Pretreatment Donors after Circulatory Death with Simvastatin Alleviates Liver Ischemia Reperfusion Injury through a KLF2‐Dependent Mechanism in Rat

Abstract

Objective Severe hepatic ischemia reperfusion injury (IRI) can result in poor short- and long-term graft outcome after transplantation. The way to improve the viability of livers from donors after circulatory death (DCD) is currently limited. The aim of the present study was to explore the protective effect of simvastatin on DCD livers and investigate the underlying mechanism. Methods 24 male rats randomly received simvastatin or its vehicle. 30 min later, rat livers were exposed to warm ischemia in situ for 30 min. Livers were removed and cold-stored in UW solution for 24 h, subsequently reperfused for 60 min with an isolated perfused rat liver system. Liver injury was evaluated during and after warm reperfusion. Results Pretreatment of DCD donors with simvastatin significantly decreased IRI liver enzyme release, increased bile output and ATP, and ameliorated hepatic pathological changes. Simvastatin maintained the expression of KLF2 and its protective target genes (eNOS, TM, and HO-1), reduced oxidative stress, inhibited innate immune responses and inflammation, and increased the expression of Bcl-2/Bax to suppress hepatocyte apoptosis compared to DCD control group. Conclusion Pretreatment of DCD donors with simvastatin improves DCD livers' functional recovery probably through a KLF2-dependent mechanism. These data suggest that simvastatin may provide a potential benefit for clinical DCD liver transplantation.

Hypothermic oxygenated perfusion (HOPE) attenuates ischemia/reperfusion injury in the liver through inhibition of the TXNIP/NLRP3 inflammasome pathway in a rat model of donation after cardiac death

“…However, even with the lack of erythrocytes, adequate oxygenation of the liver can be attained with high enough perfusate flow, but the perfusion technique is only feasible for relatively short-term experiments (65). We guaranteed the oxygenation of the liver via actively oxygenating perfusate at a minimum of 500 mmHg, which is consistent with other studies (44)(45)(46)66). We realize that this is a major limitation of our study.…”

“…The temperature of the perfusate was maintained at 36-37°C during reperfusion. Perfusates were actively oxygenated at a minimum of 500 mmHg (partial pressure of oxygen) under exposure of carbogen (95% oxygen and 5% carbon dioxide) (44)(45)(46). Time 0 was the point at which the portal catheter was connected to the circuit.…”

Mild Hypothermia Attenuates Hepatic Ischemia–Reperfusion Injury through Regulating the JAK2/STAT3-CPT1a-Dependent Fatty Acid β-Oxidation

“…Hepatic IR injury is a complex pathological process that can result in serious liver injury and severely threatens the shortand long-term prognosis of the patients who undergo liver surgery [3,32,33]. The limited number of currently available therapeutic strategies for IR injury urged us to explore more methods that can effectively prevent and attenuate IR injury.…”

“…The ischemic phase mainly causes cellular metabolic disturbances that result from glycogen consumption, lack of oxygen supply, and ATP depletion, while the reperfusion phase results not only in metabolic disturbances but also in a profound inflammatory immune response that involves both direct and indirect cytotoxic mechanisms [1]. The complicated IR injury is one of the main reasons for early graft failure and the increased risk of organ rejection and liver dysfunction [3]. Unfortunately, currently, the promising interventions for the treatment of hepatic IR injury are limited in number [4][5][6].…”

Roles of pyroptosis in myocardial ischemia/reperfusion injury diseases

“…As an emerging researching field that combines inflammation reaction and PCD, pyroptosis provides a new perspective and has a broad prospect in realizing the occurrence, development, and outcome of diseases, including. 40,41 Taking the high morbidity and mortality into account, more detailed studies on pyroptosis in ischemia diseases may provide new ideas and new drug targets for the intervention and treatment of related diseases.…”