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.
Highlights
Liver transplantation is the only successful life-saving treatment for patients with most types of end-stage liver failure [1]
5(f), and 5(g), compared with the donors after circulatory death (DCD) control group, simvastatin pretreatment dramatically suppressed the mRNA expression of interleukin-1β (IL-1β), IL-6, and intercellular adhesion molecule 1 (ICAM-1). These results provided strong evidence that DCD liver pretreatment with simvastatin could significantly reduce the release of high-mobility group box 1 (HMGB1), Toll-like receptor 4 (TLR4), CD68, IL-1β, IL-6, and ICAM-1 after warm reperfusion subjected to 24 h cold preservation in rats
Hepatic ischemia reperfusion injury (IRI) injury is a complex pathological process associated with liver transplantation, shock, and trauma
Summary
Liver transplantation is the only successful life-saving treatment for patients with most types of end-stage liver failure [1]. The shortage of adequate organs all over the world has led to the use of extended-criteria donor (ECD) organs from steatotic donors or donors after circulatory death (DCD) These DCD organs often suffer from an unpredictable longer warm ischemia time, which are much more prone to a higher risk of early allograft dysfunction (EAD) or primary graft failure (PNF) after transplantation [2, 3]. Kruppel-like factor 2 (KLF2) is a laminar flow inducible transcription factor primarily expressed by the endothelial cell and plays an important role in the regulation of endothelial function [6,7,8] It induces factor expression of vasodilators and antithrombotic, antioxidant, and anti-inflammatory genes (e.g., endothelial nitric oxide synthase (eNOS), thrombomodulin (TM), and heme oxygenase-1 (HO-1)) and reduces the expression of adhesion molecules (vascular cell adhesion molecule 1 (VCAM-1) and E-selectin), conferring a vasoprotective endothelial phenotype [9,10,11]
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