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

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  • Additional Information
    • Source:
      Publisher: Wiley Country of Publication: England NLM ID: 7502536 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5381 (Electronic) Linking ISSN: 00071188 NLM ISO Abbreviation: Br J Pharmacol Subsets: MEDLINE
    • Publication Information:
      Publication: London : Wiley
      Original Publication: London, Macmillian Journals Ltd.
    • Subject Terms:
      Smoke* ; Tobacco Products*; Cyclic AMP/*metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 3/*metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 4/*metabolism; Animals ; Biosensing Techniques ; Cell Line ; Epithelial Cells/metabolism ; Fluorescence Resonance Energy Transfer ; Humans ; Mice, Transgenic ; Myocytes, Smooth Muscle/metabolism ; Phosphodiesterase 3 Inhibitors/pharmacology ; Phosphodiesterase 4 Inhibitors/pharmacology ; Quinolones/pharmacology ; Respiratory System/cytology ; Respiratory System/metabolism ; Rolipram/pharmacology ; Up-Regulation
    • 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.
      (© 2018 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
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    • Accession Number:
      0 (Phosphodiesterase 3 Inhibitors)
      0 (Phosphodiesterase 4 Inhibitors)
      0 (Quinolones)
      0 (Smoke)
      45S5605Q18 (cilostamide)
      E0399OZS9N (Cyclic AMP)
      EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 3)
      EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 4)
      K676NL63N7 (Rolipram)
    • Publication Date:
      Date Created: 20180504 Date Completed: 20191028 Latest Revision: 20210109
    • Publication Date:
      20231215
    • Accession Number:
      PMC6016635
    • Accession Number:
      10.1111/bph.14347
    • Accession Number:
      29722436