Chronic obstructive pulmonary disease (COPD), which comprises the phenotypes of chronic bronchitis and emphysema, is often associated with pulmonary hypertension (PH). However, currently, no approved therapy exists for PH-COPD. Signalling of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) axis plays an important role in PH and COPD.We investigated the treatment effect of riociguat, which promotes the NO-cGMP pathway, in the mouse model of smoke-induced PH and emphysema in a curative approach, and retrospectively analysed the effect of riociguat treatment on PH in single patients with PH-COPD.In mice with established PH and emphysema (after 8 months of cigarette smoke exposure), riociguat treatment for another 3 months fully reversed PH. Moreover, histological hallmarks of emphysema were decreased. Microarray analysis revealed involvement of different signalling pathways, e.g. related to matrix metalloproteinases (MMPs). MMP activity was decreased in vivo by riociguat. In PH-COPD patients treated with riociguat (n=7), the pulmonary vascular resistance, airway resistance and circulating MMP levels decreased, while oxygenation at rest was not significantly changed.Riociguat may be beneficial for treatment of PH-COPD. Further long-term prospective studies are necessary to investigate the tolerability, efficacy on functional parameters and effect specifically on pulmonary emphysema in COPD patients.
- Pichl, A.
- Sommer, N.
- Bednorz, M.
- Seimetz, M.
- Hadzic, S.
- Kuhnert, S.
- Kraut, S.
- Roxlau, E. T.
- Kojonazarov, B.
- Wilhelm, J.
- Gredic, M.
- Gall, H.
- Tello, K.
- Richter, M. J.
- Pak, O.
- Petrovic, A.
- Hecker, M.
- Schermuly, R. T.
- Grimminger, F.
- Seeger, W.
- Ghofrani, H. A.
- Weissmann, N.
Keywords
- Animals
- Cyclic GMP/*metabolism
- Disease Models, Animal
- Humans
- Hypertension, Pulmonary/*drug therapy/etiology/metabolism
- Lung/pathology
- Male
- Mice
- Mice, Inbred C57BL
- Nitric Oxide/*metabolism
- Pulmonary Disease, Chronic Obstructive/*complications/physiopathology
- Pulmonary Emphysema/physiopathology
- Pyrazoles/*pharmacology
- Pyrimidines/*pharmacology
- Retrospective Studies
- Signal Transduction
- Soluble Guanylyl Cyclase/metabolism
- Translational Medical Research
- Sommer has nothing to disclose. Conflict of interest: M. Bednorz has nothing to
- disclose. Conflict of interest: M. Seimetz has nothing to disclose. Conflict of
- interest: S. Hadzic has nothing to disclose. Conflict of interest: S. Kuhnert
- reports nonfinancial (travel) support from Teva, Bayer and Astellas, personal
- fees for advisory board work from Chiesi, personal fees for advisory board work
- and nonfinancial (travel) support from GSK, personal fees for advisory board
- work, honoraria and nonfinancial (travel) support from Novartis, honoraria from
- Berlin-Chemie Menarini and AstraZeneca, outside the submitted work. Conflict of
- interest: S. Kraut has nothing to disclose. Conflict of interest: E.T. Roxlau has
- nothing to disclose. Conflict of interest: B. Kojonazarov has nothing to
- disclose. Conflict of interest: J. Wilhelm has nothing to disclose. Conflict of
- interest: M. Gredic has nothing to disclose. Conflict of interest: H. Gall
- reports grants and personal fees from Actelion, AstraZeneca, Bayer, BMS, GSK,
- Janssen Cilag, Lilly, MSD, Novartis, Pfizer, and United Therapeutics/OMT, outside
- the submitted work. Conflict of interest: K. Tello has nothing to disclose.
- Conflict of interest: M.J. Richter reports grants from United Therapeutics,
- grants and personal fees for consultancy and lecturing from Bayer, personal fees
- for lecturing from Actelion, Mundipharma, Roche and OMT, outside the submitted
- work. Conflict of interest: O. Pak has nothing to disclose. Conflict of interest:
- A. Petrovic has nothing to disclose. Conflict of interest: M. Hecker has nothing
- to disclose. Conflict of interest: R.T. Schermuly has nothing to disclose.
- Conflict of interest: F. Grimminger has nothing to disclose. Conflict of
- interest: W. Seeger has received honoraria for consultant activities from Bayer,
- United Therapeutics and Liquidia, outside the submitted work. Conflict of
- interest: H.A. Ghofrani reports personal fees for advisory board work from
- Actelion, Bayer, GSK, Novartis and Pfizer, personal fees for consultancy from
- Actelion, Bayer, GSK, MSD, Novartis and Pfizer, personal fees for lecturing from
- Actelion, Bayer, GSK, Novartis and Pfizer, personal fees for meeting attendance
- from Actelion, Bayer, GSK, MSD, Novartis and Pfizer, and grants from Deutsche
- Forschungsgemeinschaft (DFG), outside the submitted work. Conflict of interest:
- N. Weissmann has nothing to disclose.
