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

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Abstract

Introduction: Recent advances suggest that the cellular redox state may play a significantrole in the progression of fibrosis in systemic sclerosis (SSc). Another,and as yet poorly accounted for, feature of SSc is its overlap with thyroidabnormalities. Previous reports demonstrate that hypothyroidism reducesoxidant stress. The aim of this study was therefore to evaluate the effectof propylthiouracil (PTU), and of the hypothyroidism induced by it, on thedevelopment of cutaneous and pulmonary fibrosis in the oxidant stress murinemodel of SSc.Methods: Chronic oxidant stress SSc was induced in BALB/c mice by daily subcutaneousinjections 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 administrationwas initiated 30 minutes after HOCl subcutaneous injection and continueddaily for 6 weeks. Skin and lung fibrosis were evaluated by histologicmethods. Immunohistochemical staining for alpha-smooth muscle actin(α-SMA) in cutaneous and pulmonary tissues was performed to evaluatemyofibroblast differentiation. Lung and skin concentrations of vascularendothelial growth factor (VEGF), extracellular signal-related kinase (ERK),rat sarcoma protein (Ras), Ras homolog gene family (Rho), and transforminggrowth factor (TGF) β were analyzed by Western blot.Results: Injections of HOCl induced cutaneous and lung fibrosis in BALB/c mice. PTUtreatment prevented both dermal and pulmonary fibrosis. Myofibroblastdifferentiation was also inhibited by PTU in the skin and lung. The increasein cutaneous and pulmonary expression of VEGF, ERK, Ras, and Rho in micetreated with HOCl was significantly prevented in mice co-administered////with PTU.Conclusions: PTU, probably through its direct effect on reactive oxygen species orindirectly through thyroid function inhibition, prevents the development ofcutaneous and pulmonary fibrosis by blocking the activation of the Ras-ERKpathway in the oxidant-stress animal model of SSc. © 2013 Bagnato et al.; licensee BioMed Central Ltd.

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Bagnato, G., Bitto, A., Irrera, N., Pizzino, G., Sangari, D., Cinquegrani, M., … Saitta, A. (2013). Propylthiouracil prevents cutaneous and pulmonary fibrosis in the reactive oxygen species murine model of systemic sclerosis. Arthritis Research and Therapy, 15(5). https://doi.org/10.1186/ar4300

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