Effect of Roflumilast and other cAMP-Elevating agents on airway ciliary beat frequency in proximal and distal airways in rat Precision-cut lung slices

Wohlsen A, Wollin L, Marx D, Beume R

ALTANA Pharma AG, Konstanz, Germany

Rationale Lung clearance, which is impaired in COPD patients, is dependent on beating cilia. β-agonists increase ciliary beat frequency (cbf) by elevating intracellular cAMP. Phosphodiesterase 4 (PDE4) degrades cAMP, thus, PDE4 inhibition leads to elevated cAMP. We studied the effects of the β‑agonist terbutaline, the adenylyl-cyclase activator forskolin, and the investigational PDE4 inhibitor roflumilast on cbf in rat lung slices prepared from proximal and distal airways. MethodS Precision-cut lung slices were prepared from the left main bronchus and distal bronchioles of Wistar rats. Cbf was assessed microscopically before (baseline), and 5, 10, 30, 60min after addition of roflumilast (up to 100µM), terbutaline (up to 10µM), or forskolin (up to 100µM). Results Baseline cbf in proximal and distal airways ranged from 12-15Hz and increased concentration-dependently after addition of cAMP-elevating agents. In proximal airways, roflumilast, terbutaline, and forskolin increased cbf versus baseline by +60%, +64%, and +55% (after 60min at maximum concentration). In distal airways, roflumilast increased cbf (+55%), whereas terbutaline (+10%) and forskolin (+1%) were ineffective. Conclusions Roflumilast increased cbf in proximal and distal airways, whereas terbutaline and forskolin increased cbf in proximal airways only. This property of roflumilast might translate into a more effective lung mucociliary clearance in COPD patients.

Back to Abstracts Menu