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A perverse cycle for fibrosis. Abstract. Transforming growth factor beta (TGF- β) is the most potent pro- fibrogenic cytokine and its expression is increased in almost all of fibrotic diseases. Although signaling through Smad pathway is believed to play a central role in TGF- β's fibrogenesis, emerging evidence indicates that reactive oxygen species (ROS) modulate TGF- β's signaling through different pathways including Smad pathway. TGF- β1 increases ROS production and suppresses antioxidant enzymes, leading to a redox imbalance. ROS, in turn, induce/activate TGF- β1 and mediate many of TGF- β's fibrogenic effects, forming a vicious cycle (see graphic flow chart on the right). Here, we review the current knowledge on the feed- forward mechanisms between TGF- β1 and ROS in the development of fibrosis. Therapeutics targeting TGF- β- induced and ROS- dependent cellular signaling represents a novel approach in the treatment of fibrotic disorders.

Keywords: TGF- β, Oxidative stress, Fibrosis, NADPH oxidases, PAI- 1. Graphical abstract. Introduction. Transforming growth factor beta (TGF- β), the most potent and ubiquitous profibrogenic cytokine, plays a central role in the development of fibrosis involving almost all organ systems [1], [2], [3], [4]. Although TGF- β1 signaling through Smad pathway is believed to be responsible for the induction of many of TGF- β's responsive genes emerging evidence indicates that reactive oxygen (ROS) mediate TGF- β's signaling through different pathways including Smad pathway, mitogen activated protein kinase (MAPK) pathways, and Rho- GTPase pathway.

TGF- β1 increases the production of ROS by impairing mitochondrial function and inducing NADPH oxidases (NOXs), mainly Nox. NOX expressed by many different types of cells.

TGF- β also suppresses antioxidant system including the synthesis of glutathione (GSH), the most abundant intracellular free thiol and an important antioxidant, and several other antioxidant enzymes, leading to oxidative stress or redox imbalance. Such a redox imbalance in turn induces/activates TGF- β1 and mediates TGF- β's fibrogenic effects [5]. In this review, we will focus on the mechanisms whereby TGF- β induces Nox. ROS activate/induce TGF- β and mediate TGF- β's fibrogenic effects. Suppression of TGF- β- induced ROS production may break this vicious cycle and have therapeutic potential for the treatment of fibrotic disorders. TGF- β1 and fibrosis.

Fibrosis is characterized by increased deposition of extracellular matrix (ECM) proteins in the interstitial, leading to stiffness and loss of organ architecture and function. Fibrosis affects almost all organ systems and accounts for 4. Many cytokines/chemokines/growth factors contribute to the development of fibrosis; however, TGF- β is considered to be the most potent and ubiquitous profibrogenic cytokine. TGF- β m. RNA and/or protein expression is increased in almost all fibrotic diseases involved in different organ systems and in experimental fibrosis models [6], [7], [8], [9], [1.

Overexpression of TGF- β induces [1. TGF- β binding proteins, anti- TGF- β antibody, or an inhibitor to TGF- β type I receptor ALK5 ameliorated fibrosis [2. All these lines of evidence suggest that TGF- β plays a pivotal role in the development of fibrosis. Although it has been well documented that TGF- β exits its profibrogenic activity through activating fibroblasts, a recent study shows that epithelium- specific deletion of TGF- β receptor type II protects mice from bleomycin- induced lung fibrosis, suggesting that TGF- β signaling in epithelial cells is also important for its fibrogenic effects [3.

TGF- β, existing in three isoforms, TGFβ1, TGFβ2, and TGFβ3, is secreted by many different types of cells and involved in various cell functions including cell proliferation, differentiation, apoptosis, adhesion, and migration. Although all three isoforms are expressed in fibrotic tissues, the development of lung fibrosis is primarily attributed to TGFβ1 [3. TGF- β1 signaling through Smad pathway, the canonical pathway, has been well described. Active TGF- β binds to type II receptor (TGFβR- II) on the cell membrane, which activates type I receptor (TGFβR- I), leading to phosphorylation of Smad.

Smad. 3. Phosphorylated Smad. Smad. 3 then form a complex with common mediator Smad (Co- Smad), Smad. Smad binding elements present in the promoter of the target genes [3. There are 7 mammalian type I receptors, termed ALK1- 7 (activin receptor- like kinase 1- 7) and TGF- β1 signaling mainly through ALK- 5 [3.

Inhibitory Smads, Smad. Smad. 7, on the other hand, negatively regulate TGF- β signaling by binding to type I receptor or by competing with Smad.

Smad. 4 [3. 8], [3. Numerous studies have shown that TGF- β1 plays a central role in the development of fibrosis in many tissues/organs under various pathological conditions through ALK- 5 and Smad. The counter- regulatory role of Smad. Besides Smad pathways, studies have shown that TGF- β signaling through other non- canonical pathways, including mitogen activated protein kinase (MAPK) pathways, phosphatidylinositol- 3- kinase (PI3. K) pathway, and Rho- like GTPase pathways, are also critical for eliciting TGF- β's profibrogenic activity [2. TGF- β has been shown to activate MAPK pathways through TGF- β- activated kinase 1 (TAK1), a MAPK kinase kinase, or through Ras [3. Importantly, it has been well documented that MAPK pathways are redox sensitivity, although the redox sensitivity molecules in these pathways remain to be identified.

Rho- GTPases, a subfamily of small GTP- binding proteins within the Ras superfamily, regulates actin cytoskeleton, cell shape, adhesion, and migration. Rho- GTPase and its downstream effector ROCK have been shown to be involved in TGF- β- induced myofibroblast differentiation [6.

Interestingly, it has been reported that ROS derived from mitochondria, NADPH oxidases, or other sources activate Rho. A [6. 8], [6. 9], [7. Nox. 4- derived ROS mediate TGF- β1- induced kidney myofibroblast differentiation through activating Rho. A/Rho kinase pathway [6.

TGF- β induces redox imbalance. Redox imbalance or oxidative stress results from an increased production of reactive oxygen or nitrogen species (ROS/RNS) and/or reduced antioxidant capacity. ROS/RNS such as superoxide, hydrogen peroxide (H2. O2), and nitric oxide (NO) are formed as a byproduct of the normal metabolism of oxygen and have important function in cell signaling and homeostasis.

Overproduction of ROS/RNS, however, contributes to the pathophysiology of many diseases. Biological systems have developed superior antioxidant mechanisms, enzymatic and non- enzymatic, to scavenge or remove ROS/RNS generated during normal metabolism or under pathological conditions. The enzymatic system comprises mainly the superoxide dismutases (SODs), catalase, glutathione peroxidase (GPx), and peroxiredoxin; whereas non- enzymatic system includes glutathione (GSH), ascorbic acid, β- carotene, and α- tocopherol. TGF- β has been shown to increase ROS production and suppress antioxidant system and thereby induce oxidative stress or redox imbalance. Such a redox imbalance contributes importantly to TGF- β's pathophysiologic effects including fibrosis [7. TGF- β increases mitochondrial ROS production.

Mitochondria are the major source of ROS in cells. TGF- β1 has been shown to increase mitochondrial ROS production in different types of cells, which mediate TGF- β- induced cell apoptosis [7. Ishikawa et al. reported that TGF- β increased ROS levels in the cytoplasm and mitochondria in mouse mammary epithelial cells (NMu. MG) and decreased mitochondrial membrane potential [8. Depletion of mitochondria (pseudo p. TGF- β- induced increase in intracellular ROS [8.