squeegee
Banned
- Reaction score
- 132
Abstract
Transforming growth factor beta (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 ROS production and decreases the concentration of glutathione (GSH), the most abundant intracellular free thiol and an important antioxidant, in various types of cells, which mediates many of TGF-β’s fibrogenic effects. 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 (NAC), 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 TGF-β’s fibrogenesis and the potential therapeutic values of antioxidant treatment in fibrotic diseases.
NTRODUCTION
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 due to incomplete understanding of underlying pathogenesis. Many cytokines, chemokines, and growth factors are involved in the development of fibrosis; however, transforming growth factor beta (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, while ROS activate TGF-β and mediate many of TGF-β’s fibrogenic effects. 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 while GSH replenishment suppresses TGF-β’s fibrogenic activity, suggesting an important role of GSH depletion in TGF-β’s fibrogenesis. Nonetheless, although intensive studies have been conducted, the molecular mechanism underlying stimulation of ROS production by TGF-β and whereby ROS mediate TGF-β’s fibrogenic effects remains obscure. This review is intended to summarize recent studies to address the role of oxidative stress and GSH depletion in TGF-β’s fibrogenesis, the underlying molecular mechanism, and the potential therapeutic value of antioxidant treatment in fibrotic diseases.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2818240/
Transforming growth factor beta (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 ROS production and decreases the concentration of glutathione (GSH), the most abundant intracellular free thiol and an important antioxidant, in various types of cells, which mediates many of TGF-β’s fibrogenic effects. 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 (NAC), 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 TGF-β’s fibrogenesis and the potential therapeutic values of antioxidant treatment in fibrotic diseases.
NTRODUCTION
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 due to incomplete understanding of underlying pathogenesis. Many cytokines, chemokines, and growth factors are involved in the development of fibrosis; however, transforming growth factor beta (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, while ROS activate TGF-β and mediate many of TGF-β’s fibrogenic effects. 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 while GSH replenishment suppresses TGF-β’s fibrogenic activity, suggesting an important role of GSH depletion in TGF-β’s fibrogenesis. Nonetheless, although intensive studies have been conducted, the molecular mechanism underlying stimulation of ROS production by TGF-β and whereby ROS mediate TGF-β’s fibrogenic effects remains obscure. This review is intended to summarize recent studies to address the role of oxidative stress and GSH depletion in TGF-β’s fibrogenesis, the underlying molecular mechanism, and the potential therapeutic value of antioxidant treatment in fibrotic diseases.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2818240/