Document Detail

Roflumilast N-oxide, a PDE4 inhibitor, improves cilia motility and ciliated human bronchial epithelial cells compromised by cigarette smoke in vitro.
MedLine Citation:
PMID:  22385203     Owner:  NLM     Status:  MEDLINE    
BACKGROUND AND PURPOSE: Mucociliary malfunction occurs in chronic obstructive pulmonary disease (COPD) and compromised functions of ciliated bronchial epithelial cells may contribute to this. Cigarette smoke, a major risk factor for COPD, impairs ciliary beat frequency (CBF). cAMP augments CBF. This in vitro study addressed, in differentiated, primary human bronchial epithelial cells, whether roflumilast N-oxide, a PDE4 inhibitor, (i) augments CBF; (ii) prevents the reduction in CBF induced by cigarette smoke extract (CSE); and (iii) protects against the loss of the ciliated phenotype following long-term CSE exposure.
EXPERIMENTAL APPROACH: Air-liquid interface cultured human bronchial epithelial cells were incubated with roflumilast N-oxide and exposed to CSE. CBF was assessed by digital high speed video microscopy (DHSV). Ciliated cells were characterized by β-tubulin IV staining and analyses of Foxj1 and Dnai2 mRNA and protein (real-time quantitative PCR, Western blotting).
KEY RESULTS: Roflumilast N-oxide concentration-dependently triggered a rapid and persistent increase in CBF and reversed the decrease in CBF following CSE. Long-term incubation of bronchial epithelial cells with CSE resulted in a loss in ciliated cells associated with reduced expression of the ciliated cell markers Foxj1 and Dnai2. The PDE4 inhibitor prevented this loss in the ciliated cell phenotype and the compromised Foxj1 and Dnai2 expression. The enhanced release of IL-13 following CSE, a cytokine that diminishes the proportion of ciliated cells and in parallel, reduces Foxj1 and Dnai2, was reversed by roflumilast N-oxide.
CONCLUSION AND IMPLICATIONS: Roflumilast N-oxide protected differentiated human bronchial epithelial cells from reduced CBF and loss of ciliated cells following CSE.
J Milara; M Armengot; P Bañuls; H Tenor; Rolf Beume; E Artigues; J Cortijo
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  166     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-07-24     Completed Date:  2012-12-10     Revised Date:  2013-08-14    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  2243-62     Citation Subset:  IM    
Copyright Information:
© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
Research Unit, University General Hospital Consortium, Valencia, Spain.
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MeSH Terms
Aminopyridines / pharmacology*
Benzamides / pharmacology*
Bronchi / cytology*
Cell Differentiation
Cells, Cultured
Cilia / drug effects,  physiology*
Cyclopropanes / pharmacology
Epithelial Cells / cytology,  drug effects*
Gene Expression Regulation / drug effects
Phosphodiesterase 4 Inhibitors / pharmacology*
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Smoke / adverse effects*
Time Factors
Tobacco Products / adverse effects
Reg. No./Substance:
0/Aminopyridines; 0/Benzamides; 0/Cyclopropanes; 0/Phosphodiesterase 4 Inhibitors; 0/Smoke; 0/roflumilast N-oxide

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