Institut George Lopez-1 (IGL-1) and Histidine-tryptophan-ketoglutarate (HTK) solutions are proposed as alternatives to UW (gold standard) in liver preservation. Their composition differs in terms of the presence/absence of oncotic agents such as HES or PEG, and is decisive for graft conservation before transplantation. This is especially so when fatty (steatotic) livers are used since these grafts are more vulnerable to ischemia insult during conservation. Their composition determines the extent of the subsequent reperfusion injury after transplantation. Aldehyde dehydrogenase-2 (ALDH2), a mitochondrial enzyme, has been reported to play a protective role in warm ischemia-reperfusion injury (IRI), but its potential in fatty liver cold ischemic injury has not yet been investigated. We evaluated the relevance of ALDH2 activity in cold ischemia injury when fatty liver grafts from Zucker Obese rats were preserved in UW, HTK, and IGL-1 solutions, in order to study the mechanisms involved. ALDH2 upregulation was highest in livers preserved in IGL-1. It was accompanied by a decrease in transaminases, apoptosis (Caspase 3 and TUNEL assay), and lipoperoxidation, which was concomitant with the effective clearance of toxic aldehydes such as 4-hydroxy-nonenal. Variations in ATP levels were also determined. The results were consistent with levels of NF-E2 p45-related factor 2 (Nrf2), an antioxidant factor. Here we report for the first time the relevance of mitochondrial ALDH2 in fatty liver cold preservation and suggest that ALDH2 could be considered a potential therapeutic target or regulator in clinical transplantation.
The 26S proteasome is the central proteolytic machinery of the ubiquitin proteasome system (UPS), which is involved in the degradation of ubiquitinated protein substrates. Recently, UPS inhibition has been shown to be a key factor in fatty liver graft preservation during organ cold storage using University of Wisconsin solution (UW) and Institute Georges Lopez (IGL-1) solutions. However, the merits of IGL-1 and histidine-tryptophan-ketoglutarate (HTK) solutions for fatty liver preservation have not been compared. Fatty liver grafts from obese Zücker rats were preserved for 24 h at 4 °C. Aspartate aminotransferase and alanine aminotransferase (AST/ALT), glutamate dehydrogenase (GLDH), ATP, adenosine monophosphate protein kinase (AMPK), e-NOS, proteasome activity and liver polyubiquitinated proteins were determined. IGL-1 solution prevented ATP breakdown during cold-storage preservation of steatotic livers to a greater extent than HTK solution. There were concomitant increases in AMPK activation, e-NOS (endothelial NOS (NO synthase)) expression and UPS inhibition. UPS activity is closely related to the composition of the solution used to preserve the organ. IGL-1 solution provided significantly better protection against ischemia-reperfusion for cold-stored fatty liver grafts than HTK solution. The effect is exerted through the activation of the protective AMPK signaling pathway, an increase in e-NOS expression and a dysregulation of the UPS.
Institute Goeorges Lopez 1 (IGL-1) and Histidine-Tryptophan-Ketoglutarate (HTK) preservation solutions are regularly used in clinical for liver transplantation besides University of Wisconsin (UW) solution and Celsior. Several clinical trials and experimental works have been carried out comparing all the solutions, however the comparative IGL-1 and HTK appraisals are poor; especially when they deal with the underlying protection mechanisms of the fatty liver graft during cold storage. Fatty livers from male obese Zücker rats were conserved for 24 h at 4 °C in IGL-1 or HTK preservation solutions. After organ recovery and rinsing of fatty liver grafts with Ringer Lactate solution, we measured the changes in mechanistic target of rapamycin (mTOR) signaling activation, liver autophagy markers (Beclin-1, Beclin-2, LC3B and ATG7) and apoptotic markers (caspase 3, caspase 9 and TUNEL). These determinations were correlated with the prevention of liver injury (aspartate and alanine aminostransferase (AST/ALT), histology) and mitochondrial damage (glutamate dehydrogenase (GLDH) and confocal microscopy findings). Liver grafts preserved in IGL-1 solution showed a marked reduction on p-TOR/mTOR ratio when compared to HTK. This was concomitant with significant increased cyto-protective autophagy and prevention of liver apoptosis, including inflammatory cytokines such as HMGB1. Together, our results revealed that IGL-1 preservation solution better protected fatty liver grafts against cold ischemia damage than HTK solution. IGL-1 protection was associated with a reduced liver damage, higher induced autophagy and decreased apoptosis. All these effects would contribute to limit the subsequent extension of reperfusion injury after graft revascularization in liver transplantation procedures.
The patient was a 5-year-old boy with a complex congenital heart disease (double-outlet right ventricle with Fallot's physiology and single coronary artery anomaly) surgically repaired with ventricular septal defect closure and pulmonary homograft conduit between the pulmonary artery and right ventricle. The patient also had a severe tracheobronchomalacia, corrected with tracheal and bronchial stents, tracheostomy and home ventilatory support. He was colonised with sensitive Pseudomonas aeruginosa that was persistently isolated in respiratory secretions and in skin swabs. Two months before admission, progressive conduit stenosis and right ventricle failure were observed, and 1 month later, a percutaneous stent implantation in the conduit was performed.The child presented to the emergency care unit with hypoxemia, hypoglycaemia and lactic acidosis. He was admitted to the paediatric intensive care unit (PICU) for haemodynamic and ventilatory support. Echocardiography at admission showed right heart failure signs and moderately stenosed right ventriclepulmonary artery conduit. A total of 24 hours after admission, he developed fever and hypotension, and blood tests showed Creactive protein of 15.49 mg/dL, 81.95 ng/mL procalcitonin, 30.6 × 1000/μL white blood cells and 27.10 × 1000/μL neutrophils. Piperacillin-tazobactam plus linezolid were started, but P. aeruginosa was isolated in blood cultures, and treatment was changed to ceftazidime plus tobramycin in accordance with antimicrobial susceptibility test. A new echocardiography was performed 72 h after admission and showed images compatible with vegetation in the pulmonary artery conduit. On the eighth day of admission, the patient developed progressive conduit stenosis, right ventricle failure, persistence of P. aeruginosa in blood cultures and absence of clinical improvement despite antibiotic therapy. The conduit was replaced, and P. aeruginosa was isolated from conduit culture.After surgery, the patient demonstrated clinical improvement and remained afebrile, with negative blood cultures during the following 3 weeks, treated with ceftazidime plus tobramycin. However, 24 days after surgery (day 32 of admission), the patient relapsed with fever and general malaise. New echocardiography showed tricuspid valve vegetation (15 × 6 mm) ( Fig. 1) with moderate tricuspid regurgitation. Then, P. aeruginosa resistant to ceftazidime, cefepime, aztreonam and fluorquinolones, and minimum inhibitory concentration (MIC) for meropenem of 4 μg/mL, was isolated in blood cultures. Treatment was changed to high-dose meropenem (120 mg/kg/day) in extended infusion (3 h), three times a day, plus tobramycin, and further cardiac surgery was planned. Despite the new antibiotic treatment, the child remained febrile, and P. aeruginosa persisted in blood cultures. On day 43, the patient presented with bacteraemic aspect, fever and tachycardia, so a possible pulmonary embolism of vegetation was suspected. Susceptibility to ceftolozane-tazobactam was tested and showed an MIC of 2 μg/mL. On day...
A major issue in organ transplantation is the development of a protocol that can preserve organs under optimal conditions. Damage to organs is commonly a consequence of flow deprivation and oxygen starvation following the restoration of blood flow and reoxygenation. This is known as ischemia-reperfusion injury (IRI): a complex multifactorial process that causes cell damage. While the oxygen deprivation due to ischemia depletes cell energy, subsequent tissue oxygenation due to reperfusion induces many cascades, from reactive oxygen species production to apoptosis initiation. Autophagy has also been identified in the pathogenesis of IRI, although such alterations and their subsequent functional significance are controversial. Moreover, proteasome activation may be a relevant pathophysiological mechanism. Different strategies have been adopted to limit IRI damage, including the supplementation of commercial preservation media with pharmacological agents or additives. In this review, we focus on novel strategies related to the ubiquitin proteasome system and oxidative stress inhibition, which have been used to minimize damage in liver transplantation.
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