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Abstract
Numerous clinical and research investigations conducted during the last two decades have implicated excessive oxidative stress caused by high levels of reactive oxygen species (ROS) in the development of the severe and frequently progressive fibrotic process in Systemic Sclerosis (SSc). The role of excessive oxidative stress in SSc pathogenesis has been supported by the demonstration of increased levels of numerous biomarkers, indicative of cellular and molecular oxidative damage in serum, plasma, and other biological fluids from SSc patients, and by the demonstration of elevated production of ROS by various cell types involved in the SSc fibrotic process. However, the precise mechanisms mediating oxidative stress development in SSc and its pathogenetic effects have not been fully elucidated. The participation of the NADPH oxidase NOX4, has been suggested and experimentally supported by the demonstration that SSc dermal fibroblasts display constitutively increased NOX4 expression and that reduction or abrogation of NOX4 effects decreased ROS production and the expression of genes encoding fibrotic proteins. Furthermore, NOX4-stimulated ROS production may be involved in the development of certain endothelial and vascular abnormalities and may even participate in the generation of SSc-specific autoantibodies. Collectively, these observations suggest NOX4 as a novel therapeutic target for SSc.
Highlights
The most severe clinical and pathologic manifestations of Systemic Sclerosis (SSc) are the result of a fibrotic process characterized by the excessive and often progressive deposition of collagen and other extracellular matrix (ECM) macromolecules in skin and numerous internal organs [1,2,3,4]
This study showed that reactive oxygen species (ROS) production was significantly higher in SSc fibroblasts, whereas protein tyrosine phosphatase 1B (PTP1B) activity was significantly reduced in these cells
To directly examine the role of NOX4 on the expression of genes encoding ECM molecules and on the levels of production of type I collagen in SSc, cultured SSc dermal fibroblasts were transfected with specific siRNA against NOX4 resulting in a 60% reduction of NOX4 mRNA
Summary
The most severe clinical and pathologic manifestations of Systemic Sclerosis (SSc) are the result of a fibrotic process characterized by the excessive and often progressive deposition of collagen and other extracellular matrix (ECM) macromolecules in skin and numerous internal organs [1,2,3,4]. In 1993, Murrell proposed a novel hypothesis to explain the pathogenesis of tissue fibrosis in various fibrotic disorders, including SSc. The hypothesis suggested that elevated oxygen free radicals caused abnormally increased systemic oxidative stress, which resulted in cellular and molecular alterations that induced tissue fibrosis [7]. Reactive oxygen species (ROS) are produced by normal cells and are essential for multiple normal cellular functions, excessive oxidative stress mediated by the uncontrolled production of deleterious ROS has been implicated in the pathogenesis of SSc [7,8,9,10,11,12,13,14,15,16], pulmonary fibrosis [17,18] and several other human fibrotic disorders [19,20]
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