Iron overload as a risk factor for hepatic ischemia‐reperfusion injury in liver transplantation: Potential role of ferroptosis

Hepatic ischemia‐reperfusion (I/R) injury is a major problem in liver transplantation (LT). Although hepatocyte cell death is the initial event in hepatic I/R injury, the underlying mechanism remains unclear. In the present study, we retrospectively analyzed the clinical data of 202 pediatric living...

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Veröffentlicht in:American journal of transplantation Jg. 20; H. 6; S. 1606 - 1618
Hauptverfasser: Yamada, Naoya, Karasawa, Tadayoshi, Wakiya, Taiichi, Sadatomo, Ai, Ito, Homare, Kamata, Ryo, Watanabe, Sachiko, Komada, Takanori, Kimura, Hiroaki, Sanada, Yukihiro, Sakuma, Yasunaru, Mizuta, Koichi, Ohno, Nobuhiko, Sata, Naohiro, Takahashi, Masafumi
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Elsevier Limited 01.06.2020
Elsevier
Schlagworte:
Animal models
Animals
Apoptosis
Cell death
Chelation
Child
Deferoxamine
Ferritin
Ferroptosis
Homeostasis
Humans
Inflammation
Iron
Iron Overload - etiology
Ischemia
Lipid peroxidation
Liver
Liver transplantation
Liver Transplantation - adverse effects
liver transplantation/hepatology
liver transplantation: living donor
Liver transplants
Mice
Pediatrics
Reperfusion
Reperfusion Injury - etiology
Retrospective Studies
Risk Factors
translational research/science
Vitamin E
liver transplantation: living donor
translational research/science
cell death
liver transplantation/hepatology
ISSN:1600-6135, 1600-6143, 1600-6143
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Zusammenfassung:Hepatic ischemia‐reperfusion (I/R) injury is a major problem in liver transplantation (LT). Although hepatocyte cell death is the initial event in hepatic I/R injury, the underlying mechanism remains unclear. In the present study, we retrospectively analyzed the clinical data of 202 pediatric living donor LT and found that a high serum ferritin level, a marker of iron overload, of the donor is an independent risk factor for liver damage after LT. Since ferroptosis has been recently discovered as an iron‐dependent cell death that is triggered by a loss of cellular redox homeostasis, we investigated the role of ferroptosis in a murine model of hepatic I/R injury, and found that liver damage, lipid peroxidation, and upregulation of the ferroptosis marker Ptgs2 were induced by I/R, and all of these manifestations were markedly prevented by the ferroptosis‐specific inhibitor ferrostatin‐1 (Fer‐1) or α‐tocopherol. Fer‐1 also inhibited hepatic I/R‐induced inflammatory responses. Furthermore, hepatic I/R injury was attenuated by iron chelation by deferoxamine and exacerbated by iron overload with a high iron diet. These findings demonstrate that iron overload is a novel risk factor for hepatic I/R injury in LT, and ferroptosis contributes to the pathogenesis of hepatic I/R injury. This study demonstrates that iron overload is a novel risk factor for hepatic ischemia‐reperfusion injury in liver transplantation, and ferroptosis contributes to the pathogenesis of hepatic ischemia‐reperfusion injury.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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USDOE
ISSN:1600-6135
1600-6143
1600-6143
DOI:10.1111/ajt.15773