Targeting Oxidative Stress for the Treatment of Liver Fibrosis

Abstract

Oxidative stress is a reflection of the imbalance between the production of reactive oxygen species (ROS) and the scavenging capacity of the antioxidant system. Excessive ROS, generated from various endogenous oxidative biochemical enzymes, interferes with the normal function of liver-specific cells and presumably plays a role in the pathogenesis of liver fibrosis. Once exposed to harmful stimuli, Kupffer cells (KC) are the main effectors responsible for the generation of ROS, which consequently affect hepatic stellate cells (HSC) and hepatocytes. ROS-activated HSC undergo a phenotypic switch and deposit an excessive amount of extracellular matrix that alters the normal liver architecture and negatively affects liver function. Additionally, ROS stimulate necrosis and apoptosis of hepatocytes, which causes liver injury and leads to the progression of end-stage liver disease. In this review, we overview the role of ROS in liver fibrosis and discuss the promising therapeutic interventions related to oxidative stress. Most importantly, novel drugs that directly target the molecular pathways responsible for ROS generation, namely, mitochondrial dysfunction inhibitors, endoplasmic reticulum stress inhibitors, NADPH oxidase (NOX) inhibitors, and Toll-like receptor (TLR)-affecting agents, are reviewed in detail. In addition, challenges for targeting oxidative stress in the management of liver fibrosis are discussed.

Counteraction of HCV-Induced Oxidative Stress Concurs to Establish Chronic Infection in Liver Cell Cultures

“…NOXs are a family of seven enzymes, generating O 2 ⋅− or H 2 O 2 from molecular oxygen [45]. Accumulating evidence indicates that NOX-mediated ROS production has a critical role in hepatic fibrosis [46,47], and in particular, NOX4 is involved in the severity of HCV-associated liver disease [19,36], as well as in the regulation of viral replication of different viruses [48][49][50]. Here, we found that NOX4 and NOX1 rise mirrored the trend of ROS production and that of viral replication; in fact, their expression was increased during the acute phase of infection, while it decreased late in infection, thus suggesting a critical role for NOXs also in regulating HCV replication cycle.…”

Liver fibrosis: Pathophysiology, pathogenetic targets and clinical issues

“…The list include vitamin E, glutathione, N-acetylcysteine, S-adenosyl-methionine, resveratrol, curcumin, herbal supplements (Sho-Saiko-to, Silymarin, Salvia Miltiorrhiza, etc. ), inhibitors of NADPH-oxidase isoforms and many others, as reviewed elsewhere (Weisenkirchen, 2016;Luangmonkong et al, 2018). Unfortunately, administration of these molecules in human patients was either ineffective or associated with very limited or transient efficacy, with few exceptions (reviewed in: Serviddio et al, 2013;Weiskirchen, 2016;Luangmonkong et al, 2018).…”

“…), inhibitors of NADPH-oxidase isoforms and many others, as reviewed elsewhere (Weisenkirchen, 2016;Luangmonkong et al, 2018). Unfortunately, administration of these molecules in human patients was either ineffective or associated with very limited or transient efficacy, with few exceptions (reviewed in: Serviddio et al, 2013;Weiskirchen, 2016;Luangmonkong et al, 2018). For example, long-term vitamin E (96 weeks) administration has been reported to be beneficial in a multicenter, randomized, placebo-controlled study performed on non-diabetic NASH patients resulting in histological regression, reduction of liver injury and inflammation, but not fibrosis (Sanyal et al, 2010).…”

Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis

“…Besides identifying key redox-dependent players in fibrogenesis, these approaches may also allow estimating the input of various ROS sources into the fibrogenic process by analyzing their proximity to redox switches. Altered redox signaling is considered a promising target for fibrosis treatment by targeting, e.g., mitochondrial dysfunctions, and NADPH oxidases, as detailed in [166].…”