%0 Journal Article
%T Abrogation of transforming growth factor-¦Â-induced tissue fibrosis in mice with a global genetic deletion of Nox4
%J -
%D 2018
%R https://doi.org/10.1038/s41374-018-0161-1
%X Excessive connective tissue deposition in skin and various internal organs is characteristic of systemic sclerosis (SSc). The profibrotic growth factor TGF-¦Â plays a crucial role in SSc pathogenesis. The expression of NADPH oxidase 4 (NOX4), a critical mediator of oxidative stress, is potently stimulated by TGF-¦Â. Here, we evaluated the effect of NOX4 on the development of TGF-¦Â-induced tissue fibrosis. C57BL6/J control mice and Nox4 knockout mice were implanted subcutaneously with osmotic pumps containing either saline or 2.5£¿¦Ìg TGF-¦Â1. After 28 days, skin and lung samples were isolated for histopathologic analysis, measurement of hydroxyproline content and gene expression analysis. Histopathology of skin and lungs from normal C57BL6/J mice treated with TGF-¦Â1 showed profound dermal fibrosis and peribronchial and diffuse interstitial lung fibrosis. In contrast, TGF-¦Â-treated Nox4 knockout mice showed normal skin and lung histology. Hydroxyproline levels in TGF-¦Â-treated C57BL6/J mice skin and lungs demonstrated significant increases, however, hydroxyproline content of TGF-¦Â-treated Nox4 knockout mice tissues was not changed. Expression of various profibrotic and fibrosis-associated genes was upregulated in skin and lungs of TGF-¦Â1-treated C57BL6/J mice but was not significantly changed in TGF-¦Â1-treated Nox4 knockout mice. The induction of skin and lung tissue fibrosis by TGF-¦Â1 parenteral administration in mice was abrogated by the genetic deletion of Nox4 confirming that NOX4 is an essential mediator of the profibrotic effects of TGF-¦Â. These results suggest Nox4 inhibition as a potential therapeutic target for SSc and other fibroproliferative disorders
%U https://www.nature.com/articles/s41374-018-0161-1