title: Simvastatin attenuates the development of pulmonary and cutaneous fibrosis in a murine model of systemic sclerosis.
abstract: OBJECTIVE
  The antifibrotic effect of simvastatin has been demonstrated in human lung fibroblasts. This study aimed to measure the effects of simvastatin in the development of pulmonary and cutaneous fibrosis in a murine model of SSc and to explore the mechanisms of these effects.
  
  
  METHODS
  Chronic oxidant stress SSc was induced in BALB/c mice by daily s.c. injections of HOCl for 6 weeks. Mice were randomized in three arms: treatment with HOCl, HOCl plus simvastatin or vehicle alone. Statin treatment was initiated 30 min after HOCl s.c. injection and continued daily for 6 weeks. Skin and lung fibrosis were evaluated by histological methods. Immunohistochemical staining for α-smooth muscle actin in cutaneous and pulmonary tissues was performed to evaluate myofibroblast differentiation. Lung and skin concentrations of VEGF, extracellular signal-related kinase (ERK), rat sarcoma protein (Ras), Ras homologue gene family (Rho) and TGF-β were analysed by western blot.
  
  
  RESULTS
  Injections of HOCl induced cutaneous and lung fibrosis in BALB/c mice. Simvastatin treatment prevented both skin thickness and pulmonary fibrosis. Myofibroblast differentiation was also inhibited by simvastatin in the skin and in the lung. Increased cutaneous and pulmonary expression of VEGF, ERK, Ras and Rho in mice treated with HOCl was significantly lower in mice treated with HOCl plus simvastatin.
  
  
  CONCLUSIONS
  Simvastatin reduces the development of pulmonary fibrosis, potentially modulating adverse lung remodelling, as shown by the reduced deposition of collagen in alveolar septae. Simvastatin also reduces skin thickness in this model.
authors.affiliation: Division of Internal Medicine, Department of Clinical and Experimental Medicine, University of Messina, 98100 Messina, Italy. gbagnato@unime.it
authors.forename: Gianluca
authors.initials: G
authors.lastname: Bagnato
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bitto
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pizzino
authors.forename: Natasha
authors.initials: N
authors.lastname: Irrera
authors.forename: Donatella
authors.initials: D
authors.lastname: Sangari
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cinquegrani
authors.forename: William Neal
authors.initials: WN
authors.lastname: Roberts
authors.forename: Marco
authors.initials: M
authors.lastname: Matucci Cerinic
authors.forename: Francesco
authors.initials: F
authors.lastname: Squadrito
authors.forename: Domenica
authors.initials: D
authors.lastname: Altavilla
authors.forename: Gianfilippo
authors.initials: G
authors.lastname: Bagnato
authors.forename: Antonino
authors.initials: A
authors.lastname: Saitta
mesh_terms: D000818:Animals; D001707:Biopsy, Needle; D015153:Blotting, Western; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D011658:Pulmonary Fibrosis / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D011897:Random Allocation; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000150:complications / Q000473:pathology*; D012680:Sensitivity and Specificity; D019821:Simvastatin / Q000494:pharmacology*; D012871:Skin Diseases / Q000209:etiology / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D019821:Simvastatin
keywords: animal model; pulmonary fibrosis; reactive oxygen species; simvastatin; systemic sclerosis