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Stimulators of soluble guanylate cyclase (sGC) inhibit experimental skin fibrosis of different aetiologies
  1. Clara Dees1,
  2. Christian Beyer1,
  3. Alfiya Distler1,
  4. Alina Soare1,2,3,
  5. Yun Zhang1,
  6. Katrin Palumbo-Zerr1,
  7. Oliver Distler4,
  8. Georg Schett1,
  9. Peter Sandner5,6,
  10. Jörg H W Distler1
  1. 1Department of Internal Medicine 3,Institute for Clinical Immunology, University of Erlangen-Nuremberg, Germany
  2. 2Internal Medicine and Rheumatology Department, Dr. I. Cantacuzino Clinical Hospital, Bucharest, Romania
  3. 3Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
  4. 4Center of Experimental Rheumatology, Research of Systemic Autoimmune Diseases, University Hospital Zurich, Switzerland
  5. 5Bayer Health Care, Global Drug Discovery—Common Mechanism Research, Wuppertal, Germany
  6. 6Hannover Medical School, Institute of Pharmacology, Hannover, Germany
  1. Correspondence to Professor Jörg H W Distler, Department of Medicine 3, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Ulmenweg 18, Erlangen D-91054, Germany; Joerg.distler{at}uk-erlangen.de

Abstract

Objectives 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.

Result 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.

  • Systemic Sclerosis
  • Fibroblasts
  • Treatment

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