A pathophysiological role of PDE3 in allergic airway inflammation
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
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
View: Text | PDF
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

×

Figure 3

Less albumin extravasation in HDM-treated PDE3–/– mice compared with WT mice.

Options: View larger image (or click on image) Download as PowerPoint
Less albumin extravasation in HDM-treated PDE3–/– mice compared with WT ...
(A) Albumin content in bronchoalveolar lavage (BAL) fluids of WT versus PDE3–/– mice was assayed with ELISA. Ranking score results of the peribronchial (B) and perivascular (C) albumin leakage judged from the lung tissue sections of WT and PDE3–/– mice. Frozen tissue sections of WT and PDE3–/– mice were stained for albumin (brown-red) and counterstained with Gills hematoxylin (blue) at ×5 (D–I) and ×20 magnification (J–L). Albumin positivity can be seen throughout the entirety of the lung tissue, but is mainly sequestered inside the large blood vessels, perivascular as well as peribronchial. Mucus was also stained for albumin. PBS-treated mice (A–C) were indistinguishable from each other concerning albumin content. WT HDM-treated mice (G and J) showed albumin positivity surrounding the bronchioles when compared with PDE3–/– mice (H, I, K, and L). Original magnification, ×100. Zooming in on (×400) the peribronchial region (highlighted with white rectangle), the smaller vasculature surrounding the bronchiole is albumin-positive in WT mice (J) (highlighted with white arrows) when compared with the PDE3–/– mice (K and L). 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.