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Cigarette Smoke Up-regulates PDE3 and PDE4 to Decrease cAMP in Airway Cells

Zuo, H., Han, B., Poppinga, W. J., Ringnalda, L., Kistemaker, L. E. M., Halayko, A. J., Gosens, R., Nikolaev, V. O. & Schmidt, M., 2018, In : British Journal of Pharmacology. 175, 14, p. 2988-3006

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BACKGROUND AND PURPOSE: 3', 5'-cyclic adenosine monophosphate (cAMP) is a central second messenger that broadly regulates cell function and can underpin pathophysiology. In chronic obstructive pulmonary disease (COPD), a lung disease primarily provoked by cigarette smoke (CS), the induction of cAMP-dependent pathways, via inhibition of hydrolyzing phosphodiesterases (PDEs), is a prime therapeutic strategy. Mechanisms that disrupt cAMP signaling 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 mouse in vivo, ex vivo precision cut lung slices (PCLS), and in human in vitro cell models to track the effects of CS exposure.

KEY RESULTS: Under fenoterol stimulated conditions, 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 upregulation of PDE4 subtypes. In ex vivo PCLS exposed to CS extract, rolipram reversed downregulation of ciliary beating frequency, whereas only cilostamide significantly increased airway relaxation of methacholine pre-contracted airways.

CONCLUSION AND IMPLICATIONS: We show that CS upregulates expression and activity of both PDE3 and PDE4, which regulate real-time cAMP dynamics. These mechanisms determine the availability of cAMP and can contribute to CS-induced pulmonary pathophysiology.

Original languageEnglish
Pages (from-to)2988-3006
JournalBritish Journal of Pharmacology
Volume175
Issue number14
Early online date2018
Publication statusPublished - 2018

    Keywords

  • OBSTRUCTIVE PULMONARY-DISEASE, CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE, BRONCHIAL EPITHELIAL-CELLS, ROFLUMILAST N-OXIDE, SMOOTH-MUSCLE, LUNG INFLAMMATION, INDUCED EMPHYSEMA, GENE-EXPRESSION, CONCISE GUIDE, LIVING CELLS

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