The effect of taurine treatment on oxidative stress in experimental liver fibrosis
Introduction
Liver cirrhosis is the terminal stage of a variety of chronic active liver diseases based on different etiologies, among which nutritive-toxic, viral, immunological, and parasitic injuries prevail. Liver injury is associated with activation of hepatic stellate cells (HSCs). In chronic injury, stellate cell activation, and the consequent secretion of matrix by activated stellate cells results in liver fibrosis and ultimately cirrhosis. Although traditionally reviewed as irreversible, reversibility of liver fibrosis has recently been described [1].
Oxidative stress is associated with liver fibrosis and activation of hepatic stellate cells either directly or through paracrin stimulation by injured hepatocytes [2], [3]. Factors increasing reactive oxygen species (ROS) generation may also be involved in stimulation of excessive matrix production in vivo [4]. Increase in hydrogen peroxide production leads to activation of a potent profibrogenic mediator TGF-β, supporting the idea that oxidative stress has important roles in fibrogenesis via both lipid peroxidation and paracrine mechanism [5]. It was also shown that the amount of glutathion-S-transferase, which is a critical antioxidant enzyme in protecting the hepatic stellate cells against ROS products decreases under oxidative stress [6]. The decrease in glutathion-S-transferase may lead to a reduction in detoxification of lipid peroxidation products and susceptibility to oxidative stress.
Taurine, 2-amino ethanesulfonic acid, is a normal constituent of the human diet and is ubiquitous. It is a potent antioxidant and prevents tissue injury mainly through antioxidation. It is also involved in cell volume homeostasis, protein stabilization, and stress responses. It can prevent DNA damage at concentrations normally found in cells [7]. Taurine was reported to be beneficial in preventing experimental diabetic neuropathy [8], lead-induced oxidative damage [9], CCl4-induced oxidative stress [10], caeurelein-induced acute pancreatitis [11], and early changes in experimental diabetic kidney [12] through antioxidant mechanisms. Protective effects on lens [13], modulating effects on human endothelial cell death are among its other effects [14]. In antifibrotic treatment studies for chronic liver diseases, taurine was reported to have beneficial effects in preventing initiation and/or progression of hepatic injury. It was found closely associated with metalloproteinase (MMP) activities in several organ failures. In bleomycine-induced lung injury [15] and glomerular basal membrane damage caused by stimulated neutrophils [16], important roles of metalloproteinases, which may be activated by oxidative stress, and preventive effect of taurine were reported. On the other hand, it has been shown that, activity of metalloproteinases, which normally degrade the excessive matrix and are critical in matrix turnover, is decreased in liver during fibrogenesis. Furthermore, regression of liver fibrosis is characterized by an increase in metalloproteinase activity and a decrease in tissue inhibitors of metalloproteinases (TIMP) expression [1].
The association of taurine with apoptosis, which is regarded as the major mechanism for resolution of liver fibrosis [1], has been examined in various cell types. Taurine inhibited arsenite-induced apoptosis of human PMN cells [17], endothelial cell apoptosis [18], [19], [20], and hyperglycemia and radiocontrast/hypertonicity-induced human renal tubular cell apoptosis [21], [22] possibly through reducing ROS production and regulating intracellular calcium flux. Release of taurine from the cell by a CD 95 receptor and caspase dependent mechanism leads to triggering of apoptotic DNA fragmentation and cell shrinkage. Loading of the cell with taurine before the apoptotic stimuli inhibits CD 95-induced DNA fragmentation and cell shrinkage [23]. Since antiapoptotic effects of taurine on renal epithelial cells subjected to radiocontrast/hypertonicity environment was not shown by N-acetyl-cysteine (NAC) [22], it can be postulated that antioxidant property is not enough for cytoprotective effect. However, taurine was not effective in preventing eosinophil apoptosis on the contrary to glutathione and NAC in vitro [24].
Our aim in this study was to identify the alterations associated with oxidative stress and fibrogenesis in liver, and the mechanisms by which long-term taurine administration ameliorates experimental hepatic fibrosis.
Section snippets
Animals
The ethic committee on Research Animal Care at Gulhane Medical Academy Hospital approved the study and all experiments were conducted in accordance with the National Institutes of Health guidelines for the care and use of laboratory animals.
Forty-five male Spraque–Dawley rats weighing 250–400 g (Gulhane Research Laboratories, Ankara) were subdivided into three groups. Group I was treated with CCl4 plus taurine, Group II with CCl4 plus saline, and Group III with saline for 12 weeks. CCl4 was
Results
Two and four animals in Groups I and II, respectively, died before the end of the experiment. CCl4 treatment produced hepatic necrosis, fibrosis, fatty accumulation, and inflamation by twelfth week. The histopathological evaluation by light microscopy of livers from animals treated with CCl4 and taurine are shown in Fig. 1 and Table 1. Since there was no histopathological abnormality in control group (Fig. 2), only the animals treated with CCl4 plus taurine (Group I) and CCl4 plus saline (Group
Discussion
Preventing the production of reactive oxygen species has been attracting considerable attention in researches for new antifibrotic treatment strategies. Okazaki et al. [30] showed that ROS-induced increase in c-myb and nuclear factor κ-B expression leading to HSC activation can be inhibited by the antioxidants 1α-tocopherol and butyrate hydroxytoluene. Endogenous aminoacids like taurine are released from the cell under oxidative stress, which is frequently associated with impairment of energy
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