Oxidative stress and glutathione in TGF-β-mediated fibrogenesis

doi:10.1016/j.freeradbiomed.2009.09.026

Free Radical Biology and Medicine

Volume 48, Issue 1, 1 January 2010, Pages 1-15

https://doi.org/10.1016/j.freeradbiomed.2009.09.026 Get rights and content

Abstract

Transforming growth factor β (TGF-β) is the most potent and ubiquitous profibrogenic cytokine, and its expression is increased in almost all the fibrotic diseases and in experimental fibrosis models. TGF-β increases reactive oxygen species production and decreases the concentration of glutathione (GSH), the most abundant intracellular free thiol and an important antioxidant, which mediates many of the fibrogenic effects of TGF-β in various types of cells. A decreased GSH concentration is also observed in human fibrotic diseases and in experimental fibrosis models. Although the biological significance of GSH depletion in the development of fibrosis remains obscure, GSH and N-acetylcysteine, a precursor of GSH, have been used in clinics for the treatment of fibrotic diseases. This review summarizes recent findings in the field to address the potential mechanism whereby oxidative stress mediates fibrogenesis induced by TGF-β and the potential therapeutic value of antioxidant treatment in fibrotic diseases.

Introduction

Fibrosis, characterized by increased deposition of extracellular matrix (ECM) proteins in basement membrane and interstitial tissue, is a common pathological feature and terminal stage of many diseases involved in almost all the organ systems. Currently, there is no FDA-approved antifibrotic drug or efficacious treatment for fibrotic disease because of an incomplete understanding of the underlying pathogenesis. Many cytokines, chemokines, and growth factors are involved in the development of fibrosis; however, transforming growth factor β (TGF-β) is considered to be the most potent and ubiquitous profibrogenic cytokine. TGF-β stimulates the production of reactive oxygen species (ROS) in various types of cells, whereas ROS activate TGF-β and mediate many of the fibrogenic effects of TGF-β. Glutathione (GSH), a tripeptide, is the most abundant intracellular free thiol and an important antioxidant. GSH concentration decreases in experimental fibrosis models and in human fibrotic diseases. The mechanism and biological significance of GSH depletion in fibrotic diseases, however, remains unclear. Importantly, TGF-β administration decreases GSH in various types of cells in vitro, whereas GSH replenishment suppresses the fibrogenic activity of TGF-β, suggesting an important role for GSH depletion in TGF-β-induced fibrogenesis. Nonetheless, although intensive studies have been conducted, the molecular mechanism underlying stimulation of ROS production by TGF-β and whereby ROS mediate the fibrogenic effects of TGF-β remains obscure. This review is intended to summarize recent studies to address the role of oxidative stress and GSH depletion in TGF-β-induced fibrogenesis, the underlying molecular mechanism, and the potential therapeutic value of antioxidant treatment in fibrotic diseases.

Section snippets

Increased oxidative stress is a common pathological feature of fibrosis

There is a substantial body of evidence supporting the hypothesis that increased oxidative stress plays an important role in the development of fibrotic diseases in humans. The lung is a major target for oxidant damage because of its direct exposure to the atmosphere. Accumulating evidence suggests that oxidants generated endogenously or inhaled from the environment play an essential role in the pathogenesis of various pulmonary fibrotic disorders, including idiopathic pulmonary fibrosis (IPF),

TGF-β and fibrosis

TGF-β, existing in three isoforms (TGF-β1, TGF-β2, and TGF-β3), is a multiple-function protein involved in the regulation of cell proliferation, differentiation, apoptosis, adhesion, and migration and therefore plays a pivotal role in the pathogenesis of many diseases. Various cytokines, chemokines, and growth factors are involved in the development of fibrosis; however, TGF-β is considered to be the most potent and ubiquitous profibrogenic cytokine. TGF-β mRNA and/or protein expression is

Glutathione: functions and homeostasis

Glutathione, a tripeptide, is the most abundant intracellular free thiol. GSH plays a critical role in regulating a variety of cellular functions, including detoxification of xenobiotics, synthesis of DNA and other endogenous compounds, modulation of gene expression, and regulation of the cell cycle. However, the most important and well-known function of GSH is antioxidant defense. Glutathione can reduce hydrogen peroxide and lipid peroxide through GPx-catalyzed reactions and can conjugate and

Antifibrotic effects of NAC and GSH in animal models

As GSH concentration decreases in many fibrotic diseases and in experimental fibrosis models, it is reasonable to assume that treatments that increase the concentration of GSH and other antioxidants in the target tissue would prevent the progression of fibrotic diseases. Numerous studies have been conducted to elucidate the antifibrotic potential of thiol reagents in experimental fibrosis models. NAC, which easily passes through the cell membrane and is hydrolyzed intracellularly to donate

Conclusion

ROS/RNS play important roles in the development of fibrosis and in TGF-β-mediated fibrogenesis. The molecular mechanism by which ROS/RNS mediate TGF-β-induced fibrosis, however, remains undetermined. GSH is the most abundant intracellular free thiol and an important antioxidant. GSH concentration decreases in the fibrotic diseases and in experimental fibrosis models. Although TGF-β decreases GSH in various types of cells in vitro, whether increased TGF-β expression is responsible for the

Acknowledgments

The work was supported by grants from the National Institute of Environmental Health Sciences (NIH ES011831 and NHLBI 5R01HL088141-02) and a grant from the American Lung Association (CI-1190-N) to R-M. Liu.

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Review ArticleOxidative stress and glutathione in TGF-β-mediated fibrogenesis

Abstract

Introduction

Section snippets

Increased oxidative stress is a common pathological feature of fibrosis

TGF-β and fibrosis

Glutathione: functions and homeostasis

Antifibrotic effects of NAC and GSH in animal models

Conclusion

Acknowledgments

Chest

Cell

Pulm. Pharmacol. Ther.

J. Hepatol.

J. Hepatol.

Am. J. Gastroenterol.

Clin. Liver Dis.

Hepatol. Res.

Free Radic. Biol. Med.

Free Radic. Biol. Med.

Clinics Liver Dis. Hepatic Fibr.

Thromb. Res.

Am. J. Transplant

Am. J. Med. Sci.

Respir. Med.

Int. J. Radiat. Oncol. Biol. Phys.

Exp. Mol. Pathol.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Hepatol.

Biochim. Biophys. Acta

Free Radic. Biol. Med.

Increased exhalation of hydrogen peroxide in patients with stable and unstable chronic obstructive pulmonary disease

Am. J. Respir. Crit. Care Med.

Systemic oxidative stress in asthma, COPD, and smokers

Am. J. Respir. Crit. Care Med.

Chronic obstructive pulmonary disease is associated with an increase in urinary levels of isoprostane F2alpha-III, an index of oxidant stress

Am. J. Respir. Crit. Care Med.

Oxidative stress and respiratory muscle dysfunction in severe chronic obstructive pulmonary disease

Am. J. Respir. Crit. Care Med.

Genetically increased antioxidative protection and decreased chronic obstructive pulmonary disease

Am. J. Respir. Crit. Care Med.

The effect of different treatment modalities on oxidative stress in COPD

Adv. Ther.

Airway biomarkers of the oxidant burden in asthma and chronic obstructive pulmonary disease: current and future perspectives

Int. J. Chronic Obstruct. Pulm. Dis.

Increased levels of oxidized methionine residues in bronchoalveolar lavage fluid proteins from patients with idiopathic pulmonary fibrosis

Am. Rev. Respir. Dis.

Carbonylated proteins in bronchoalveolar lavage of patients with sarcoidosis, pulmonary fibrosis associated with systemic sclerosis and idiopathic pulmonary fibrosis

Proteomics

Exhaled markers of oxidative stress in idiopathic pulmonary fibrosis

Eur. J. Clin. Invest.

Free radicals in exhaled breath condensate in cystic fibrosis and healthy subjects

Free Radic. Res.

Oxidative stress and lipid-derived inflammatory mediators during acute exacerbations of cystic fibrosis

Respirology

8-Hydroxydeoxyguanosine in leukocyte DNA and urine of quartz-exposed workers and patients with silicosis

Int. Arch. Occup. Environ. Health

Urinary 8-hydroxy-2′-deoxyguanosine as a biomarker of oxidative DNA damage in workers exposed to fine particulates

Environ. Health Perspect.

Increased 8-isoprostane, a marker of oxidative stress in exhaled breath condensate in subjects with asbestos exposure

Ind. Health

Crucial role of interleukin-1beta and nitric oxide synthase in silica-induced inflammation and apoptosis in mice

Am. J. Respir. Crit. Care Med.

Nitric oxide and reactive oxygen species production causes progressive damage in rats after cessation of silica inhalation

Toxicol. Sci.

Heme oxygenase-1, a potential biomarker of chronic silicosis, attenuates silica-induced lung injury

Am. J. Respir. Crit. Care Med.

The absence of reactive oxygen species production protects mice against bleomycin-induced pulmonary fibrosis

Respir. Res.

Therapeutic effects of alpha-lipoic acid on bleomycin-induced pulmonary fibrosis in rats

Int. J. Mol. Med.

Oxidation of extracellular cysteine/cystine redox state in bleomycin-induced lung fibrosis

Am. J. Physiol. Lung Cell Mol. Physiol.

Mechanisms of alcohol-induced hepatic fibrosis: a summary of the Ron Thurman Symposium

Hepatology

Oxidative stress in alcoholic liver disease: role of NADPH oxidase complex

J. Gastroenterol. Hepatol.

Evaluation of blood oxidative stress-related parameters in alcoholic liver disease and non-alcoholic fatty liver disease

Scand. J. Clin. Lab. Invest.

Review Article
Oxidative stress and glutathione in TGF-β-mediated fibrogenesis