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Open Access Research article

Propylthiouracil prevents cutaneous and pulmonary fibrosis in the reactive oxygen species murine model of systemic sclerosis

Gianluca Bagnato1*, Alessandra Bitto2, Natasha Irrera2, Gabriele Pizzino2, Donatella Sangari3, Maurizio Cinquegrani1, William Neal Roberts4, Marco Atteritano3, Domenica Altavilla2, Francesco Squadrito2, Gianfilippo Bagnato3 and Antonino Saitta1

Author Affiliations

1 Department of Clinical and Experimental Medicine, Division of Internal Medicine, University of Messina, Via Consolare Valeria n°1, 98100, Messina, Italy

2 Department of Clinical and Experimental Medicine, Division of Pharmacology, University of Messina, Via Consolare Valeria n°1, 98100, Messina, Italy

3 Department of Clinical and Experimental Medicine, Division of Rheumatology, University of Messina, Via Consolare Valeria n°1, 98100, Messina, Italy

4 Department of Internal Medicine, Division of Rheumatology, University of Louisville, Louisville, KY 40292, Kentucky, USA

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Arthritis Research & Therapy 2013, 15:R120  doi:10.1186/ar4300

Published: 16 September 2013

Abstract

Introduction

Recent advances suggest that the cellular redox state may play a significant role in the progression of fibrosis in systemic sclerosis (SSc). Another, and as yet poorly accounted for, feature of SSc is its overlap with thyroid abnormalities. Previous reports demonstrate that hypothyroidism reduces oxidant stress. The aim of this study was therefore to evaluate the effect of propylthiouracil (PTU), and of the hypothyroidism induced by it, on the development of cutaneous and pulmonary fibrosis in the oxidant stress murine model of SSc.

Methods

Chronic oxidant stress SSc was induced in BALB/c mice by daily subcutaneous injections of hypochlorous acid (HOCl) for 6 weeks. Mice (n = 25) were randomized into three arms: HOCl (n = 10), HOCl plus PTU (n = 10) or vehicle alone (n = 5). PTU administration was initiated 30 minutes after HOCl subcutaneous injection and continued daily for 6 weeks. Skin and lung fibrosis were evaluated by histologic methods. Immunohistochemical staining for alpha-smooth muscle actin (α-SMA) in cutaneous and pulmonary tissues was performed to evaluate myofibroblast differentiation. Lung and skin concentrations of vascular endothelial growth factor (VEGF), extracellular signal-related kinase (ERK), rat sarcoma protein (Ras), Ras homolog gene family (Rho), and transforming growth factor (TGF) β were analyzed by Western blot.

Results

Injections of HOCl induced cutaneous and lung fibrosis in BALB/c mice. PTU treatment prevented both dermal and pulmonary fibrosis. Myofibroblast differentiation was also inhibited by PTU in the skin and lung. The increase in cutaneous and pulmonary expression of VEGF, ERK, Ras, and Rho in mice treated with HOCl was significantly prevented in mice co-administered ////with PTU.

Conclusions

PTU, probably through its direct effect on reactive oxygen species or indirectly through thyroid function inhibition, prevents the development of cutaneous and pulmonary fibrosis by blocking the activation of the Ras-ERK pathway in the oxidant-stress animal model of SSc.