Abrogation of transforming growth factor-?-induced tissue fibrosis in mice with a global genetic deletion of Nox4.

ABSTRACT: Excessive connective tissue deposition in skin and various internal organs is characteristic of systemic sclerosis (SSc). The profibrotic growth factor TGF-? 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-?. Here, we evaluated the effect of NOX4 on the development of TGF-?-induced tissue fibrosis. C57BL6/J control mice and Nox4 knockout mice were implanted subcutaneously with osmotic pumps containing either saline or 2.5?µg TGF-?1. 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-?1 showed profound dermal fibrosis and peribronchial and diffuse interstitial lung fibrosis. In contrast, TGF-?-treated Nox4 knockout mice showed normal skin and lung histology. Hydroxyproline levels in TGF-?-treated C57BL6/J mice skin and lungs demonstrated significant increases, however, hydroxyproline content of TGF-?-treated Nox4 knockout mice tissues was not changed. Expression of various profibrotic and fibrosis-associated genes was upregulated in skin and lungs of TGF-?1-treated C57BL6/J mice but was not significantly changed in TGF-?1-treated Nox4 knockout mice. The induction of skin and lung tissue fibrosis by TGF-?1 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-?. These results suggest Nox4 inhibition as a potential therapeutic target for SSc and other fibroproliferative disorders.

SUBMITTER: Wermuth PJ 

PROVIDER: S-EPMC6530913 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature