Protective action of glutamine in rats with severe acute liver failure

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 NFκBmediated 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 inflammatoryinfiltration, 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 NO2and NO3levels(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.