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.
Theerut Luangmonkong and Su Suriguga contributed equally to this work.
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- ADP:
-
Adenosine diphosphate
- ALD:
-
Alcoholic liver disease
- ALT:
-
Alanine transaminase
- BDL:
-
Bile duct-ligated
- Ca2+:
-
Calcium
- CCl4:
-
Carbon tetrachloride
- CoA:
-
Coenzyme A
- CoQ10:
-
Coenzyme Q10
- CYP:
-
Cytochrome P450
- CytC:
-
Cytochrome C
- DHA:
-
Docosahexaenoic acid
- ECM:
-
Extracellular matrix
- eIF2α:
-
Eukaryotic translation initiation factor 2 alpha
- EPA:
-
Eicosapentaenoic acid
- ER:
-
Endoplasmic reticulum
- Ero1α:
-
Endoplasmic reticulum oxidoreductin 1 alpha
- FADH2:
-
Flavin adenine dinucleotide
- GSH:
-
Glutathione
- H2O2:
-
Hydrogen peroxide
- HBV:
-
Hepatitis B virus
- HCV:
-
Hepatitis C virus
- HMGB:
-
High-mobility group box
- HNE:
-
4-Hydroxynonenal
- HO•:
-
Hydroxyl radical
- HSC:
-
Hepatic stellate cells
- IRAK-1:
-
Interleukin-1 receptor-associated kinase-1
- KC:
-
Kupffer cells
- Ldlr:
-
Low-density lipoprotein receptor
- LPS:
-
Lipopolysaccharide
- MDA:
-
Malondialdehyde
- NADH:
-
Nicotinamide adenine dinucleotide
- NAFLD:
-
Nonalcoholic fatty liver disease
- NASH:
-
Nonalcoholic steatohepatitis
- NFE2L2:
-
Nuclear factor (erythroid-derived 2)-like 2
- NF-κB:
-
Nuclear factor kappa-light-chain-enhancer of activated B cells
- NLRP3:
-
Nucleotide-binding domain, leucine-rich repeat family, pyrin domain-containing 3
- NOX:
-
NADPH oxidase
- O2:
-
Oxygen
- O2•−:
-
Superoxide anion
- PDGF:
-
Platelet-derived growth factor
- PDI:
-
Protein disulfide isomerase
- PERK:
-
Protein kinase R (PKR)-like endoplasmic reticulum kinase
- ROS:
-
Reactive oxygen species
- TGF-β:
-
Transforming growth factor beta
- TLR:
-
Toll-like receptor
- TNF-α:
-
Tumor necrosis factor alpha
- UPR:
-
Unfolded protein response
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This work was supported by ZonMw (grant number: 114021010), China Scholarship Council, and Lundbeckfonden (grant number: R231-2016-2344).
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T. Luangmonkong and S. Suriguga, searching, analyzing, and selecting publications and drafting and editing of the manuscript; H. A. M. Mutsaers and G. Groothuis, revising of the manuscript for important intellectual content; P. Olinga, supervising the scope of the manuscript and revising the manuscript for important intellectual content; M. Boersema, reviewing the drafted manuscript and contributing important intellectual content to the final manuscript.
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Luangmonkong, T., Suriguga, S., Mutsaers, H.A.M., Groothuis, G.M.M., Olinga, P., Boersema, M. (2018). Targeting Oxidative Stress for the Treatment of Liver Fibrosis. In: Nilius, B., de Tombe, P., Gudermann, T., Jahn, R., Lill, R. (eds) Reviews of Physiology, Biochemistry and Pharmacology, Vol. 175. Reviews of Physiology, Biochemistry and Pharmacology, vol 175. Springer, Cham. https://doi.org/10.1007/112_2018_10
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