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

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 hypothyroi...

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Autores principales: Bagnato, Gianluca, Bitto, Alessandra, Irrera, Natasha, Pizzino, Gabriele, Sangari, Donatella, Cinquegrani, Maurizio, Roberts, William Neal, Atteritano, Marco, Altavilla, Domenica, Squadrito, Francesco, Bagnato, Gianfilippo, Saitta, Antonino
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3978728/
https://www.ncbi.nlm.nih.gov/pubmed/24286160
http://dx.doi.org/10.1186/ar4300
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author Bagnato, Gianluca
Bitto, Alessandra
Irrera, Natasha
Pizzino, Gabriele
Sangari, Donatella
Cinquegrani, Maurizio
Roberts, William Neal
Atteritano, Marco
Altavilla, Domenica
Squadrito, Francesco
Bagnato, Gianfilippo
Saitta, Antonino
author_facet Bagnato, Gianluca
Bitto, Alessandra
Irrera, Natasha
Pizzino, Gabriele
Sangari, Donatella
Cinquegrani, Maurizio
Roberts, William Neal
Atteritano, Marco
Altavilla, Domenica
Squadrito, Francesco
Bagnato, Gianfilippo
Saitta, Antonino
author_sort Bagnato, Gianluca
collection PubMed
description 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.
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spelling pubmed-39787282014-04-09 Propylthiouracil prevents cutaneous and pulmonary fibrosis in the reactive oxygen species murine model of systemic sclerosis Bagnato, Gianluca Bitto, Alessandra Irrera, Natasha Pizzino, Gabriele Sangari, Donatella Cinquegrani, Maurizio Roberts, William Neal Atteritano, Marco Altavilla, Domenica Squadrito, Francesco Bagnato, Gianfilippo Saitta, Antonino Arthritis Res Ther Research Article 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. BioMed Central 2013 2013-09-16 /pmc/articles/PMC3978728/ /pubmed/24286160 http://dx.doi.org/10.1186/ar4300 Text en Copyright © 2013 Bagnato et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Bagnato, Gianluca
Bitto, Alessandra
Irrera, Natasha
Pizzino, Gabriele
Sangari, Donatella
Cinquegrani, Maurizio
Roberts, William Neal
Atteritano, Marco
Altavilla, Domenica
Squadrito, Francesco
Bagnato, Gianfilippo
Saitta, Antonino
Propylthiouracil prevents cutaneous and pulmonary fibrosis in the reactive oxygen species murine model of systemic sclerosis
title Propylthiouracil prevents cutaneous and pulmonary fibrosis in the reactive oxygen species murine model of systemic sclerosis
title_full Propylthiouracil prevents cutaneous and pulmonary fibrosis in the reactive oxygen species murine model of systemic sclerosis
title_fullStr Propylthiouracil prevents cutaneous and pulmonary fibrosis in the reactive oxygen species murine model of systemic sclerosis
title_full_unstemmed Propylthiouracil prevents cutaneous and pulmonary fibrosis in the reactive oxygen species murine model of systemic sclerosis
title_short Propylthiouracil prevents cutaneous and pulmonary fibrosis in the reactive oxygen species murine model of systemic sclerosis
title_sort propylthiouracil prevents cutaneous and pulmonary fibrosis in the reactive oxygen species murine model of systemic sclerosis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3978728/
https://www.ncbi.nlm.nih.gov/pubmed/24286160
http://dx.doi.org/10.1186/ar4300
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