Cytoprotective Mechanisms in Fatty Liver Preservation against Cold Ischemia Injury: A Comparison between IGL-1 and HTK

Abstract

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.

Role of aldehyde dehydrogenase 2 in ischemia reperfusion injury: An update

“…Autophagy has two paradoxically opposite behaviors, depending on the stage of the I/R condition: during ischemia, certain levels of autophagy are cytoprotective[ 35 ], but during reperfusion it is detrimental[ 32 , 33 ]. One of the key elements that regulate autophagy is the mammalian target of rapamycin (mTOR), an autophagy inhibitor.…”

The Novel N,N‐bis‐2‐Hydroxyethyl‐2‐Aminoethanesulfonic Acid–Gluconate–Polyethylene Glycol–Hypothermic Machine Perfusion Solution Improves Static Cold Storage and Reduces Ischemia/Reperfusion Injury in Rat Liver Transplant

“…The gold standard preservation solutions used in liver transplantation have been the UW and HTK. Recently, the need to have new alternatives has opened the field to new solutions, such as Celsior and Institut Georges Lopez 1, but researchers do not completely agree regarding which one provides better short‐term and longterm outcomes . Although there are a significant number of research projects going on, there is still a lack of evidence supporting the development of new alternatives that will not only improve results but also will allow us to extend the required times for the engraftment.…”

“…Recently, the need to have new alternatives has opened the field to new solutions, such as Celsior and Institut Georges Lopez 1, but researchers do not completely agree regarding which one provides better short-term and longterm outcomes. (29)(30)(31)(32)(33)(34)(35) Although there are a significant number of research projects going on, there is still a lack of evidence supporting the development of new Original article | 1383 alternatives that will not only improve results but also will allow us to extend the required times for the engraftment. This possibility will clearly improve quality of life for the surgical time, result for the recipients, and availability of organs, as well as perhaps the costs.…”

Aldehyde Dehydrogenase 2 (ALDH2) in Rat Fatty Liver Cold Ischemia Injury

“…We might suspect that the differences found in ALDH2/4-HNE levels may be associated with the presence/absence of the oncotic agent PEG35. This theory is supported by the fact that the presence or absence of PEG35-rinse solutions for liver grafts protects against mitochondrial damage [ 41 , 42 ], and by the comparison of IGL-1 (with PEG35) vs. HTK (without PEG35) in fatty liver graft preservation [ 43 ]. Moreover, recent preliminary research comparing IGL-1 with the same solution without oncotic agent PEG35 (IGL-0) found that the absence of PEG35 significantly reduced the fatty liver graft protection against ischemic insult after 24 h at 4 °C [ 44 ].…”