Balance between oxidative damage and proliferative potential in an experimental rat model of CCl4-induced cirrhosis: Protective role of adenosine administration

Abstract

Oxidative stress and its consequent lipid peroxidation (LP) exert harmful effects, which have been currently involved in the generation of carbon tetrachloride-induced cirrhosis. However, the recent report that "physiological" LP can be associated with liver regeneration (LR) makes it necessary to discriminate between oxidative stress-induced and LR-associated LP. In rats rendered cirrhotic by continuous CCl4 administration for 4 weeks, moderate cell necrosis and fine fatty infiltration were found. The histological abnormalities were accompanied by increased LP, mainly accounted for by the microsomal and cytosolic fractions and evidence of oxidative stress (decreased hepatic glutathione content and changes in xanthine oxidase and pentose phosphate pathway activities). After 8 weeks, a micronodular cirrhosis developed, but oxidative stress was greatly attenuated, only persisting in the enhanced LP confined to microsomes. Simultaneous administration of adenosine, a reliable hepatoprotector that readily prevents the onset of liver fibrosis, was able to block the oxidative stress induced by the long-term CCl4 treatment but elicited a selective subcellular distribution of increased LP, similar to that found during LR. The adenosine-induced changes in liver LP (mainly in the nuclear fraction) correlated with an increased activity of thymidine kinase. Therefore, data suggest that adenosine-mediated preservation of energy availability and mitochondrial function could participate in preventing the onset of oxidative stress in cirrhotic rats. The latter could induce a successful liver recovery, curtailing the sequence of events leading to fibrogenesis.

Urine metabolic profile changes of CCl4-liver fibrosis in rats and intervention effects of Yi Guan Jian Decoction using metabonomic approach

“…BCAA-enriched nutrients were found to reduce oxidative stress and stimulate antioxidant DNA repair in a rat model of CCl 4 -induced liver injury [48]. In addition, glutamate is one of three amino acids of the GSH biosynthesis, and GSH is a major antioxidant, which quenches the endogenous oxidant species and attacks exogenous oxidative stress and has been seen as a major molecular mechanism in CCl 4 toxicity [49]. Previous studies reported that ferulic acid protects from CCl 4 -induced acute liver injury through reduction of oxidative damage and inflammatory signaling pathways [50].…”

cAMP Signaling in Pathobiology of Alcohol Associated Liver Disease

“…Several studies have found that activation of the A 2A receptor promotes HSC activation and fibrosis [ 155 , 156 , 157 , 158 , 159 ]. However, other studies showed that adenosine or its derivatives have opposite effects on fibrosis [ 160 , 161 , 162 ]. Additionally, adenosine-induced cAMP/PKA signaling has been shown to desensitize endothelin A receptor in activated HSCs leading to decreased contractility [ 163 ].…”

Persistence of Liver Cirrhosis in Association with Proliferation of Nonparenchymal Cells and Altered Location of α-Smooth Muscle Actin-Positive Cells

“…It is well known that cirrhosis results from excess deposition of extracellular matrix component, mainly type I collagen that is produced by hepatic stellate cells (HSCs) (Eng and Friedman, 2000), and during the process, there is an impaired capability for liver regeneration (Andiran et al, 2000). Most therapy for cirrhosis is focused on elimination of direct cause (Hammel et al, 2001;Kweon et al, 2001), and on inducing liver regeneration and increased extracellular matrix (ECM) degradation (Hernandez-Munoz et al, 2001).…”