GastrointestinalErgothioneine pretreatment protects the liver from ischemia-reperfusion injury caused by increasing hepatic heat shock protein 70
Introduction
Ischemic liver injury is caused by a deficiency of oxygen, which occurs by total interruption of hepatic blood flow during liver resection or cold preservation before liver transplantation. On revascularization and reoxygenation, the organ undergoes a process termed “reperfusion injury” that further impairs organ function. The underlying mechanisms of hepatic ischemia-reperfusion (IR) injury are complex and multifactorial. During ischemia, mitochondrial adenosine triphosphate (ATP) depletion and consecutive loss of cellular membrane integrity cause hepatocyte damage. Kupffer cell activation is a central hepatic pathophysiologic mechanism of the early reperfusion injury. Activated Kupffer cells release reactive oxygen species (ROS), which leads to the generation of byproducts of lipid peroxidation, such as malondialdehyde (MDA) [1, 2, 3]. In particular, during the early hours of reperfusion, an increase occurs in the amount of heat shock proteins (HSP) [4, 5]. These proteins have been reported to be induced by various external stresses, including hyperthermic preconditioning or long-term fasting, and to have a cytoprotective function as a molecular chaperon [6, 7, 8]. Either thermal or fasting stress, however, is not a conditioning treatment that would be considered reasonable for clinical usage. A method to induce HSP in the ischemic liver without detrimental side effects is currently desired to facilitate this approach. Ergothioneine (EGT) is a fungal metabolite found in plant and animal tissues [9]. It is an efficient inhibitor of lipid peroxide formation in mouse liver [10], scavenger peroxyl radicals [11], hydroxyl radicals [12], and peroxynitrite [13]. In this study, we hypothesized that EGT can inhibit ROS-mediated lipid peroxidation and induce HSP in the hepatic IR injury.
Section snippets
Materials and methods
This study followed the guideline of the Clinical Research Institute, Erciyes University Hospital for the care and use of laboratory animals.
Results
Among the control group, three rats died of acute liver failure within 24 h and two died on the second day after the surgical procedure. In the EGT group, two rats died on the first postoperative day. The 7-day survival rate was 80% (8 of 10) among EGT and 50% (5 of 10) among controls (P < 0.01). No deaths occurred in the sham group (Table 1).
Changes in serum AST, ALT, and LDH levels 30, 60, 120 min after reperfusion following 60 min of warm ischemia in each group are shown in Fig. 1. The
Discussion
Cells primed by sublethal stress transiently overproduce HSP and thereby develop tolerance to the next lethal stress. This response in organism, called the “stress response,” involves the induction of HSP. Although the exact functions of HSP are not fully understood, it is thought that they are important chaperones; that is, they are involved in protein folding and trafficking across membranes. They are protective to the cell through stabilizing newly synthesized peptides and reactivating
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