PMID- 29722436 OWN - NLM STAT- MEDLINE DCOM- 20191028 LR - 20210109 IS - 1476-5381 (Electronic) IS - 0007-1188 (Print) IS - 0007-1188 (Linking) VI - 175 IP - 14 DP - 2018 Jul TI - Cigarette smoke up-regulates PDE3 and PDE4 to decrease cAMP in airway cells. PG - 2988-3006 LID - 10.1111/bph.14347 [doi] AB - 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 Forster 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. CI - (c) 2018 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. FAU - Zuo, Haoxiao AU - Zuo H AUID- ORCID: 0000-0001-5810-3799 AD - Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands. AD - University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, GRIAC, Groningen, The Netherlands. AD - Institute of Experimental Cardiovascular Research, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany. FAU - Han, Bing AU - Han B AD - Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands. AD - University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, GRIAC, Groningen, The Netherlands. FAU - Poppinga, Wilfred J AU - Poppinga WJ AUID- ORCID: 0000-0002-2711-2411 AD - Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands. AD - University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, GRIAC, Groningen, The Netherlands. FAU - Ringnalda, Lennard AU - Ringnalda L AD - Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands. FAU - Kistemaker, Loes E M AU - Kistemaker LEM AUID- ORCID: 0000-0002-7742-8748 AD - Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands. AD - University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, GRIAC, Groningen, The Netherlands. FAU - Halayko, Andrew J AU - Halayko AJ AUID- ORCID: 0000-0002-7865-4552 AD - Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Canada. FAU - Gosens, Reinoud AU - Gosens R AUID- ORCID: 0000-0002-5595-152X AD - Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands. AD - University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, GRIAC, Groningen, The Netherlands. FAU - Nikolaev, Viacheslav O AU - Nikolaev VO AUID- ORCID: 0000-0002-7529-5179 AD - Institute of Experimental Cardiovascular Research, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany. AD - German Center for Cardiovascular Research (DZHK), Hamburg, Germany. FAU - Schmidt, Martina AU - Schmidt M AUID- ORCID: 0000-0003-3075-0630 AD - Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands. AD - University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, GRIAC, Groningen, The Netherlands. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180603 PL - England TA - Br J Pharmacol JT - British journal of pharmacology JID - 7502536 RN - 0 (Phosphodiesterase 3 Inhibitors) RN - 0 (Phosphodiesterase 4 Inhibitors) RN - 0 (Quinolones) RN - 0 (Smoke) RN - 45S5605Q18 (cilostamide) RN - E0399OZS9N (Cyclic AMP) RN - EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 3) RN - EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 4) RN - K676NL63N7 (Rolipram) SB - IM MH - Animals MH - Biosensing Techniques MH - Cell Line MH - Cyclic AMP/*metabolism MH - Cyclic Nucleotide Phosphodiesterases, Type 3/*metabolism MH - Cyclic Nucleotide Phosphodiesterases, Type 4/*metabolism MH - Epithelial Cells/metabolism MH - Fluorescence Resonance Energy Transfer MH - Humans MH - Mice, Transgenic MH - Myocytes, Smooth Muscle/metabolism MH - Phosphodiesterase 3 Inhibitors/pharmacology MH - Phosphodiesterase 4 Inhibitors/pharmacology MH - Quinolones/pharmacology MH - Respiratory System/cytology/metabolism MH - Rolipram/pharmacology MH - *Smoke MH - *Tobacco Products MH - Up-Regulation PMC - PMC6016635 EDAT- 2018/05/04 06:00 MHDA- 2019/10/29 06:00 PMCR- 2018/06/03 CRDT- 2018/05/04 06:00 PHST- 2017/07/31 00:00 [received] PHST- 2018/03/16 00:00 [revised] PHST- 2018/04/10 00:00 [accepted] PHST- 2018/05/04 06:00 [pubmed] PHST- 2019/10/29 06:00 [medline] PHST- 2018/05/04 06:00 [entrez] PHST- 2018/06/03 00:00 [pmc-release] AID - BPH14347 [pii] AID - 10.1111/bph.14347 [doi] PST - ppublish SO - Br J Pharmacol. 2018 Jul;175(14):2988-3006. doi: 10.1111/bph.14347. Epub 2018 Jun 3.