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

2018; Elsevier BV; Volume: 99; Issue: 4 Linguagem: Inglês

10.1038/s41374-018-0161-1

1530-0307

Peter J. Wermuth, Fabian A. Mendoza, Sergio A. Jiménez,

Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis

Excessive connective tissue deposition in skin and various internal organs is characteristic of systemic sclerosis (SSc). The profibrotic growth factor TGF-β 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-β. Here, we evaluated the effect of NOX4 on the development of TGF-β-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-β1. 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-β1 showed profound dermal fibrosis and peribronchial and diffuse interstitial lung fibrosis. In contrast, TGF-β-treated Nox4 knockout mice showed normal skin and lung histology. Hydroxyproline levels in TGF-β-treated C57BL6/J mice skin and lungs demonstrated significant increases, however, hydroxyproline content of TGF-β-treated Nox4 knockout mice tissues was not changed. Expression of various profibrotic and fibrosis-associated genes was upregulated in skin and lungs of TGF-β1-treated C57BL6/J mice but was not significantly changed in TGF-β1-treated Nox4 knockout mice. The induction of skin and lung tissue fibrosis by TGF-β1 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-β. These results suggest Nox4 inhibition as a potential therapeutic target for SSc and other fibroproliferative disorders.