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Cigarette smoke up-regulates PDE3 and PDE4 to decrease cAMP in airway cells.

ABSTRACT: BACKGROUND AND PURPOSE:cAMP is a central second messenger that broadly regulates cell function and can underpin pathophysiology. In chronic obstructive pulmonary disease, a lung disease primarily provoked by cigarette smoke (CS), the activation of cAMP-dependent pathways, via inhibition of hydrolyzing PDEs, is a major therapeutic strategy. Mechanisms that disrupt cAMP signalling in airway cells, in particular regulation of endogenous PDEs, are poorly understood. EXPERIMENTAL APPROACH:We used a novel Förster resonance energy transfer (FRET) based cAMP biosensor in mice in vivo, ex vivo precision cut lung slices (PCLS) and in human cell models, in vitro, to track the effects of CS exposure. KEY RESULTS:Under fenoterol stimulation, FRET responses to cilostamide were significantly increased in in vivo, ex vivo PCLS exposed to CS and in human airway smooth muscle cells exposed to CS extract. FRET signals to rolipram were only increased in the in vivo CS model. Under basal conditions, FRET responses to cilostamide and rolipram were significantly increased in in vivo, ex vivo PCLS exposed to CS. Elevated FRET signals to rolipram correlated with a protein up-regulation of PDE4 subtypes. In ex vivo PCLS exposed to CS extract, rolipram reversed down-regulation of ciliary beating frequency, whereas only cilostamide significantly increased airway relaxation of methacholine pre-contracted airways. CONCLUSION AND IMPLICATIONS:Exposure to CS, in vitro or in vivo, up-regulated expression and activity of both PDE3 and PDE4, which affected real-time cAMP dynamics. These mechanisms determine the availability of cAMP and can contribute to CS-induced pulmonary pathophysiology.

SUBMITTER: Zuo H

PROVIDER: S-EPMC6016635 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Cigarette smoke up-regulates PDE3 and PDE4 to decrease cAMP in airway cells.

Zuo Haoxiao H Han Bing B Poppinga Wilfred J WJ Ringnalda Lennard L Kistemaker Loes E M LEM Halayko Andrew J AJ Gosens Reinoud R Nikolaev Viacheslav O VO Schmidt Martina M

British journal of pharmacology 20180603 14

<h4>Background and purpose</h4>cAMP is a central second messenger that broadly regulates cell function and can underpin pathophysiology. In chronic obstructive pulmonary disease, a lung disease primarily provoked by cigarette smoke (CS), the activation of cAMP-dependent pathways, via inhibition of hydrolyzing PDEs, is a major therapeutic strategy. Mechanisms that disrupt cAMP signalling in airway cells, in particular regulation of endogenous PDEs, are poorly understood.<h4>Experimental approach< ...[more]

PMID: 29722436

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Cigarette smoke up-regulates PDE3 and PDE4 to decrease cAMP in airway cells.

Publications

Cigarette smoke up-regulates PDE3 and PDE4 to decrease cAMP in airway cells.

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