Elabela alleviates ischemia/reperfusion-induced hepatic and remote organ injury by inhibiting oxidative stress in rats

Abstract

Hepatic injury is one of the most critical problems in major liver surgeries, trauma, sepsis or shock. The novel Elabela (ELA) peptide was shown to exert protective effects against cardiac and renal injury. We hypothesized that ELA could also have protective effects in hepatic ischemia-reperfusion (HI/R) injury and associated remote organ injury. Male (n = 37) and female (n = 37) Sprague-Dawley rats were used. Rats were divided into short-term and long-term HI/R injury groups. Each group was then divided into saline-treated, N-acetylcysteine-treated (NAC, 150 mg/kg) and ELA-treated (40 μg/kg) subgroups. Immediately before hepatic ischemia and during reperfusion, rats were subcutaneously injected with saline, NAC or ELA, while injections in long-term groups were continued twice a day for four days. Short-term and long-term sham-operation groups received saline injections. Hepatic blood flow was measured via laser Doppler flowmetry. Intracardiac blood was obtained for analyses of aminotransferase, alanine aminotransferase, bilirubin, urea, creatinine and interleukin (IL)-6. Caspase-3 and 8-hydroxy-2'-deoxyguanosine levels were determined and histopathological analyses (hematoxylin-eosin and alpha-smooth muscle actin (SMA) immunohistochemical staining) were performed in hepatic tissues. Levels of malondialdehyde, antioxidant glutathione, myeloperoxidase activity, luminol and lucigenin-enhanced chemiluminescence were measured in liver, lung, and kidney. Significant improvement in hepatic blood flow was observed in both short- and long-term ELA-treated groups. HI/R-induced elevations in reactive oxygen species in all the studied tissues were decreased by ELA, indicating its efficient radical scavenging function similar to NAC treatment. ELA treatment improved hepatic function tests and alleviated liver fibrosis, as detected by increased alpha-SMA-immunoreactivity. Serum IL-6 levels were increased by ELA treatment, suggesting its role in the activation of IL-6-dependent intracellular pathways which may contribute to hepatocyte proliferation and liver regeneration. Similar to the common use of NAC in hepatic surgery, Elabela appears to have a therapeutic potential in alleviating the consequences of hepatic postreperfusion injury.

Keywords: Elabela; Hepatic ischemia–reperfusion; N-acetylcysteine; Oxidative injury; Rat.