Abstract
N-acetylcysteine (NAC) is a pharmacological alternative with great potential for reducing the deleterious effects of surgical procedures on patients with steatohepatitis. We evaluated the effect of NAC on hepatic ischemia/reperfusion (I/R) injury in C57BL/6J mice, 8 weeks-old, weighing 25–30 g, with steatohepatitis induced by a methionine- and choline-deficient (MCD) diet. Groups: MCD group (steatohepatitis), MCD-I/R group (steatohepatitis plus 30 min of 70% liver ischemia and 24 h of reperfusion), MCD-I/R+NAC group (same as MCD-I/R group plus 150 mg/kg NAC 15 min before ischemia), and control group (normal AIN-93M diet). Liver enzymes and histopathology; nitrite and TBARS (thiobarbituric acid reactive substances) levels; pro-inflammatory cytokines; antioxidants enzymes; Nrf2 (nuclear factor erythroid-2-related factor 2) expression; and apoptosis were evaluated. In the group treated with NAC, reductions in inflammatory infiltration; AST (aspartate aminotransferase), nitrite, and TBARS levels; GPx (gutathione peroxidase) activity; cytokines synthesis; and number of apoptotic cells were observed while the GR (glutathione reductase) activity was increased. No differences were observed in Nfr2 expression or in SOD (superoxide dismutase), CAT (catalase), and GST (glutathione S-transferase) activities. Thus, it may be concluded that NAC exerts beneficial effects on mice livers with steatohepatitis submitted to I/R by reducing oxidative stress, inflammatory response, and cell death.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent hepatic diseases in the global population [1,2], affecting 4 to 46% of individuals [3,4], and 90% of cases occur in morbidly obese individuals [1]
The histological spectrum of NAFLD may range from simple steatosis to nonalcoholic steatohepatitis (NASH), with progression to liver fibrosis and cirrhosis [5,6,7]
Cells of the immune system are recruited to the place of injury; resident innate immune cells and liver cells, through a nuclear factor κ-light-chain enhancer-activated B cells (NF-κB)-mediated mechanism, release pro-inflammatory cytokines that intensify the hepatic damage by increasing the production of reactive oxygen species (ROS)/reactive nitrogen species (RNS) and activate the pro-apoptotic signal via a caspase cascade
Summary
Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent hepatic diseases in the global population [1,2], affecting 4 to 46% of individuals [3,4], and 90% of cases occur in morbidly obese individuals [1]. Cytokines derived from Kupffer cells, such as TGF-β, TNF-α, and IL-1, may induce the hepatic stellate cells (HSC), previously activated by ROS, RSN, and malondialdehyde (MDA), to proliferate and transform into myofibroblasts, promoting increased production of collagen and causing fibrosis in the liver [17] Endogenous antioxidants, such as glutathione (GSH), superoxide dismutase, catalase, and reduced glutathione-related enzymes, play a vital role in the maintenance of the oxidative/antioxidant balance by their capability to scavenge free radicals, contributing to a reduction in tissue damage [18]. To decrease oxidative stress and inflammation that leads to cell death in the liver, pharmacological therapy involving administration of exogenous antioxidants has recently been evaluated in animal models [21] Among these antioxidants, N-acetylcysteine has great potential for reducing the deleterious effects of oxidative stress and inflammatory response in different types of diseases by acting on detoxification of ROS, inhibition the synthesis of NO, upregulation of antioxidant enzymes, immunomodulatory activity, and regulation of apoptosis [22]. TL,hMe CleDveglrsooufpI:F2N94-γ± 2in phge/pmaLti,cMtiCsDsu-Ie/Rwgerroeuspi:m22il3a±r 3a8mpogn/mg Lth, aengdroups (contMroICnltD.gJ.-rMIo/Roul.p+Sc:Ni. 22A072C60,g±2r1o,1xu5FpO:pR3g1P/4EmE±RL7R,5EMpVgICE/WmDLg).roup: 294 ± 26 pg/mL, MCD-I/R group: 223 ± 386 opf g20/mL, and MCD-I/R + NAC group: 314 ± 75 pg/mL)
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