolated hearts. Pharmacol Res. 2011;64:381–392.
Choi SH, Park JY. Regulation of the hypoxic tumor environment in hepatocellular carcinoma using RNA interference. Cancer Cell Int. 2017;17:3.
Mueller M, Kalisvaart M, O’Rourke J, et al. Hypothermic oxygenated liver perfusion (HOPE) prevents tumor recurrence in liver transplantation from donation after circulatory death. Ann Surg. 2020;272:759–765.
Nagai S, Yoshida A, Facciuto M, et al. Ischemia time impacts recurrence of hepatocellular carcinoma after liver transplantation. Hepatology. 2015;61:895–904.
Margraf A, Germena G, Drexler HCA, et al. The integrin-linked kinase is required for chemokine-triggered high-affinity conformation of the neutrophil beta2-integrin LFA-1. Blood. 2020;136:2200–2205.
Zhang S, Liu W, Liu X, et al. Biomarkers identification for acute myocardial infarction detection via weighted gene co-expression network analysis. Medicine (Baltimore). 2017;96:e8375.
Maitre JL, Heisenberg CP. Three functions of cadherins in cell adhesion. Curr Biol. 2013;23:R626–633.
Sun M, Opavsky MA, Stewart DJ, et al. Temporal response and localization of integrins beta1 and beta3 in the heart after myocardial infarction: regulation by cytokines. Circulation. 2003;107:1046–1052.
Sakai T, Johnson KJ, Murozono M, et al. Plasma fibronectin supports neuronal survival and reduces brain injury following transient focal cerebral ischemia but is not essential for skin-wound healing and hemostasis. Nat Med. 2001;7:324–330.
Gonzalez-Nieves R, Desantis AI, Cutler ML. Rsu1 contributes to regulation of cell adhesion and spreading by PINCH1-dependent and - independent mechanisms. J Cell Commun Signal. 2013;7:279–293.
Mathow D, Chessa F, Rabionet M, et al. Zeb1 affects epithelial cell adhesion by diverting glycosphingolipid metabolism. EMBO Rep. 2015;16:321–331.
Li L, Madu CO, Lu A, et al. HIF-1alpha promotes a hypoxia-independent cell migration. Open Biol J. 2010;3:8–14.
Tanimura S, Takeda K. ERK signalling as a regulator of cell motility. J Biochem. 2017;162:145–154.
Sendoel A, Hengartner MO. Apoptotic cell death under hypoxia. Physiology (Bethesda). 2014;29:168–176.
Lehwald N, Tao GZ, Jang KY, et al. Wnt-beta-catenin signaling protects against hepatic ischemia and reperfusion injury in mice. Gastroenterology. 2011;141:707–718. 718 e701–705.
Yan W, Lin C, Guo Y, et al. N-cadherin overexpression mobilizes the protective effects of mesenchymal stromal cells against ischemic heart injury through a beta-catenin-dependent manner. Circ Res. 2020;126:857–874.
Pfister R, Acksteiner C, Baumgarth J, et al. Loss of beta1D-integrin function in human ischemic cardiomyopathy. Basic Res Cardiol. 2007;102:257–264.
Li D, Lang W, Zhou C, et al. Upregulation of microglial ZEB1 ameliorates brain damage after acute ischemic stroke. Cell Rep. 2018;22:3574–3586.
Trial J, Rossen RD, Rubio J, et al. Inflammation and ischemia: macrophages activated by fibronectin fragments enhance the survival of injured cardiac myocytes. Exp Biol Med (Maywood). 2004;229:538–545.
Lu Z, Xu S. ERK1/2 MAP kinases in cell survival and apoptosis. IUBMB Life. 2006;58:621–631.
Peralta C, Jimenez-Castro MB, Gracia-Sancho J. Hepatic ischemia and reperfusion injury: effects on the liver sinusoidal milieu. J Hepatol. 2013;59:1094–1106.
Zhai Y, Petrowsky H, Hong JC, et al. Ischaemia-reperfusion injury in liver transplantation-from bench to bedside. Nat Rev Gastroenterol Hepatol. 2013;10:79–89.
Prabhakar NR, Semenza GL. Oxygen sensing and homeostasis. Physiology (Bethesda). 2015;30:340–348.
Lehwald N, Tao GZ, Jang KY, et al. beta-Catenin regulates hepatic mitochondrial function and energy balance in mice. Gastroenterology. 2012;143:754–764.
Lavoie H, Gagnon J, Therrien M. ERK signalling: a master regulator of cell behaviour, life and fate. Nat Rev Mol Cell Biol. 2020;21:607–632.
Mylonis I, Kourti M, Samiotaki M, et al. Mortalin-mediated and ERK- controlled targeting of HIF-1alpha to mitochondria confers resistance to apoptosis under hypoxia. J Cell Sci. 2017;130:466–479.
Katoh M, Katoh M. Molecular genetics and targeted therapy of WNT-related human diseases (Review). Int J Mol Med. 2017;40:587–606.
Liu F, Yang X, Geng M, et al. Targeting ERK, an Achilles’ Heel of the MAPK pathway, in cancer therapy. Acta Pharm Sin B. 2018;8:552–562.
Ferrigno A, Di Pasqua LG, Palladini G, et al. Transient expression of reck under hepatic ischemia/reperfusion conditions is associated with mapk signaling pathways. Biomolecules. 2020;10:747.
Nasralla D, Coussios CC, Mergental H, et al. A randomized trial of normothermic preservation in liver transplantation. Nature. 2018;557:50–56.