title: Stimulators of soluble guanylate cyclase (sGC) inhibit experimental skin fibrosis of different aetiologies.
abstract: OBJECTIVE
  Stimulators of the soluble guanylate cyclase (sGC) have recently been shown to inhibit transforming growth factor-β signalling. Here, we aimed to demonstrate that riociguat, the drug candidate for clinical trials in systemic sclerosis (SSc), is effective in experimental fibrosis and to compare its efficacy to that of phosphodiesterase V inhibitors that also increase the intracellular levels of cyclic guanosine monophosphate.
  
  
  METHODS
  The antifibrotic effects of riociguat and sildenafil were compared in the tight-skin 1 model, in bleomycin-induced fibrosis and in a model of sclerodermatous chronic graft-versus-host-disease (cGvHD). Doses of 0.1-3 mg/kg twice a day for riociguat and of 3-10 mg/kg twice a day for sildenafil were used.
  
  
  RESULTS
  Riociguat dose-dependently reduced skin thickening, myofibroblast differentiation and accumulation of collagen with potent antifibrotic effects at 1 and 3 mg/kg. Riociguat also ameliorated fibrosis of the gastrointestinal tract in the cGvHD model. The antifibrotic effects were associated with reduced phosphorylation of extracellular signal-regulated kinases. Sildenafil at doses of 3 and 10 mg/kg exerted mild antifibrotic effects that were significantly less pronounced compared with 1 and 3 mg/kg riociguat.
  
  
  CONCLUSIONS
  These data demonstrated potent antifibrotic effects of riociguat on experimental skin and organ fibrosis. These findings suggest a role for riociguat for the treatment of fibrotic diseases, especially for the treatment of SSc. A phase II study with riociguat in patients with SSc is currently starting.
authors.affiliation: Department of Internal Medicine 3,Institute for Clinical Immunology, University of Erlangen-Nuremberg, Germany.
authors.forename: Clara
authors.initials: C
authors.lastname: Dees
authors.affiliation: Department of Internal Medicine 3,Institute for Clinical Immunology, University of Erlangen-Nuremberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Beyer
authors.affiliation: Department of Internal Medicine 3,Institute for Clinical Immunology, University of Erlangen-Nuremberg, Germany.
authors.forename: Alfiya
authors.initials: A
authors.lastname: Distler
authors.affiliation: Department of Internal Medicine 3,Institute for Clinical Immunology, University of Erlangen-Nuremberg, Germany Internal Medicine and Rheumatology Department, Dr. I. Cantacuzino Clinical Hospital, Bucharest, Romania Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
authors.forename: Alina
authors.initials: A
authors.lastname: Soare
authors.affiliation: Department of Internal Medicine 3,Institute for Clinical Immunology, University of Erlangen-Nuremberg, Germany.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine 3,Institute for Clinical Immunology, University of Erlangen-Nuremberg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Palumbo-Zerr
authors.affiliation: Center of Experimental Rheumatology, Research of Systemic Autoimmune Diseases, University Hospital Zurich, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Distler
authors.affiliation: Department of Internal Medicine 3,Institute for Clinical Immunology, University of Erlangen-Nuremberg, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.affiliation: Bayer Health Care, Global Drug Discovery-Common Mechanism Research, Wuppertal, Germany Hannover Medical School, Institute of Pharmacology, Hannover, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Sandner
authors.affiliation: Department of Internal Medicine 3,Institute for Clinical Immunology, University of Erlangen-Nuremberg, Germany.
authors.forename: Jörg H W
authors.initials: JH
authors.lastname: Distler
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis; D006162:Guanylate Cyclase / Q000187:drug effects*; D051379:Mice; D008815:Mice, Inbred Strains; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D012595:Scleroderma, Systemic / Q000188:drug therapy; D000068677:Sildenafil Citrate / Q000494:pharmacology; D012867:Skin / Q000473:pathology*
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D000068677:Sildenafil Citrate; D006162:Guanylate Cyclase; C542595:riociguat
keywords: Fibroblasts; Systemic Sclerosis; Treatment