Ischemia and Reperfusion Injury in Liver Transplantation

doi:10.1016/j.transproceed.2005.03.134

Transplantation Proceedings

Volume 37, Issue 4, May 2005, Pages 1653-1656

https://doi.org/10.1016/j.transproceed.2005.03.134 Get rights and content

Abstract

Ischemia/reperfusion (I/R) injury is a multifactorial process detrimental to liver graft function. An understanding of the mechanisms involved in I/R injury is essential for the design of therapeutic strategies to improve the outcome of liver transplantation. The generation of reactive oxygen species subsequent to reoxygenation inflicts tissue damage and initiates a cellular cascade leading to inflammation, cell death, and ultimate organ failure. The accruing evidence suggests that Kupffer cells and T cells mediate the activation of neutrophil inflammatory responses. Activated neutrophils infiltrate the injured liver in parallel with increased expression of adhesion molecules on endothelial cells. The heme oxygenase (HO) system is among the most critical of the cytoprotective mechanisms activated during the cellular stress, exerting anti-oxidant and anti-inflammatory functions, modulating the cell cycle, and maintaining the microcirculation. The activation of toll-like receptors (TLR) on Kupffer cells may provide the triggering signal for pro-inflammatory responses in the I/R injury sequence. Indeed, dissecting TLR downstream signaling pathways plays a fundamental role in exploring novel therapeutic strategies based on the concept that hepatic I/R injury represents a case for host “innate” immunity.

Section snippets

Cell Cascades

Ample evidence suggests that activation of Kupffer cells, PMN, endothelial cells (EC) and reactive oxygen species (ROS) are all critical in the pathogenesis of I/R injury.1, 2 The final consequence of these interrelated processes are structural tissue alterations causing hepatocellular dysfunction. The histopathologic changes that occur in ischemic liver after reperfusion include cellular swelling, vacuolization, EC disruption, and PMN infiltration. It seems that nonparenchymal cells (Kupffer,

Heme oxygenase system

Heme oxygenases (HO) are ubiquitous enzymes that catalyze the rate-limiting steps in the oxidative degradation of heme into biliverdin, carbon monoxide (CO) and free iron. Biliverdin is reduced to bilirubin by bilirubin reductase, and the free iron used in intracellular metabolism or sequestered in ferritin. It is believed that the byproducts derived from the catalysis of heme by HO, namely biliverdin, bilirubin, and ferritin accumulated from released iron, and finally CO, can all mediate the

Future research

The primary nonspecific injury (such as I/R injury) to the donor organ induces events of the two distinct immunologic defense systems: (1) a more broadly directed innate immune host defense (evolutionary directed normally against infections), resulting in (2) a definite adaptive immune host defense that leads ultimately to a specific graft injury (i.e., rejection). Indeed, I/R injury may create a milieu of inflammation that operates as a “danger” signal in OLTs, and in analogy to the infectious

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Hydroxychloroquine inhibiting neutrophil extracellular trap formation alleviates hepatic ischemia/reperfusion injury by blocking TLR9 in mice
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Hepatic ischemia/reperfusion (I/R) injury may arise after partial hepatectomy and liver transplantation. Neutrophil extracellular traps (NETs) were involved in hepatic I/R injury. This study tested the hypothesis that blocking NETs formation could be a potential therapeutic target against hepatic I/R injury. NETs were excessively formed within liver and in serum of I/R mice models and were testified to be an independent contributor to hepatic I/R injury. Hydroxychloroquine (HCQ) alleviated hepatic I/R injury by inhibiting NETs formation in SCID and c57BL/6 mice models. In vitro, HCQ inhibited neutrophils to form NETs at a concentration of 100 μg/ml. CpG-ODN reversed the effect of HCQ inhibiting NETs formation. HCQ inhibited PAD4 and Rac2 expressions by blocking TLR9. NETs are essential contributors to hepatic I/R injury. HCQ blocking TLR9 protects against hepatic I/R injury by inhibiting NETs formation, which may suggest utility of HCQ or other TLR9 agonists for preventing hepatic I/R injury in clinical practices.
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FO pretreated livers had less necrosis after HIRI than saline pretreated livers in both WT (mean ± SEM 25.9 ± 7.3% less, P = 0.007) and KO (36.6 ± 7.3% less, P < 0.0001) mice. There was no significant difference in percent necrosis between WT-FO and KO-FO groups. Sham groups demonstrated minimal necrosis (0–1.9%). Mean [95% CI] ALT after HIRI was significantly higher (P = 0.04) in WT-Saline mice (1604 U/L [751–3427]) compared to WT-FO (321 U/L [150–686]) but was not significantly higher in KO-Saline mice compared to KO-FO. There were no differences in ALT between WT-FO and KO-FO mice who underwent HIRI or between groups who underwent sham surgery. There were no differences in NFκB or IKKβ activation among groups as measured by Western blot analysis.
IV FO pretreatment was able to reduce HIRI in GPR120 KO mice, suggesting the hepatoprotective effects of FO are not mediated by GPR120 alone.
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: Supported by NIH Grant DK63560, AI23847, AI42223, and The Dumont Research Foundation.

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Special presentationIschemia and Reperfusion Injury in Liver Transplantation

Abstract

Section snippets

Cell Cascades

Heme oxygenase system

Future research

Transplant Rev

Exp Mol Pathol

Am J Transplant

Hepatology

Am J Transplant

Chem Biol Interact

Hepatology

Transpl Immunol

Apoptosis of sinusoidal endothelial cells is a critical mechanism of preservation injury in rat liver transplantation

Hepatology

Principles of solid-organ preservation by cold storage

Transplantation

Kupffer cell activation and endothelial cell damage after storage of rat liverseffects of reperfusion

Hepatology

CD18 integrin and CD54-dependent neutrophil adhesion to cytokine-stimulated human hepatocytes

Am J Physiol

The reduction of hepatic ischemia/reperfusion injury by a soluble P-selectin glycoprotein ligand-1

Ann Surg

Biologically active products of stimulated liver macrophages (Kupffer cells)

Eur J Biochem

Reperfusion injury to endothelial cells following cold ischemic storage of rat livers

Hepatology

Improved graft survival after renal transplantation in the United States, 1988 to 1996

N Engl J Med

Special presentation
Ischemia and Reperfusion Injury in Liver Transplantation