Abstract
IntroductionRecent 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.MethodsChronic 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.ResultsInjections 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.ConclusionsPTU, 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.
Highlights
Recent advances suggest that the cellular redox state may play a significant role in the progression of fibrosis in systemic sclerosis (SSc)
Propylthiouracil treatment prevents hypochlorous acid (HOCl)-induced pulmonary fibrosis We investigated whether PTU affects HOClinduced pulmonary fibrosis
High levels of vascular endothelial growth factor (VEGF), p-extracellular signal-related kinase (ERK), RAS, and RHO in cutaneous and pulmonary tissues of HOCl-treated mice are reduced by propylthiouracil treatment Higher amounts of VEGF, p-ERK, RAS, and RHO proteins were found both in the skin (Figure 5) and in the lungs (Figure 6) of HOCl compared with Sham mice, as demonstrated with Western blot analyses
Summary
Recent advances suggest that the cellular redox state may play a significant role in the progression of fibrosis in systemic sclerosis (SSc). Whereas the association of Graves disease with SSc [10,11] is supported by case reports, the literature related to Hashimoto thyroiditis and hypothyroidism in general, either subclinical or symptomatic, in SSc patients is more robust [12]. It was recently demonstrated by Cianfarani et al [13] that thyroid-stimulating hormone (TSH)-receptor messenger RNA is consistently detected in both skin biopsies and cultured primary keratinocytes and, more interestingly, in dermal fibroblasts of patients with SSc. A previous report confirmed the occurrence of a state of oxidizing stress in relation to hyperthyroidism [14]
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