Abstract
Background: Effective therapies for pulmonary fibrosis (PF) are currently lacking. Patients with PF develop pulmonary hypertension (PH), in part due to impaired production of endogenous nitric oxide (NO) that activates soluble guanylate cyclase (sGC). We hypothesized that the NO-independent stimulation of sGC might attenuate PF.
Methods: Male C57/BL6 mice (10-12 wks) were subjected to intratracheal bleomycin (0.5 U/kg) and gavage-feeding with the sGC stimulator riociguat (1, 3 or 10 mg/kg/day), the phosphodiesterase 5 (PDE5) inhibitor sildenafil (100 mg/kg/day), a combination of riociguat (1 mg/kg/day) and sildenafil (100 mg/kg/day), or vehicle alone for two weeks.
Results: Bleomycin-induced PH (an increase in the right ventricle systolic pressure and a decrease in the pulmonary acceleration time/ejection time ratio) and the right ventricular hypertrophy were attenuated by riociguat and the combination of riociguat and sildenafil to a greater extent than by sildenafil alone. In the vehicle-treated mice, fibrosis and inflammation diffusely involved lung parenchyma. Riociguat and its combination with sildenafil but not sildenafil alone markedly ameliorated PF and inflammation that was mainly confined to subpleural areas and/or peripheral lung in a patchy distribution. Riociguat increased plasma cGMP levels and also reduced mortality.
Conclusions: Pharmacological stimulation of sGC with riociguat attenuates PF, PH, right ventricular hypertrophy and mortality in the bleomycin-exposed mice. This therapeutic approach appears to be superior to treatment with sildenafil. Stimulation of sGC might represent a new modality for treating PF and related conditions.
- © 2011 ERS