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Phosphodiesterases As Therapeutic Targets for Respiratory Diseases University of Groningen Phosphodiesterases as therapeutic targets for respiratory diseases Zuo, Haoxiao; Cattani-Cavalieri, Isabella; Musheshe, Nshunge; Nikolaev, Viacheslav O; Schmidt, Martina Published in: Pharmacology & Therapeutics DOI: 10.1016/j.pharmthera.2019.02.002 IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2019 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Zuo, H., Cattani-Cavalieri, I., Musheshe, N., Nikolaev, V. O., & Schmidt, M. (2019). Phosphodiesterases as therapeutic targets for respiratory diseases. Pharmacology & Therapeutics, 197, 225-242. https://doi.org/10.1016/j.pharmthera.2019.02.002 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 27-09-2021 Pharmacology & Therapeutics 197 (2019) 225–242 Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Phosphodiesterases as therapeutic targets for respiratory diseases Haoxiao Zuo a,c,⁎, Isabella Cattani-Cavalieri a,b,d,NshungeMusheshea, Viacheslav O. Nikolaev c,e, Martina Schmidt a,b a Department of Molecular Pharmacology, University of Groningen, the Netherlands b Groningen Research Institute for Asthma and COPD, GRIAC, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands c Institute of Experimental Cardiovascular Research, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany d Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil e German Center for Cardiovascular Research (DZHK), 20246 Hamburg, Germany article info abstract Chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and asthma, affect millions Keywords: of people all over the world. Cyclic adenosine monophosphate (cAMP) which is one of the most important second phosphodiesterases messengers, plays a vital role in relaxing airway smooth muscles and suppressing inflammation. Given its vast cAMP cGMP role in regulating intracellular responses, cAMP provides an attractive pharmaceutical target in the treatment COPD of chronic respiratory diseases. Phosphodiesterases (PDEs) are enzymes that hydrolyze cyclic nucleotides and asthma help control cyclic nucleotide signals in a compartmentalized manner. Currently, the selective PDE4 inhibitor, roflumilast, is used as an add-on treatment for patients with severe COPD associated with bronchitis and a history of frequent exacerbations. In addition, other novel PDE inhibitors are in different phases of clinical trials. The current review provides an overview of the regulation of various PDEs and the potential application of selective PDE inhibitors in the treatment of COPD and asthma. The possibility to combine various PDE inhibitors as a way to increase their therapeutic effectiveness is also emphasized. © 2019 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Contents 1. Introduction............................................... 226 2. SystematicoverviewofthePDEsuperfamily................................ 226 3. PDE3.................................................. 227 4. PDE4.................................................. 228 5. PDE5.................................................. 231 6. PDE7.................................................. 232 7. PDE8.................................................. 232 8. DualPDEinhibitors........................................... 233 9. Futuredirections............................................. 234 Authorcontributions............................................. 235 Conflictsofinterest.............................................. 235 Acknowledgments.............................................. 236 References.................................................. 236 Abbreviations: COPD, chronic obstructive pulmonary disease; β2-AR, β2-adrenoceptor; PDE, phosphodiesterase; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; ASM, airway smooth muscle; ACs, adenylyl cyclases; PKA, cAMP-dependent protein kinase; PKG, cGMP-dependent protein kinase; Epacs, exchange proteins directly ac- tivated by cAMP; UCRs, upstream conserved regions; CS, cigarette smoke; PCLS, precision cut lung slices; MMP, matrix metalloproteinase; GM-CSF, granulocyte/macrophage colony- stimulating factor; CCL, C-C motif ligand; CXCL, C-X-C motif ligand; TNF-α, tumor necrosis factor-α; LPS, lipopolysaccharides; TNF-α, tumor necrosis factor-α; IL, interleukin; IFN-γ,in- terferon gamma; BAL, bronchoalveolar lavage; NF-κB, nuclear factor kappa B; EMT, epithelial-to-mesenchymal transition; TGF-β1, transforming growth factor beta1; HDM, house dust mite; WT, wild type; NO, nitric oxide; PAH, polycyclic aromatic hydrocarbons; EP, E prostanoid receptors.. ⁎ Corresponding author at: Antonius Deusinglaan 1, Groningen, the Netherlands. E-mail address: [email protected] (H. Zuo). https://doi.org/10.1016/j.pharmthera.2019.02.002 0163-7258/© 2019 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 226 H. Zuo et al. / Pharmacology & Therapeutics 197 (2019) 225–242 1. Introduction asthma treatment. The possibility to combine various PDE inhibitors to increase their therapeutic effectiveness is also emphasized. Respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma are among the leading causes of morbidity and 2. Systematic overview of the PDE superfamily mortality today. COPD and asthma combined affect at least 300 million people worldwide, making investigation of more therapeutic targets Cyclic adenosine monophosphate (cAMP) and cyclic guanosine and the development of effective drugs a relevant task in the treatment monophosphate (cGMP) are ubiquitous second messengers. cAMP of these respiratory diseases (Vogelmeier et al., 2017). and cGMP play important roles in regulating numerous cellular func- COPD and asthma are characterized by airway obstruction, chronic tions in physiology and pathology of the lung, including but not limited inflammation, and airway remodeling. Despite both COPD and asthma to the airway smooth muscle (ASM) tone, cell proliferation, differentia- being characterized by airway obstruction, the airway obstruction in tion, apoptosis, migration, secretion of inflammatory mediators, deposi- COPD is progressive and not fully reversible, while that in asthma tion of extracellular matrix, and the maintenance of the endothelial and is reversible by bronchodilators and is associated with airway epithelial barrier (Beavo & Brunton, 2002; Billington, Ojo, Penn, & Ito, hyperresponsiveness (Guerra, 2009; Hogg & Timens, 2009; Meurs, 2013; Sayner, 2011; Zhang, Zhang, Qi, & Xu, 2016). Gosens, & Zaagsma, 2008). In addition, airway inflammation in COPD is Following activation of adenylyl cyclases (ACs) or guanylyl cyclases, characterized by an increased number of neutrophils, macrophages cAMP and cGMP are synthesized from adenosine triphosphate and gua- and CD8+ T-lymphocytes, while that in asthma is characterized by the nosine triphosphate, respectively (Omori & Kotera, 2007). Subse- infiltration of eosinophils, mast cells and CD4+ T-lymphocytes (Mauad quently, cAMP and cGMP bind to specific intracellular effector & Dolhnikoff, 2008; Vogelmeier et al., 2017; Welte & Groneberg, 2006). proteins, such as: cyclic nucleotide-gated ion channels, cAMP- Currently, therapeutic management of COPD relies mainly on the use dependent protein kinase (PKA), cGMP-dependent protein kinase of bronchodilators (β2-adrenoceptor (β2-AR) agonists, anticholinergics (PKG), exchange proteins directly activated by cAMP (Epacs) and theophylline), and a combination therapy of inhaled corticosteroid (Oldenburger, Maarsingh, & Schmidt, 2012; Omori & Kotera, 2007; plus long-acting β2-AR agonists. In patients with severe COPD associated Pfeifer, Kilić, & Hoffmann, 2013) and the most recently described with bronchitis and a history of frequent exacerbations, the phosphodies- Popeye domain containing proteins which bind cAMP with a high affin- terase (PDE) 4 inhibitor roflumilast is typically used as an add-on treat- ity (Schindler & Brand, 2016). The intracellular cyclic nucleotide concen- ment to the above mentioned therapies (Giembycz & Maurice, 2014). In trations are substantially determined by PDEs (shown in Fig. 1), which asthma treatment and/or management, the combination therapies of in- hydrolyze cAMP and cGMP and prevent it from diffusing to other com- haled corticosteroid and short-acting β2-AR agonists or long-acting β2- partments thereby compartmentalizing the cyclic nucleotide signal.
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