Cigarette Smoke-Induced Emphysema and Pulmonary Hypertension Can Be Prevented by Phosphodiesterase 4 and 5 Inhibition in Mice.

Michael Seimetz,Hossein Ardeschir Ghofrani,Friedrich Grimminger,Werner Seeger,Nirmal Parajuli,Norbert Weissmann,Ralph Theo Schermuly,Alexandra Pichl,Mariola Bednorz,Tim Lahm

doi:10.1371/journal.pone.0129327

Michael Seimetz, Hossein Ardeschir Ghofrani + Show 8 more

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https://doi.org/10.1371/journal.pone.0129327

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Abstract

RationaleChronic obstructive pulmonary disease (COPD) is a widespread disease, with no curative therapies available. Recent findings suggest a key role of NO and sGC-cGMP signaling for the pathogenesis of the disease. Previous data suggest a downregulation/inactivation of the cGMP producing soluble guanylate cyclase, and sGC stimulation prevented cigarette smoke-induced emphysema and pulmonary hypertension (PH) in mice. We thus aimed to investigate if the inhibition of the cGMP degrading phosphodiesterase (PDE)5 has similar effects. Results were compared to the effects of a PDE 4 inhibitor (cAMP elevating) and a combination of both.MethodsC57BL6/J mice were chronically exposed to cigarette smoke and in parallel either treated with Tadalafil (PDE5 inhibitor), Piclamilast (PDE4 inhibitor) or both. Functional measurements (lung compliance, hemodynamics) and structural investigations (alveolar and vascular morphometry) as well as the heart ratio were determined after 6 months of tobacco smoke exposure. In addition, the number of alveolar macrophages in the respective lungs was counted.ResultsPreventive treatment with Tadalafil, Piclamilast or a combination of both almost completely prevented the development of emphysema, the increase in lung compliance, tidal volume, structural remodeling of the lung vasculature, right ventricular systolic pressure, and right ventricular hypertrophy induced by cigarette smoke exposure. Single, but not combination treatment prevented or reduced smoke-induced increase in alveolar macrophages.ConclusionCigarette smoke-induced emphysema and PH could be prevented by inhibition of the phosphodiesterases 4 and 5 in mice.

Highlights

Chronic obstructive pulmonary disease (COPD) is a collective term for chronic bronchitis and emphysema and is one of the major causes of death worldwide [1]
Preventive treatment with Tadalafil, Piclamilast or a combination of both almost completely prevented the development of emphysema, the increase in lung compliance, tidal volume, structural remodeling of the lung vasculature, right ventricular systolic pressure, and PLOS ONE | DOI:10.1371/journal.pone
Cigarette smoke-induced emphysema and pulmonary hypertension (PH) could be prevented by inhibition of the phosphodiesterases 4 and 5 in mice

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is a collective term for chronic bronchitis and emphysema and is one of the major causes of death worldwide [1]. COPD/emphysema is increasingly viewed as a systemic disease, involving skeletal muscle wasting, diaphragmatic dysfunction, and systemic inflammation [3]. Recent observations suggest an essential role of endothelial dysfunction and pulmonary hypertension (PH) for the development of COPD [7]. Cigarette smoke-induced emphysema was accompanied by pulmonary vascular remodeling and PH [8,9,10,11], and we and others could recently show that such vascular alterations even preceded alveolar destruction [8, 9]. The observations in animal models are supported by human studies showing that vascular remodeling can already occur in smokers without COPD [12, 13]. The involvement of the pulmonary vasculature in COPD is reflected by the fact that up to 70% of COPD patients suffer from PH [14]

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