title: Propylthiouracil prevents cutaneous and pulmonary fibrosis in the reactive oxygen species murine model of systemic sclerosis.
abstract: BACKGROUND
  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.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Bagnato
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bitto
authors.forename: Natasha
authors.initials: N
authors.lastname: Irrera
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pizzino
authors.forename: Donatella
authors.initials: D
authors.lastname: Sangari
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cinquegrani
authors.forename: William
authors.initials: W
authors.lastname: Roberts
authors.forename: Marco
authors.initials: M
authors.lastname: Atteritano
authors.forename: Domenica
authors.initials: D
authors.lastname: Altavilla
authors.forename: Francesco
authors.initials: F
authors.lastname: Squadrito
authors.forename: Gianfilippo
authors.initials: G
authors.lastname: Bagnato
authors.forename: Antonino
authors.initials: A
authors.lastname: Saitta
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D013956:Antithyroid Agents / Q000494:pharmacology / Q000633:toxicity; D015153:Blotting, Western; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005355:Fibrosis / Q000150:complications / Q000378:metabolism / Q000517:prevention & control; D006997:Hypochlorous Acid; D007037:Hypothyroidism / Q000097:blood / Q000139:chemically induced; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D009130:Muscle, Smooth / Q000737:chemistry; D016877:Oxidants; D011441:Propylthiouracil / Q000494:pharmacology* / Q000633:toxicity; D011658:Pulmonary Fibrosis / Q000150:complications / Q000378:metabolism / Q000517:prevention & control*; D011897:Random Allocation; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood; D014284:Triiodothyronine / Q000097:blood; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000199:Actins; D013956:Antithyroid Agents; D016877:Oxidants; D042461:Vascular Endothelial Growth Factor A; D014284:Triiodothyronine; D006997:Hypochlorous Acid; D011441:Propylthiouracil; D013972:Thyrotropin; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins; D013974:Thyroxine