Hypothermic oxygenated machine perfusion alleviates liver injury in donation after circulatory death through activating autophagy in mice

Abstract

Hypothermic oxygenated machine perfusion (HOPE) is a safe and reliable method that could alleviate liver injury in donation after circulatory death (DCD). This study focuses on the role of autophagy in HOPE’s protective effect on DCD liver injury. A 30‐minute warm ischemic liver model was established in mice. After 4 hours of cold storage (CS), 1 hour of hypothermic machine perfusion (HMP) with 100% O2 or 100% N2 was employed. During 2 hours of reperfusion, liver tissue and perfusate were collected to evaluate liver function, oxidative stress level, apoptosis, and necrosis. Western blotting was used to explore the level of autophagy. When the liver experienced warm ischemic injury, LC3B‐II expression was significantly enhanced. Compared with the CS, HOPE induced lower release of AST and ALT, as well as lower oxidative stress levels, apoptosis, and necrosis cell numbers, and led to higher tissue ATP content. Meanwhile, expression of autophagy‐related proteins, such as ULK1, Atg5, and LC3B‐II, increased. When oxygen was completely replaced by nitrogen, the washout effect of HMP did not activate autophagy and did not relieve DCD liver injury. When the autophagy inhibitor 3‐methyladenine was used in HOPE, the protective effect of HOPE was attenuated. In conclusion, DCD liver injury activated autophagy compared with healthy liver, while HOPE alleviated DCD liver injury by increasing autophagy levels further in this mouse model. However, HMP with 100% of N2 had no beneficial effect on DCD liver injury or on autophagy levels compared with CS. The research on autophagy may provide a new strategy for alleviating DCD liver injury in clinical practice.

Remote Ischemic Preconditioning Attenuates Hepatic Ischemia/Reperfusion Injury after Hemorrhagic Shock by Increasing Autophagy

“…It has been reported that programmed transient ischemia-reperfusion during shock, or during resuscitation also has protective effects [16]. Second, the protective effect of IPC is more prominent in primary hepatic I/RI in special cases, such as fatty and senile liver [10,13,29]. This study showed that RIPC-activated autophagy plays a role in hepatoprotection after hemorrhagic shock, but to what extent autophagy is the underlying mechanism and whether RIPC plays a more prominent role in special groups need further investigation.…”

“…Autophagy eliminates damaged organelles, increases ATP and amino acid levels to stabilize cell morphology, maintain function, or promote apoptosis [5][6][7]. Hepatocytes have an abundance of mitochondria and autophagy plays a crucial role in hepatic I/RI [8][9][10].…”

Artificial Organs 2019: A year in review

“…Xianpeng Zeng et al of Transplant Center of Wuhan University, Wuhan, China investigated the use of hypothermic oxygenated machine perfusion (HOPE) in liver donation after circulatory death (DCD) through activating autophagy in mice. A 30‐minute warm ischemic liver model was established.…”

Ice, ice, maybe? Is it time to ditch the igloo cooler? Benefits of machine perfusion preservation of donor hearts

“…Hypothermic perfusion is successfully used for recovery of donor kidneys, particularly from extended criteria or DCDD donors with excellent results . Most kidney perfusion systems do not oxygenate the perfusate though this is essential to meet the metabolic demands for donor hearts.…”

“…Hypothermic perfusion is successfully used for recovery of donor kidneys, particularly from extended criteria or DCDD donors with excellent results. [36][37][38][39] Most kidney perfusion systems do not oxygenate the perfusate though this is essential to meet the metabolic demands for donor hearts. Although an oxygen carrier, erythrocyte based or otherwise, 40,41 can be included in the preservation solution of cold perfused organs, dissolved oxygen in crystalloid solutions is sufficient to support myocardial oxidative metabolism.…”