Abstract
The need to meet the demand for transplants entails the use of steatotic livers, more vulnerable to ischemia-reperfusion (IR) injury. Therefore, finding the optimal composition of static cold storage (SCS) preservation solutions is crucial. Given that ROS regulation is a therapeutic strategy for liver IR injury, we have added increasing concentrations of PEG35 and glutathione (GSH) to the preservation solutions (IGL-1 and IGL-2) and evaluated the possible protection against energy depletion and oxidative stress. Fatty livers from obese Zücker rats were isolated and randomly distributed in the control (Sham) preserved (24 h at 4 °C) in IGL-0 (without PEG35 and 3 mmol/L GSH), IGL-1 (1 g/L PEG35, and 3 mmol/L GSH), and IGL-2 (5 g/L PEG35 and 9 mmol/L GSH). Energy metabolites (ATP and succinate) and the expression of mitochondrial oxidative phosphorylation complexes (OXPHOS) were determined. Mitochondrial carrier uncoupling protein 2 (UCP2), PTEN-induced kinase 1 (PINK1), nuclear factor-erythroid 2 related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and the inflammasome (NLRP3) expressions were analyzed. As biomarkers of oxidative stress, protein oxidation (AOPP) and carbonylation (DNP derivatives), and lipid peroxidation (malondialdehyde (MDA)–thiobarbituric acid (TBA) adducts) were measured. In addition, the reduced and oxidized glutathione (GSH and GSSG) and enzymatic (Cu–Zn superoxide dismutase (SOD), CAT, GSH S-T, GSH-Px, and GSH-R) antioxidant capacities were determined. Our results showed that the cold preservation of fatty liver graft depleted ATP, accumulated succinate and increased oxidative stress. In contrast, the preservation with IGL-2 solution maintained ATP production, decreased succinate levels and increased OXPHOS complexes I and II, UCP2, and PINK-1 expression, therefore maintaining mitochondrial integrity. IGL-2 also protected against oxidative stress by increasing Nrf2 and HO-1 expression and GSH levels. Therefore, the presence of PEG35 in storage solutions may be a valuable option as an antioxidant agent for organ preservation in clinical transplantation.
Highlights
We found that liver grafts preserved in IGL-2 maintained mitochondrial integrity and redox status; this solution would be recommended for clinical liver transplantation purposes
The results showed a significant significant increase in the expression of uncoupling protein 2 (UCP2) in those livers preserved with IGL-2 (Figure increase in the expression of UCP2 in those livers preserved with IGL-2 (Figure 3a)
We found that the preservation with IGL-2 induces a significant increase in the expression of mitochondrial protein UCP2, an anion carrier involved in the regulation of various processes, such as maintaining mitochondrial membrane potential and limiting the generation of reactive oxygen species [33,34]
Summary
The increasing incidences of obesity and unhealthy lifestyles in the world population are both responsible for the metabolic syndrome and the consequent accumulation of fat in the liver. Given the global shortage of livers for transplantation, studies on the conditions that allow the use of steatotic livers are needed to broaden donation criteria [1]. The use of steatotic liver grafts and suboptimal increases the risk of later impaired function leading to cell necrosis, which is caused by the higher vulnerability to suffer an ischemia-reperfusion (IR) injury [2,3]. The purpose of the researchers is to find and define the optimal composition of commercial solutions used during cold ischemia, so that the functionality of the stored organ is maintained, ensuring the viability of the steatotic organ after reperfusion [4]
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