Protective mechanisms of end-ischemic cold machine perfusion in DCD liver grafts

Hypothermic machine perfusion in liver transplantation

“…Previous work, however, confirmed that hypothermic liver perfusion with completely deoxygenated perfusate failed to protect from reperfusion injury [22,29 & ]. Of note, the rate of oxygen consumption during HOPE is not stable but decreases rapidly during the first hour, and ceases after 90 min at a low baseline level [13,22,34]. This effect relates to a decrease of electron-rich substrates during hypothermic oxygenation [22].…”

“…In fact, delivery of oxygen under cold conditions turned out to be very effective in uploading cellular energy with only minor oxidative stress, in sharp contrast to exposure of any ischemic tissue to oxygen at normothermic conditions [21]. The underlying mechanism involves predominantly a mitochondrial repair [22,23]. Accordingly, short periods of hypothermic oxygenated perfusion (HOPE) or hypothermic oxygen persufflation increase ATP significantly in several tissues within 1-2 h [24,25 & ], and decrease radical oxygen species (ROS) and danger-associated molecular patterns (DAMPs) subsequently (HighMobility-Group-Box Protein 1, DNA fragments, and histones) that release during implantation [21,22,26].…”

“…The underlying mechanism involves predominantly a mitochondrial repair [22,23]. Accordingly, short periods of hypothermic oxygenated perfusion (HOPE) or hypothermic oxygen persufflation increase ATP significantly in several tissues within 1-2 h [24,25 & ], and decrease radical oxygen species (ROS) and danger-associated molecular patterns (DAMPs) subsequently (HighMobility-Group-Box Protein 1, DNA fragments, and histones) that release during implantation [21,22,26]. Subsequently, several Toll-like receptors 2,4,9 and also receptor for advanced glycation end products on membrane surfaces become less activated [26][27][28], and lead to less release of chemokines (TNFa, CXCL2, and CXCL10) with less immune response [21,23,27,29 ,30,31].…”

Untitled

“…[58][59][60] The role of aeration of the cold-stored liver also was clarified. A study by Schlegel and associates 61 provided evidence that machine perfusion in the complete absence of oxygen failed to prevent reperfusion injury and, instead, provoked mitochondrial and nuclear injury with the release of high mobility group box 1 protein. Oxygen, provided either by surface diffusion (surface oxygenation) or intravascular diffusion (oxygen persufflation), is needed in DCD grafts, and it helps to improve the energy status of organs and promote early recovery.…”

“…Although machine perfusion has been increasingly discussed as a promising tool to optimize livers before transplant, the mechanisms underlying protection by liver perfusion techniques have not been fully addressed. Research undertaken by Schlegel and associates 61 reported that there appeared to be at least 2 mechanisms of protection by hypothermic machine perfusion. First, oxygenation under hypothermic conditions protected against mitochondrial and nuclear injury via down-regulation of mitochondrial activity before reperfusion.…”