Abstract
Background Reactive oxygen species- (ROS-) mediated ischemia-reperfusion injury (IRI) detrimentally impacts liver transplantation and resection. 12/15-Lipoxygenase (12/15-LOX), an antagonistic protein of the glutathione peroxidase 4 (GPX4) signaling cascade, was proven to mediate cell death in postischemic cerebral and myocardial tissue. The aim of this study was to investigate the impact of 12/15-LOX inhibition on hepatic IRI. Methods Livers of C57BL/6 mice were exposed to 60 minutes of partial warm ischemia and 90 minutes of reperfusion after previous Baicalein administration, an inhibitor of 12/15-LOX. Tissue samples were analyzed by TUNEL assay, Western blot, and spectral photometry. Results TUNEL labeling showed a significant reduction of hepatic cell death following baicalein pretreatment. Western Blot analysis revealed a significant downregulation of Jun-amino-terminal-kinase (JNK), caspase-3, and poly-ADP-ribose-polymerase (PARP), besides considerably lowered p44/42-MAP-kinase (ERK1/2) expression after Baicalein administration. A significant elevation of glutathione oxidation was measured in Baicalein pretreated livers. Conclusion Our data show that inhibition of 12/15-lipoxygenase causes significant cell death reduction after hepatic ischemia and reperfusion by enhancing glutathione metabolism. We conclude that GPX4-dependent cell death signaling cascade might play a major role in development of hepatic IRI, in which the investigated proteins JNK, caspase-3, ERK1/2, and PARP might contribute to tissue damage.
Highlights
Hepatic ischemia-reperfusion injury (IRI) is associated with significant morbidity and mortality and occurs during liver resection, transplantation, and trauma, as well as septic and hemorrhagic shock [1,2,3]
After the attenuation of the effects of cold ischemia in orthotopic liver transplantation (OLT) has been a crucial approach in transplant research for a long period, warm ischemia has attracted considerable interest throughout recent years as it is known to affect predominantly parenchymal liver cells and biliary injury [50,51,52]
Different modes of cell death are known to play a role in hepatic IRI [8, 20]
Summary
Hepatic ischemia-reperfusion injury (IRI) is associated with significant morbidity and mortality and occurs during liver resection, transplantation, and trauma, as well as septic and hemorrhagic shock [1,2,3]. IRI is characterized by a complex cascade of intracellular signaling processes leading to different forms of cell death mainly due to reoxygenation during reperfusion (oxidative stress) [4, 5]. The accumulation of reactive oxygen species (ROS) inducing oxidative stress represents a strong inducer for many forms of cell death [9, 12,13,14] This ROSmediated liver damage leads to limited postoperative liver function but is regarded as an immediate origin of allograft rejection, delayed graft function, and primary nonfunction after liver transplantation [2, 15]. We conclude that GPX4-dependent cell death signaling cascade might play a major role in development of hepatic IRI, in which the investigated proteins JNK, caspase, ERK1/2, and PARP might contribute to tissue damage
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