Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Mar 27, 2019; 11(3): 273-286
Published online Mar 27, 2019. doi: 10.4254/wjh.v11.i3.273
Protective action of glutamine in rats with severe acute liver failure
Elizângela G Schemitt, Renata M Hartmann, Josieli R Colares, Francielli Licks, Jéferson O Salvi, Cláudio A Marroni, Norma P Marroni
Elizângela G Schemitt, Renata M Hartmann, Josieli R Colares, Francielli Licks, Jéferson O Salvi, Cláudio A Marroni, Norma P Marroni, Laboratory of Experimental Hepatology and Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90040060, Brazil
Elizângela G Schemitt, Renata M Hartmann, Josieli R Colares, Francielli Licks, Jéferson O Salvi, Norma P Marroni, Laboratory of Oxidative Stress and Antioxidants, Universidade Luterana do Brasil, Canoas 92425900, Brazil
Author contributions: Schemitt EG, Hartmann RM, Colares JR and Marroni NP contributed to study conception and design; Schemitt EG, Hartmann RM, Colares JR, Licks F and Salvi JO contributed to data acquisition, data analysis and interpretation, and writing of article; Schemitt EG, Marrini CA and Marroni NP contributed to editing and reviewing of article; all authors have read and approved of the final version of the article.
Supported by: FIPE/Hospital de Clinicas of Porto Alegre.
Institutional review board statement: This study was conducted at the Animal Experimentation Unit and the Laboratory of Experimental Hepatology and Gastroenterology, Hospital de Clínicas of Porto Alegre, after approval from the Institutional Animal Care and Use Committee, No. CEUA 15-0175.
Conflict-of-interest statement: The authors have no conflicts of interest to disclose.
ARRIVE guidelines statement: The authors followed the ARRIVE checklist.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Claudio A Marroni, PhD, Professor, Laboratory of Experimental Hepatology and Gastroenterology, Hospital de Clínicas de Porto Alegre, Rua José Kanan Aranha 102, Porto Alegre 90040060, Brazil. nmarroni@terra.com.br
Telephone: +55-51-999638306
Received: October 30, 2018
Peer-review started: October 30, 2018
First decision: December 21, 2018
Revised: January 29, 2019
Accepted: March 12, 2019
Article in press: March 12, 2019
Published online: March 27, 2019
Processing time: 148 Days and 18.1 Hours
Abstract
BACKGROUND

Severe acute liver failure (SALF) is a rare, but high-mortality, rapidly evolving syndrome that leads to hepatocyte degeneration with impaired liver function. Thioacetamide (TAA) is a known xenobiotic, which promotes the increase of the formation of reactive oxygen species. Erythroid 2-related factor 2 (Nrf2) activates the antioxidant protection of cells. Studies have evidenced the involvement of inflammatory mediators in conditions of oxidative stress.

AIM

To evaluate the antioxidant effects of glutamine on Nrf2 activation and NFκB-mediated inflammation in rats with TAA-induced IHAG.

METHODS

Male Wistar rats (n = 28) were divided into four groups: control, control+glutamine, TAA, and TAA + glutamine. Two TAA doses (400 mg/kg) were administered intraperitoneally, 8 h apart. Glutamine (25 mg/kg) was administered at 30 min, 24 h, and 36 h. At 48 h, blood was collected for liver integrity analysis [aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP)]. The liver was harvested for histology and assessment of oxidative stress [thiobarbituric acid-reactive substances (TBARS), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST), glutathione (GSH), Nrf2, Kelch-like ECH-associated protein 1 (Keap1), NADPH quinone oxidoreductase1 (NQO1), superoxide dismutase (SOD)] and inflammatory process.

RESULTS

TAA caused disruption of the hepatic parenchyma, with inflammatory infiltration, massive necrosis, and ballooning degeneration. Glutamine mitigated this tissue damage, with visible regeneration of hepatic parenchyma; decreased TBARS (P < 0.001), GSH (P < 0.01), IL-1β, IL6, and TNFα levels (P <0.01) in hepatic tissue; and decreased blood levels of AST, ALT, and ALP (P <0.05). In addition, CAT, GPx, and GST activities were restored in the glutamine group (P <0.01, P <0.01, and P <0.001, respectively vs TAA alone). Glutamine increased expression of Nrf2 (P < 0.05), NQO1, and SOD (P < 0.01), as well as levels of IL-10 (P <0.001), while decreasing expression of Keap1, TLR4, NFκB (P < 0.001), COX-2 and iNOS, (P < 0.01), and reducing NO2 and NO3 levels (P < 0.05).

CONCLUSION

In the TAA experimental model of IHAG, glutamine activated the Nrf2 pathway, thus promoting antioxidant protection, and blunted the NFκB-mediated pathway, reducing inflammation.

Keywords: Thioacetamide; Cytokines; Oxidative stress; Inflammation; Liver failure; Chemical and drug induced liver injury; Glutamine

Core tip: Severe acute liver failure (SALF) is a rare syndrome characterized by rapid deterioration of liver function, usually in patients without underlying liver disease; the only effective treatment is transplantation. In this study, we used thioacetamide (TAA), a known xenobiotic hepatotoxicant, to induce SALF in rats. This was followed by administration of glutamine in an attempt to activate antioxidative defenses via the erythroid 2-related factor 2 (Nrf2) pathway and mitigate liver injury. Glutamine successfully activated Nrf2 and inhibited TLR4/NFκB-mediated inflammation, allowing restoration of parenchymal architecture and recovery of several parameters to near-control levels.