1. A pathophysiological role of PDE3 in allergic airway inflammation.
- Author
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Beute J, Lukkes M, Koekoek EP, Nastiti H, Ganesh K, de Bruijn MJ, Hockman S, van Nimwegen M, Braunstahl GJ, Boon L, Lambrecht BN, Manganiello VC, Hendriks RW, and KleinJan A
- Subjects
- Allergens immunology, Animals, Asthma drug therapy, Asthma pathology, Biopsy, CD11b Antigen immunology, CD11b Antigen metabolism, Cells, Cultured, Cyclic Nucleotide Phosphodiesterases, Type 3 analysis, Cyclic Nucleotide Phosphodiesterases, Type 3 genetics, Cyclic Nucleotide Phosphodiesterases, Type 3 immunology, Disease Models, Animal, Enoximone pharmacology, Enoximone therapeutic use, Eosinophils drug effects, Eosinophils metabolism, Humans, Lung immunology, Lung pathology, Mice, Mice, Inbred C57BL, Mice, Knockout, Milrinone pharmacology, Milrinone therapeutic use, Off-Label Use, Phosphodiesterase 3 Inhibitors therapeutic use, Primary Cell Culture, Pyroglyphidae immunology, Up-Regulation drug effects, Asthma immunology, Cyclic Nucleotide Phosphodiesterases, Type 3 metabolism, Eosinophils immunology, Phosphodiesterase 3 Inhibitors pharmacology
- Abstract
Phosphodiesterase 3 (PDE3) and PDE4 regulate levels of cyclic AMP, which are critical in various cell types involved in allergic airway inflammation. Although PDE4 inhibition attenuates allergic airway inflammation, reported side effects preclude its application as an antiasthma drug in humans. Case reports showed that enoximone, which is a smooth muscle relaxant that inhibits PDE3, is beneficial and lifesaving in status asthmaticus and is well tolerated. However, clinical observations also showed antiinflammatory effects of PDE3 inhibition. In this study, we investigated the role of PDE3 in a house dust mite-driven (HDM-driven) allergic airway inflammation (AAI) model that is characterized by T helper 2 cell activation, eosinophilia, and reduced mucosal barrier function. Compared with wild-type (WT) littermates, mice with a targeted deletion of the PDE3A or PDE3B gene showed significantly reduced HDM-driven AAI. Therapeutic intervention in WT mice showed that all hallmarks of HDM-driven AAI were abrogated by the PDE3 inhibitors enoximone and milrinone. Importantly, we found that enoximone also reduced the upregulation of the CD11b integrin on mouse and human eosinophils in vitro, which is crucial for their recruitment during allergic inflammation. This study provides evidence for a hitherto unknown antiinflammatory role of PDE3 inhibition in allergic airway inflammation and offers a potentially novel treatment approach.
- Published
- 2018
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