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Review
. 2020 Sep:157:75-82.
doi: 10.1016/j.freeradbiomed.2020.02.012. Epub 2020 Feb 19.

Heme Oxygenase-1 in liver transplant ischemia-reperfusion injury: From bench-to-bedside

Hirofumi Hirao  1 , Kenneth J Dery  1 , Shoichi Kageyama  1 , Kojiro Nakamura  2 , Jerzy W Kupiec-Weglinski  3
Affiliations
Review

Heme Oxygenase-1 in liver transplant ischemia-reperfusion injury: From bench-to-bedside

Hirofumi Hirao et al. Free Radic Biol Med. 2020 Sep.

Abstract

Hepatic ischemia-reperfusion injury (IRI), a major risk factor for early allograft dysfunction (EAD) and acute or chronic graft rejection, contributes to donor organ shortage for life-saving orthotopic liver transplantation (OLT). The graft injury caused by local ischemia (warm and/or cold) leads to parenchymal cell death and release of danger-associated molecular patterns (DAMPs), followed by reperfusion-triggered production of reactive oxygen species (ROS), activation of inflammatory cells, hepatocellular damage and ultimate organ failure. Heme oxygenase 1 (HO-1), a heat shock protein-32 induced under IR-stress, is an essential component of the cytoprotective mechanism in stressed livers. HO-1 regulates anti-inflammatory responses and may be crucial in the pathogenesis of chronic diseases, such as arteriosclerosis, hypertension, diabetes and steatosis. An emerging area of study is macrophage-derived HO-1 and its pivotal intrahepatic homeostatic function played in IRI-OLT. Indeed, ectopic hepatic HO-1 overexpression activates intracellular SIRT1/autophagy axis to serve as a key cellular self-defense mechanism in both mouse and human OLT recipients. Recent translational studies in rodents and human liver transplant patients provide novel insights into HO-1 mediated cytoprotection against sterile hepatic inflammation. In this review, we summarize the current bench-to-bedside knowledge on HO-1 molecular signaling and discuss their future therapeutic potential to mitigate IRI in OLT.

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Conflict of interest statement

Declaration of competing interest The authors have nothing to disclose.

Figures

Figure 1:
Figure 1:
The distinct stages of liver IRI. The ischemia insult, an initial process of hepatic disturbances, results from the lack of oxygen supply. Subsequently, DAMPs released by dead cells up-regulate the expression of adhesion molecules by liver sinusoidal endothelial cells (LSEC) and production of ROS by activated Kupffer cells. Excessive heme released from damaged erythrocytes may trigger inflammatory responses through TLR4-heme signaling axis. Reperfusion injury, triggered by oxygenation, accelerates hepatic IR-immune response via Kupffer cell activation in concert with monocyte-derived macrophage, T cell and neutrophil infiltration. The IRI proinflammatory immune cascade sustains itself by recruiting peripheral immune cells from the circulation.
Figure 2:
Figure 2:
The heme degradation cascade. Heme released from damaged cells produces ROS. HO-1, induced by various stimuli such as heme, ROS, hypoxia, infection or transplantation, catabolizes heme into biliverdin, Fe2+ and CO. Biliverdin scavenges ROS to exert anti-inflammatory effects. Ferritin provides anti-apoptotic effects via its anti-oxidant function. CO promotes anti-apoptosis and anti-inflammatory effects via MAPK activation, modulates the vascular tone and inhibits platelet aggregation, leading to the microcirculatory maintainance.
Figure 3:
Figure 3:
IR-stress induced HO-1 in liver macrophage and hepatocyte function. Stressed hepatocytes release DAMPs, which activate macrophages through PRRs, leading to pro-inflammatory mediator release. By activating SIRT1, myeloid cell-derived HO-1 may also control macrophage polarization towards the anti-inflammatory phenotype. It remains unknown how macrophage HO-1 regulates this “cytoprotective” autophagy pathway in IR-stressed hepatocytes.
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