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. |