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• W4327921881 abstract "Ischemia/reperfusion injury is an inevitable process during liver transplantation and can lead to a high incidence of early allograft dysfunction and graft failure. The mechanism of hepatic ischemia/reperfusion injury has been elucidated as the sequelae of microcirculation dysfunction, hypoxia, oxidative stress, and cell death. In addition, the essential role of innate and adaptive immune response in hepatic ischemia/reperfusion injury and its deleterious outcomes have been discovered. Furthermore, mechanistic studies of living donor liver transplantation have elucidated distinct features of mitochondrial and metabolic dysfunction in steatotic and small-for-size graft injury. The mechanistic findings of hepatic ischemia/reperfusion injury have laid the foundation for exploring new biomarkers; however, they are yet to be validated in large cohorts. Moreover, the molecular and cellular mechanistic analysis of hepatic ischemia/reperfusion injury has promoted the development of potential therapeutics in preclinical and clinical trials. This review summarizes the most up to date evidence for liver ischemia/reperfusion injury and puts forward the importance of the spatiotemporal microenvironment that results from microcirculation dysfunction, hypoxia, metabolic dysfunction, oxidative stress, innate immunologic response, adaptive immunity, and cell death signaling. Ischemia/reperfusion injury is an inevitable process during liver transplantation and can lead to a high incidence of early allograft dysfunction and graft failure. The mechanism of hepatic ischemia/reperfusion injury has been elucidated as the sequelae of microcirculation dysfunction, hypoxia, oxidative stress, and cell death. In addition, the essential role of innate and adaptive immune response in hepatic ischemia/reperfusion injury and its deleterious outcomes have been discovered. Furthermore, mechanistic studies of living donor liver transplantation have elucidated distinct features of mitochondrial and metabolic dysfunction in steatotic and small-for-size graft injury. The mechanistic findings of hepatic ischemia/reperfusion injury have laid the foundation for exploring new biomarkers; however, they are yet to be validated in large cohorts. Moreover, the molecular and cellular mechanistic analysis of hepatic ischemia/reperfusion injury has promoted the development of potential therapeutics in preclinical and clinical trials. This review summarizes the most up to date evidence for liver ischemia/reperfusion injury and puts forward the importance of the spatiotemporal microenvironment that results from microcirculation dysfunction, hypoxia, metabolic dysfunction, oxidative stress, innate immunologic response, adaptive immunity, and cell death signaling. SummaryHepatic ischemia/reperfusion injury post liver transplantation is characterized as spatiotemporal microenvironmental disturbance including microcirculatory dysfunction, metabolic dysregulation, oxidative stress, innate and adaptive immunologic response, and cell death signaling. The mechanistic understanding enables novel biomarkers and therapeutics development in preclinical models and clinical trials. Hepatic ischemia/reperfusion injury post liver transplantation is characterized as spatiotemporal microenvironmental disturbance including microcirculatory dysfunction, metabolic dysregulation, oxidative stress, innate and adaptive immunologic response, and cell death signaling. The mechanistic understanding enables novel biomarkers and therapeutics development in preclinical models and clinical trials. The liver is subjected to ischemia and reperfusion injury during hepatectomy, liver transplantation, and systemic shock. With improvement in surgical techniques and medical treatment, to date hepatic ischemia/reperfusion injury mostly occurs in the setting of liver transplantation. Liver transplantation provides curative treatment for end-stage liver disease and is superior to any other modality. However, allograft ischemia/reperfusion injury is an inevitable process that may lead to early allograft dysfunction (EAD), primary nonfunction, or even graft failure in the acute phase after liver transplantation.1Lee D.D. Croome K.P. Shalev J.A. et al.Early allograft dysfunction after liver transplantation: an intermediate outcome measure for targeted improvements.Ann Hepatol. 2016; 15: 53-60Crossref PubMed Scopus (76) Google Scholar,2Ito T. Naini B.V. Markovic D. et al.Ischemia-reperfusion injury and its relationship with early allograft dysfunction in liver transplant patients.Am J Transplant. 2021; 21: 614-625Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Moreover, it has been suggested that allograft ischemia/reperfusion injury also renders the new liver more susceptible to recurrent diseases, such as cancer, viral hepatitis, fibrosis, and nonalcoholic fatty liver disease.3Burra P. Becchetti C. Germani G. NAFLD and liver transplantation: disease burden, current management and future challenges.JHEP Rep. 2020; 2100192PubMed Google Scholar, 4Liu J. Lo C.M. Man K. Role of intrahepatic regional immunity in post-transplant cancer recurrence.Eng Proc. 2022; 10: 57-64Google Scholar, 5Liu X.B. Lo C.M. Cheng Q. et al.Oval cells contribute to fibrogenesis of marginal liver grafts under stepwise regulation of aldose reductase and notch signaling.Theranostics. 2017; 7: 4879-4893Crossref PubMed Scopus (6) Google Scholar Clinically, several techniques have been developed to alleviate the allograft ischemia/reperfusion injury through rapid graft procurement, shortened graft transportation, continuing machine perfusion, remote or in situ ischemic preconditioning, or even ischemia-free transplantation.6Belon A.R. Tannuri A.C.A. de Albuquerque Rangel Moreira D. et al.Impact of three methods of ischemic preconditioning on ischemia-reperfusion injury in a pig model of liver transplantation.J Invest Surg. 2022; 35: 900-909Crossref PubMed Scopus (2) Google Scholar, 7Hessheimer A.J. Polak W. Antoine C. et al.Regulations and procurement surgery in DCD liver transplantation: expert consensus guidance from the International Liver Transplantation Society.Transplantation. 2021; 105: 945-951Crossref PubMed Scopus (0) Google Scholar, 8Tang Y. Wang T. Ju W. et al.Ischemic-free liver transplantation reduces the recurrence of hepatocellular carcinoma after liver transplantation.Front Oncol. 2021; 11773535Crossref Scopus (3) Google Scholar, 9van Rijn R. Schurink I.J. de Vries Y. et al.Hypothermic machine perfusion in liver transplantation: a randomized trial.N Engl J Med. 2021; 384: 1391-1401Crossref PubMed Scopus (49) Google Scholar However, the incidence of EAD still ranges from 2%–23%.10Deschenes M. Early allograft dysfunction: causes, recognition, and management.Liver Transpl. 2013; 19: S6-8Crossref PubMed Scopus (61) Google Scholar Unfortunately, the situation is even worse when using marginal grafts from extended-criteria donors. The use of marginal grafts, such as steatotic, aged, or reduced-size graft, or organs from donors after cardiac death or HBcAb-positive individuals has greatly expanded the donor pool; however, all these conditions are independent risk factors to EAD or graft loss.11Liu J. Pang L. Ng K.T.P. et al.Compromised AMPK-PGCIα axis exacerbated steatotic graft injury by dysregulating mitochondrial homeostasis in living donor liver transplantation.Ann Surg. 2022; 276: e483-e492Crossref PubMed Scopus (0) Google Scholar,12Zhang T. Dunson J. Kanwal F. et al.Trends in outcomes for marginal allografts in liver transplant.JAMA Surg. 2020; 155: 926-932Crossref PubMed Scopus (5) Google Scholar Among them, the steatotic liver is the predominant extended-criteria graft, because of the high prevalence of nonalcoholic fatty liver disease throughout the world. To minimize the risk of graft loss, the acceptable cutoff of graft steatosis for deceased organ donors is less than 30%. When a graft with steatosis degree between 30% and 60% is used, caution should be taken because these organs’ use increases primary nonfunction from 4%–13%.13Kulik U. Lehner F. Klempnauer J. et al.Primary non-function is frequently associated with fatty liver allografts and high mortality after re-transplantation.Liver Int. 2017; 37: 1219-1228Crossref PubMed Scopus (0) Google Scholar,14Mikolasevic I. Milic S. Filipec-Kanizaj T. Fatty liver allografts are associated with primary graft non-function and high mortality after transplantation.Liver Int. 2017; 37: 1113-1115Crossref PubMed Scopus (7) Google Scholar The use of steatotic graft is less acceptable in the setting of living donor liver transplantation, because steatotic grafts are more susceptible to ischemia/reperfusion injury and are associated with higher incidence of acute phase allograft dysfunction, small-for-size syndrome, and long-term graft loss.11Liu J. Pang L. Ng K.T.P. et al.Compromised AMPK-PGCIα axis exacerbated steatotic graft injury by dysregulating mitochondrial homeostasis in living donor liver transplantation.Ann Surg. 2022; 276: e483-e492Crossref PubMed Scopus (0) Google Scholar Mechanistically, mitochondrial dysfunction has been suggested as the underlying mechanism,11Liu J. Pang L. Ng K.T.P. et al.Compromised AMPK-PGCIα axis exacerbated steatotic graft injury by dysregulating mitochondrial homeostasis in living donor liver transplantation.Ann Surg. 2022; 276: e483-e492Crossref PubMed Scopus (0) Google Scholar although further investigation is necessary. Hepatic ischemia/reperfusion injury can arise from hypoxic injury, intracellular metabolic dysfunction, oxidative stress, innate immunologic responses, adaptive immunity, and cell death signaling.15Hirao H. Nakamura K. Kupiec-Weglinski J.W. Liver ischaemia-reperfusion injury: a new understanding of the role of innate immunity.Nat Rev Gastroenterol Hepatol. 2022; 19: 239-256Crossref PubMed Scopus (29) Google Scholar A better understanding of the spatiotemporal mechanisms of these processes will lay the foundation for the development of novel biomarkers and therapeutics and can result in more precise selection criteria. Here, we summarize recent progress in the investigation of the molecular and cellular mechanisms of hepatic ischemia/reperfusion injury, and their implications in clinical practice as indicated by preclinical studies and clinical trials. Hepatic ischemia/reperfusion injury is initiated by hemodynamic change (Figure 1). The ischemic injury occurs as early as organ procurement and graft preservation, during which warm and cold ischemia damage the hepatocytes, cholangiocytes, and liver sinusoidal endothelial cells by hypoxia-induced metabolic dysfunction.16Zhai Y. Petrowsky H. Hong J.C. et al.Ischaemia-reperfusion injury in liver transplantation--from bench to bedside.Nat Rev Gastroenterol Hepatol. 2013; 10: 79-89Crossref PubMed Scopus (530) Google Scholar Reperfusion, however, exacerbates the injury by transient portal hypertension and hyperdynamic stress. Transient portal hypertension is the initial event that causes hyperdynamic stress to the endothelial lining. Portal pressure can increase from 30–35 cm H2O to as high as 60–70 cm H2O immediately after the reperfusion.17Man K. Fan S.T. Lo C.M. et al.Graft injury in relation to graft size in right lobe live donor liver transplantation: a study of hepatic sinusoidal injury in correlation with portal hemodynamics and intragraft gene expression.Ann Surg. 2003; 237: 256-264Crossref PubMed Google Scholar The shearing force causes direct damage to the liver sinusoidal endothelial cells and exposes the vessel wall for circulating platelets and leukocytes adhesion. Platelet aggregation then narrows the venule, and platelet activation releases large amounts of cytokines, chemokines, and vasoactive molecules.18Esch J.S. Jurk K. Knoefel W.T. et al.Platelet activation and increased tissue factor expression on monocytes in reperfusion injury following orthotopic liver transplantation.Platelets. 2010; 21: 348-359Crossref PubMed Scopus (32) Google Scholar, 19Himmelreich G. Hundt K. Neuhaus P. et al.Evidence that intraoperative prostaglandin E1 infusion reduces impaired platelet aggregation after reperfusion in orthotopic liver transplantation.Transplantation. 1993; 55: 819-826Crossref PubMed Google Scholar, 20Nishiyama R. Nakamura S. Suzuki S. et al.Platelet-activating factor in hepatic ischemia/reperfusion injury. The effects of a PAF antagonist combined with a prostaglandin I2 analogue.Transplantation. 1993; 55: 1261-1265Crossref PubMed Google Scholar, 21Sindram D. Porte R.J. Hoffman M.R. et al.Platelets induce sinusoidal endothelial cell apoptosis upon reperfusion of the cold ischemic rat liver.Gastroenterology. 2000; 118: 183-191Abstract Full Text Full Text PDF PubMed Google Scholar, 22Miyashita T. Nakanuma S. Ahmed A.K. et al.Ischemia reperfusion-facilitated sinusoidal endothelial cell injury in liver transplantation and the resulting impact of extravasated platelet aggregation.Eur Surg. 2016; 48: 92-98Crossref PubMed Scopus (40) Google Scholar The imbalance of vasocontraction and vasodilation factors further exacerbates the dysfunction of the microcirculation. Levels of the vasoconstricting peptide endothelin-1 were found to increase by 1.6-fold, whereas the endothelial nitric oxide synthase, which produces nitric oxide, decreased by 17.4 μmol/L, respectively.17Man K. Fan S.T. Lo C.M. et al.Graft injury in relation to graft size in right lobe live donor liver transplantation: a study of hepatic sinusoidal injury in correlation with portal hemodynamics and intragraft gene expression.Ann Surg. 2003; 237: 256-264Crossref PubMed Google Scholar Collectively, this decrease in microcirculation worsens the hyperdynamic stress in return, resulting in congestion of the sinusoids and collapse of the space of Disse between endothelial cells and hepatocytes, thereby prolonging hypoxia.23Man K. Lo C.M. Lee T.K. et al.Intragraft gene expression profiles by cDNA microarray in small-for-size liver grafts.Liver Transpl. 2003; 9: 425-432Crossref PubMed Scopus (58) Google Scholar Microcirculatory dysfunction is often worse in marginal grafts. In small-for-size graft during living donor liver transplantation, the hyperdynamic inflow lasts longer than in normal or large-sized grafts. In such cases, small-for-size syndrome or small-for-flow syndrome results in higher incidence of allograft dysfunction or graft loss.11Liu J. Pang L. Ng K.T.P. et al.Compromised AMPK-PGCIα axis exacerbated steatotic graft injury by dysregulating mitochondrial homeostasis in living donor liver transplantation.Ann Surg. 2022; 276: e483-e492Crossref PubMed Scopus (0) Google Scholar,24Ikegami T. Onda S. Furukawa K. et al.Small-for-size graft, small-for-size syndrome and inflow modulation in living donor liver transplantation.J Hepatobiliary Pancreat Sci. 2020; 27: 799-809Crossref PubMed Scopus (13) Google Scholar The hemodynamic mechanisms have been interpreted as unmatched high inflow with small-for-size graft, because surgical inflow modulation or simultaneous splenectomy have been demonstrated to reduce the incidence of small-for-size syndrome.25Sanchez-Cabus S. Cherqui D. Rashidian N. et al.Left-liver adult-to-adult living donor liver transplantation: can it be improved? A retrospective multicenter European study.Ann Surg. 2018; 268: 876-884Crossref PubMed Scopus (6) Google Scholar,26Yoshizumi T. Itoh S. Shimokawa M. et al.Simultaneous splenectomy improves outcomes after adult living donor liver transplantation.J Hepatol. 2021; 74: 372-379Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Reperfusion injury is more deleterious through the production of large amounts of reactive oxygen species (ROS), which mainly come from intrahepatic neutrophils and Kupffer cells.27Amersi F. Buelow R. Kato H. et al.Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury.J Clin Invest. 1999; 104: 1631-1639Crossref PubMed Google Scholar,28Lemasters J.J. Peng X.X. Bachmann S. et al.Dual role of Kupffer cell activation and endothelial cell damage in reperfusion injury to livers stored for transplantation surgery.J Gastroenterol Hepatol. 1995; 10: S84-87Crossref PubMed Google Scholar Increased ROS production is primarily caused by mitochondrial respiratory dysfunction, and by diminished activity of endogenous antioxidants, such as heme oxygenase 1 and superoxide dismutase (SOD) (Figure 1). Mitochondrial respiratory dysfunction involves the reversal of the electron transition from complex II to complex I during ischemia/reperfusion injury.29Chouchani E.T. Pell V.R. Gaude E. et al.Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS.Nature. 2014; 515: 431-435Crossref PubMed Scopus (1583) Google Scholar In addition, inactivation of complex II and complex IV exacerbates ROS production.11Liu J. Pang L. Ng K.T.P. et al.Compromised AMPK-PGCIα axis exacerbated steatotic graft injury by dysregulating mitochondrial homeostasis in living donor liver transplantation.Ann Surg. 2022; 276: e483-e492Crossref PubMed Scopus (0) Google Scholar In steatotic grafts, mitochondrial dysfunction is more severe and multifaceted, including impairments in mitochondrial biogenesis, membrane depolarization, calcium overload, and enhanced glycolysis.11Liu J. Pang L. Ng K.T.P. et al.Compromised AMPK-PGCIα axis exacerbated steatotic graft injury by dysregulating mitochondrial homeostasis in living donor liver transplantation.Ann Surg. 2022; 276: e483-e492Crossref PubMed Scopus (0) Google Scholar Inadequate metabolism of accumulated fatty acids can lead to increased production of lipid superoxide, which results from decreased activity of key enzymes in the mitochondrial beta-oxidation.30Xue Y. Liu H. Yang X.X. et al.Inhibition of carnitine palmitoyltransferase 1A aggravates fatty liver graft injury via promoting mitochondrial permeability transition.Transplantation. 2021; 105: 550-560Crossref PubMed Scopus (1) Google Scholar Additionally, downregulation of heme oxygenase 1 and SOD renders the graft more vulnerable to ROS attack.31Nakamura K. Zhang M. Kageyama S. et al.Macrophage heme oxygenase-1-SIRT1-p53 axis regulates sterile inflammation in liver ischemia-reperfusion injury.J Hepatol. 2017; 67: 1232-1242Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar,32Zwacka R.M. Zhou W. Zhang Y. et al.Redox gene therapy for ischemia/reperfusion injury of the liver reduces AP1 and NF-kappaB activation.Nat Med. 1998; 4: 698-704Crossref PubMed Scopus (250) Google Scholar Many preclinical studies have reported that delivering heme oxygenase 1 and SOD or increasing their expression can reduce the ROS levels and protect the graft from ischemia/reperfusion injury.27Amersi F. Buelow R. Kato H. et al.Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury.J Clin Invest. 1999; 104: 1631-1639Crossref PubMed Google Scholar,33Fondevila C. Shen X.D. Tsuchiyashi S. et al.Biliverdin therapy protects rat livers from ischemia and reperfusion injury.Hepatology. 2004; 40: 1333-1341Crossref PubMed Scopus (146) Google Scholar, 34Ke B. Shen X.D. Gao F. et al.Adoptive transfer of ex vivo HO-1 modified bone marrow-derived macrophages prevents liver ischemia and reperfusion injury.Mol Ther. 2010; 18: 1019-1025Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 35Lehmann T.G. Wheeler M.D. Schwabe R.F. et al.Gene delivery of Cu/Zn-superoxide dismutase improves graft function after transplantation of fatty livers in the rat.Hepatology. 2000; 32: 1255-1264Crossref PubMed Google Scholar Consequently, the oxidative stress peaks around 2–6 hours after reperfusion, leading to metabolic dysfunction, mitochondrial swelling, and cell death of liver sinusoidal endothelial cells and hepatocytes.17Man K. Fan S.T. Lo C.M. et al.Graft injury in relation to graft size in right lobe live donor liver transplantation: a study of hepatic sinusoidal injury in correlation with portal hemodynamics and intragraft gene expression.Ann Surg. 2003; 237: 256-264Crossref PubMed Google Scholar As the result of cell injury, damage-associated molecular patterns are released into the circulation and activate the innate immune response. Hepatic ischemia/reperfusion injury is accompanied by an activated innate immune response from residential and circulating immune cells (Figure 2). The remodeled intrahepatic immune microenvironment also renders the graft more susceptible to primary disease recurrence, such as steatosis, fibrosis, viral hepatitis, and malignancies.5Liu X.B. Lo C.M. Cheng Q. et al.Oval cells contribute to fibrogenesis of marginal liver grafts under stepwise regulation of aldose reductase and notch signaling.Theranostics. 2017; 7: 4879-4893Crossref PubMed Scopus (6) Google Scholar,36Li C.X. Ling C.C. Shao Y. et al.CXCL10/CXCR3 signaling mobilized-regulatory T cells promote liver tumor recurrence after transplantation.J Hepatol. 2016; 65: 944-952Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar,37Yeung O.W. Lo C.M. Ling C.C. et al.Alternatively activated (M2) macrophages promote tumour growth and invasiveness in hepatocellular carcinoma.J Hepatol. 2015; 62: 607-616Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar The release of damage-associated molecular patterns (eg, nucleic acids, heat shock protein, high-mobility group protein 1) activates the first wave of residential Kupffer cells and adhesive neutrophils by binding to pattern recognition receptors on their cell surface.38Corbitt N. Kimura S. Isse K. et al.Gut bacteria drive Kupffer cell expansion via MAMP-mediated ICAM-1 induction on sinusoidal endothelium and influence preservation-reperfusion injury after orthotopic liver transplantation.Am J Pathol. 2013; 182: 180-191Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 39Kadono K. Uchida Y. Hirao H. et al.Thrombomodulin attenuates inflammatory damage due to liver ischemia and reperfusion injury in mice in toll-like receptor 4-dependent manner.Am J Transplant. 2017; 17: 69-80Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 40Wang F. Birch S.E. He R. et al.Remote ischemic preconditioning by hindlimb occlusion prevents liver ischemic/reperfusion injury: the role of High Mobility Group-Box 1.Ann Surg. 2010; 251: 292-299Crossref PubMed Scopus (0) Google Scholar, 41Yang M.Q. Du Q. Goswami J. et al.Interferon regulatory factor 1-Rab27a regulated extracellular vesicles promote liver ischemia/reperfusion injury.Hepatology. 2018; 67: 1056-1070Crossref PubMed Scopus (31) Google Scholar Among them, toll-like receptor 4 (TLR4) is the predominant pattern recognition receptor that is expressed on almost all the innate immune cells. Our previous studies have shown the pathogenic involvement of TLR4 in inducing and promoting ischemia/reperfusion injury in liver graft.36Li C.X. Ling C.C. Shao Y. et al.CXCL10/CXCR3 signaling mobilized-regulatory T cells promote liver tumor recurrence after transplantation.J Hepatol. 2016; 65: 944-952Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar,42Liu H. Ling C.C. Yeung W.H.O. et al.Monocytic MDSC mobilization promotes tumor recurrence after liver transplantation via CXCL10/TLR4/MMP14 signaling.Cell Death Dis. 2021; 12: 489Crossref PubMed Scopus (16) Google Scholar Increased expression of TLR4 not only enhances the proinflammatory activity of macrophages, but also recruits more polymorphonuclear neutrophils from circulation.39Kadono K. Uchida Y. Hirao H. et al.Thrombomodulin attenuates inflammatory damage due to liver ischemia and reperfusion injury in mice in toll-like receptor 4-dependent manner.Am J Transplant. 2017; 17: 69-80Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar,41Yang M.Q. Du Q. Goswami J. et al.Interferon regulatory factor 1-Rab27a regulated extracellular vesicles promote liver ischemia/reperfusion injury.Hepatology. 2018; 67: 1056-1070Crossref PubMed Scopus (31) Google Scholar,43Kuriyama N. Duarte S. Hamada T. et al.Tenascin-C: a novel mediator of hepatic ischemia and reperfusion injury.Hepatology. 2011; 54: 2125-2136Crossref PubMed Scopus (43) Google Scholar Recently, intracellular pattern recognition receptors were also found to be involved in macrophage activation during ischemia/reperfusion injury. Activation of the DNA-sensing STING pathway after reperfusion induced the macrophage to become proinflammatory,44Jiao J. Jiang Y. Qian Y. et al.Expression of STING is increased in monocyte-derived macrophages and contributes to liver inflammation in hepatic ischemia-reperfusion injury.Am J Pathol. 2022; 192: 1745-1762Abstract Full Text Full Text PDF PubMed Google Scholar,45Zhong W. Rao Z. Rao J. et al.Aging aggravated liver ischemia and reperfusion injury by promoting STING-mediated NLRP3 activation in macrophages.Aging Cell. 2020; 19e13186Crossref Scopus (47) Google Scholar with mitochondrial DNA as the key stimulatory factor. On activation, macrophages and polymorphonuclear neutrophils, along with injured liver sinusoidal endothelial cells, secret large amounts of cytokines and chemokines into the sinusoid, exacerbating the inflammatory reaction, and recruiting more innate and adaptive immune cells into the graft. A cytokine storm can be observed as early as 2 hours and peaks at 6–24 hours following reperfusion.17Man K. Fan S.T. Lo C.M. et al.Graft injury in relation to graft size in right lobe live donor liver transplantation: a study of hepatic sinusoidal injury in correlation with portal hemodynamics and intragraft gene expression.Ann Surg. 2003; 237: 256-264Crossref PubMed Google Scholar Within the proinflammatory microenvironment, the cytokines involved are, interleukin (IL)1β, IL2, IL6, IL15, interferon-γ (IFNγ), and tumor necrosis factor-α;and the chemokines are, CCL2, CXCL8, CXCL10, among others.16Zhai Y. Petrowsky H. Hong J.C. et al.Ischaemia-reperfusion injury in liver transplantation--from bench to bedside.Nat Rev Gastroenterol Hepatol. 2013; 10: 79-89Crossref PubMed Scopus (530) Google Scholar,17Man K. Fan S.T. Lo C.M. et al.Graft injury in relation to graft size in right lobe live donor liver transplantation: a study of hepatic sinusoidal injury in correlation with portal hemodynamics and intragraft gene expression.Ann Surg. 2003; 237: 256-264Crossref PubMed Google Scholar In steatotic graft and small-for-size grafts, the inflammatory response is even more severe. Additional signaling pathways are activated during steatotic graft injury, including lipocalin-2, NLR protein 3, aldose reductase, and repressor activator protein 1.46Cheng Q. Ng K.T. Xu A. et al.The roles of lipocalin-2 in small-for-size fatty liver graft injury.Ann Surg. 2014; 260: 1062-1072Crossref PubMed Scopus (11) Google Scholar,47Liu H. Lo C.M. Yeung O.W.H. et al.NLRP3 inflammasome induced liver graft injury through activation of telomere-independent RAP1/KC axis.J Pathol. 2017; 242: 284-296Crossref PubMed Scopus (24) Google Scholar Their activation in macrophage and neutrophils enables the immune system to recruit even more proinflammatory cells by increasing CXCL10 and CXCL2 secretion.46Cheng Q. Ng K.T. Xu A. et al.The roles of lipocalin-2 in small-for-size fatty liver graft injury.Ann Surg. 2014; 260: 1062-1072Crossref PubMed Scopus (11) Google Scholar, 47Liu H. Lo C.M. Yeung O.W.H. et al.NLRP3 inflammasome induced liver graft injury through activation of telomere-independent RAP1/KC axis.J Pathol. 2017; 242: 284-296Crossref PubMed Scopus (24) Google Scholar, 48Li C.X. Ng K.T. Shao Y. et al.The inhibition of aldose reductase attenuates hepatic ischemia-reperfusion injury through reducing inflammatory response.Ann Surg. 2014; 260: 317-328Crossref PubMed Scopus (42) Google Scholar Other myeloid immune cells, such as residential and blood-borne dendritic cells, were found to play a bidirectional role in mediating hepatic ischemia/reperfusion injury.49Zhang M. Ueki S. Kimura S. et al.Roles of dendritic cells in murine hepatic warm and liver transplantation-induced cold ischemia/reperfusion injury.Hepatology. 2013; 57: 1585-1596Crossref PubMed Scopus (36) Google Scholar Dendritic cells are antigen-presenting cells that activate T cells during adaptive immunity. Mechanistically, studies in mouse liver transplant models showed that downregulation of the costimulatory molecule B7-H1 on dendritic cells has the potential to promote hepatic ischemia/reperfusion injury by exaggerating CD8+ T-cell proliferation and infiltration.50Ueki S. Castellaneta A. Yoshida O. et al.Hepatic B7 homolog 1 expression is essential for controlling cold ischemia/reperfusion injury after mouse liver transplantation.Hepatology. 2011; 54: 216-228Crossref PubMed Scopus (35) Google Scholar Regulatory signaling molecules, such as DAP12-TREM2 and YAP-CD47-CD172α, inhibit dendritic cell maturation and/or activation.51Nakao T. Ono Y. Dai H. et al.DNAX activating protein of 12 kDa/triggering receptor expressed on myeloid cells 2 expression by mouse and human liver dendritic cells: functional implications and regulation of liver ischemia-reperfusion injury.Hepatology. 2019; 70: 696-710Crossref PubMed Scopus (0) Google Scholar,52Yuan Z. Ye L. 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• W4327921881 created "2023-03-21" @default.
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• W4327921881 date "2023-01-01" @default.
• W4327921881 modified "2023-10-13" @default.
• W4327921881 title "Mechanistic Insight and Clinical Implications of Ischemia/Reperfusion Injury Post Liver Transplantation" @default.
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