Roflumilast Partially Reverses Smoke-induced Mucociliary Dysfunction

Andreas Schmid; Nathalie Baumlin; Pedro Ivonnet; John S. Dennis; Michael Campos; Stefanie Krick; Matthias Salathe

Disclosures

Respiratory Research. 2015;16(135) 

In This Article

Background

The airways are continuously exposed to dust and infectious agents. To prevent damage caused by irritants, they require effective clearing mechanisms, the physiologically most important one being mucociliary clearance (MCC). Two major determinants of effective MCC are directly regulated by cAMP: Ciliary beat frequency (CBF)[1] and the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), a major anion channel regulating airway surface liquid (ASL) volume.[2]

Phosphodiesterases (PDEs) belong to a family of enzymes that catalyze the breakdown of the second messengers cAMP and cGMP to their inactive forms.[3] PDE4 gene products have a higher affinity to cAMP (Km 1–10 μM) than cGMP (Km > 50 μM) and reveal a broad tissue distribution, including the brain, gastrointestinal tract, spleen, lung, heart, testis and kidney.[4] The lack of effective drug therapy for chronic obstructive pulmonary disease (COPD) has increased the interest in PDE4 inhibition in recent years,[5] as PDEs are not only highly expressed in airway epithelial cells, but also in leukocytes and other inflammatory cells, which are involved in the pathogenesis of COPD.[3] Roflumilast, a PDE4 inhibitor with an IC50 of 0.6 nM,[3] has been approved in the United States and Europe to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations.[6]

CFTR function is decreased in patients with COPD[7,8] and in smokers.[9] Furthermore, PDE inhibitors have been shown to increase chloride transport through CFTR.[10] PDE4 is one of the major isoforms expressed in the airways.[11] These observations suggest that PDE inhibitors could play a key role in improving MCC by restoring depleted ASL in patients with COPD as well as in smokers.

In this study, we examined the role of roflumilast on parameters of MCC in normal human bronchial epithelial (NHBE) cells. We found that roflumilast increased intracellular cAMP concentrations, improved CFTR function and enhanced CBF in cigarette smoke-exposed NHBE cells. For some of these parameters, formoterol had an additive effect. These results indicate that roflumilast rescues at least part of the dysfunctional MCC after acute smoke exposure.

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