Pro-Resolving Lipid Mediator Resolvin E1 Mitigates the Progress of Diethylnitrosamine-Induced Liver Fibrosis in Sprague-Dawley Rats by Attenuating Fibrogenesis and Restricting Proliferation.

Maria José Rodríguez,Wendy Donoso,Daniel R González,Roxana Orrego,Iván Castillo,Jessica Zúñiga-Hernández,Francisca Herrera

doi:10.3390/ijms21228827

Abstract

Liver fibrosis is a complex process associated to most types of chronic liver disease, which is characterized by a disturbance of hepatic tissue architecture and the excessive accumulation of extracellular matrix. Resolvin E1 (RvE1) is a representative member of the eicosapentaenoic omega-3 lipid derivatives, and is a drug candidate of the growing family of endogenous resolvins. Considering the aforementioned, the main objective of this study was to analyze the hepatoprotective effect of RvE1 in a rat model of liver fibrosis. Male Sprague-Dawley rats received diethylnitrosamine (DEN, 70 mg/mg body weight intraperitoneally (i.p)) as an inductor of liver fibrosis once weekly and RvE1(100 ng/body weight i.p) twice weekly for four weeks. RvE1 suppressed the alterations induced by DEN, normalizing the levels of alanine aminotransferase (ALT), albumin, and lactate dehydrogenase (LDH), and ameliorated DEN injury by decreasing the architecture distortion, inflammatory infiltration, necrotic areas, and microsteatosis. RvE1 also limited DEN-induced proliferation through a decrease in Ki67-positive cells and cyclin D1 protein expression, which is related to an increase of the levels of cleaved caspase-3. Interestingly, we found that RvE1 promotes higher nuclear translocation of nuclear factor κB (NF-κB)p65 than DEN. RvE1 also increased the levels of nuclear the nuclear factor erythroid 2–related factor 2 (Nrf2), but with no antioxidant effect, measured as an increase in glutathione disulfide (GSSG) and a decrease in the ratio of glutathione (GSH)/GSSG. Taken together, these results suggest that RvE1 modulates the fibrogenesis, steatosis, and cell proliferation in a model of DEN induced fibrosis.

Highlights

Liver fibrosis is a dynamic response to chronic liver injury caused by various agents, such as viruses, alcohol, metabolic and autoimmune disorders [1]
Biochemical parameters analysis show that DEN induced liver alterations related to increases in ALT, aspartate transaminase (AST), and lactate dehydrogenase (LDH) values, and reductions of albumin levels (Table 1), with insignifficant alterations in the values of Alkaline phosphatase (ALP) or γ-glutamyl transferase in relation to control
Masson’s Trichrome and α-smooth muscle Actin (α-SMA) staining analysis (Figure 2A) revealed, as expected, an exaggeration of extracellular matrix (ECM) and a tendency to form fibrotic bridges in the DEN groups when is compared with all the other groups, situation that is reversed by the administration of Resolvin E1 (RvE1), where it is observed a reduced of the fibrotic total area

Summary

Introduction

Liver fibrosis is a dynamic response to chronic liver injury caused by various agents, such as viruses, alcohol, metabolic and autoimmune disorders [1]. Liver fibrosis is a complex process that involves several cells of the hepatic sinusoid, which is characterized by a disturbance of the architecture and composition of extracellular matrix (ECM) [2]. Hepatic inflammation is a hallmark of the early stage fibrosis, which can progress to extensive fibrosis and cirrhosis [4]. According to the last report from the Centers for Disease Control and prevention (CDC), cirrhosis and chronical liver disease (CLD) are the eleventh cause of death affecting millions of patients worldwide [5]. The age-standardized incidence rate of cirrhosis and CLD was 20.7 per 100,000 inhabitants, and the estimated incidence of cirrhosis in Europe is 26.0 per 100,000 [6]

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