A pathophysiological role of PDE3 in allergic airway inflammation
Jan Beute, … , Rudi W. Hendriks, Alex KleinJan
Jan Beute, … , Rudi W. Hendriks, Alex KleinJan
Published January 25, 2018
Citation Information: JCI Insight. 2018;3(2):e94888. https://doi.org/10.1172/jci.insight.94888.
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Research Article Inflammation Pulmonology

A pathophysiological role of PDE3 in allergic airway inflammation

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.

Authors

Jan Beute, Melanie Lukkes, Ewout P. Koekoek, Hedwika Nastiti, Keerthana Ganesh, Marjolein J.W. de Bruijn, Steve Hockman, Menno van Nimwegen, Gert-Jan Braunstahl, Louis Boon, Bart N. Lambrecht, Vince C. Manganiello, Rudi W. Hendriks, Alex KleinJan

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Figure 1

PDE3–/– mice showed diminished allergic airway inflammation.

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PDE3–/– mice showed diminished allergic airway inflammation. (A) An exp...
(A) An experimental house dust mite (HDM) asthma model was designed using intratracheal sensitization (s) and challenge (c) of 10 μg HDM or PBS as control. Analyses (a) were performed 1 day after the last challenge. Days after sensitization are indicated at the top. (B) Frozen lung sections were obtained from WT, PDE3A–/–, and PDE3B–/– mice treated with PBS or HDM and immunohistochemically stained with rat antibodies against Siglec F (red) to identify eosinophils. The nuclei stained blue by means of Gills hematoxylin. All images are centered on at least one bronchiole with an accompanying blood vessel, surrounded by parenchymal alveolar space. Strongly positive dark red cells with a donut- or lobe-shaped nucleus were identified as eosinophils, whereas the larger, fainter red cells with a membrane staining were identified as alveolar macrophages. Original magnification, ×100. Scale bars: 100 μm. (C) FACS analysis and quantification of bronchoalveolar lavage (BAL) cells (total cells, eosinophils, T cells, DCs, macrophages, and neutrophils) were plotted in indicated populations. Kruskal-Wallis test for multiple comparisons was used followed by Mann-Whitney U test. Data represent 2 separate experiments (n = 3 for all PBS groups, n = 7 for WT HDM, n = 5 for both PDE3A–/– and PDE3B–/– HDM groups) and are shown as the mean ± SEM. *P < 0.05, **P < 0.01.