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Roflumilast N-oxide, a PDE4 inhibitor, improves cilia motility and ciliated human bronchial epithelial cells compromised by cigarette smoke in vitro

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Roflumilast N-oxide, a PDE4 inhibitor, improves cilia motility and ciliated human bronchial epithelial cells compromised by cigarette smoke in vitro

dc.contributor.author	Milara Payá, Javier	es_ES
dc.contributor.author	Armengot Carceller, Miguel	es_ES
dc.contributor.author	Bañuls, P.	es_ES
dc.contributor.author	Tenor, Herman	es_ES
dc.contributor.author	Beume, Rolf	es_ES
dc.contributor.author	Artigues, E.	es_ES
dc.contributor.author	Cortijo Gimeno, Julio	es_ES
dc.date.accessioned	2015-06-19T10:21:21Z
dc.date.available	2015-06-19T10:21:21Z
dc.date.issued	2012	es_ES
dc.identifier.citation	British Journal of Pharmacology Vol. 166 Issue 8: pp. 2243-2262	es_ES
dc.identifier.uri	http://hdl.handle.net/10550/44570
dc.description.abstract	BACKGROUND AND PURPOSEMucociliary 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 APPROACHAir-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 RESULTSRoflumilast 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 IMPLICATIONSRoflumilast N-oxide protected differentiated human bronchial epithelial cells from reduced CBF and loss of ciliated cells following CSE.	es_ES
dc.subject	bronchial epithelial cells	es_ES
dc.subject	ciliary motility	es_ES
dc.subject	phosphodiesterase-4	es_ES
dc.subject	roflumilast	es_ES
dc.title	Roflumilast N-oxide, a PDE4 inhibitor, improves cilia motility and ciliated human bronchial epithelial cells compromised by cigarette smoke in vitro	es_ES
dc.type	journal article	es_ES
dc.identifier.doi	10.1111/j.1476-5381.2012.01929.x	es_ES
dc.identifier.idgrec	087228	es_ES