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A pathophysiological role of PDE3 in allergic airway inflammation

Jan Beute, Melanie Lukkes, Ewout P Koekoek, Hedwika Nastiti, Keerthana Ganesh, Marjolein JW de Bruijn, Steve Hockman, Menno van Nimwegen, Gert-Jan Braunstahl, Louis Boon, et al.
(2018) JCI INSIGHT. 3(2).
Author
Organization
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.
Keywords
OBSTRUCTIVE PULMONARY-DISEASE, CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES, L-SELECTIN EXPRESSION, CHRONIC HEART-FAILURE, BROWN-NORWAY RATS, EPITHELIAL-CELLS, GENE-EXPRESSION, IN-VITRO, T-CELLS, ASTHMA

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Citation

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MLA
Beute, Jan, et al. “A Pathophysiological Role of PDE3 in Allergic Airway Inflammation.” JCI INSIGHT, vol. 3, no. 2, 2018, doi:10.1172/jci.insight.94888.
APA
Beute, J., Lukkes, M., Koekoek, E. P., Nastiti, H., Ganesh, K., de Bruijn, M. J., … Kleinjan, A. (2018). A pathophysiological role of PDE3 in allergic airway inflammation. JCI INSIGHT, 3(2). https://doi.org/10.1172/jci.insight.94888
Chicago author-date
Beute, Jan, Melanie Lukkes, Ewout P Koekoek, Hedwika Nastiti, Keerthana Ganesh, Marjolein JW de Bruijn, Steve Hockman, et al. 2018. “A Pathophysiological Role of PDE3 in Allergic Airway Inflammation.” JCI INSIGHT 3 (2). https://doi.org/10.1172/jci.insight.94888.
Chicago author-date (all authors)
Beute, Jan, Melanie Lukkes, Ewout P Koekoek, Hedwika Nastiti, Keerthana Ganesh, Marjolein JW de Bruijn, Steve Hockman, Menno van Nimwegen, Gert-Jan Braunstahl, Louis Boon, Bart Lambrecht, Vince C Manganiello, Rudi W Hendriks, and Alex Kleinjan. 2018. “A Pathophysiological Role of PDE3 in Allergic Airway Inflammation.” JCI INSIGHT 3 (2). doi:10.1172/jci.insight.94888.
Vancouver
1.
Beute J, Lukkes M, Koekoek EP, Nastiti H, Ganesh K, de Bruijn MJ, et al. A pathophysiological role of PDE3 in allergic airway inflammation. JCI INSIGHT. 2018;3(2).
IEEE
[1]
J. Beute et al., “A pathophysiological role of PDE3 in allergic airway inflammation,” JCI INSIGHT, vol. 3, no. 2, 2018.
@article{8564416,
  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.}},
  articleno    = {{e94888}},
  author       = {{Beute, Jan and Lukkes, Melanie and Koekoek, Ewout P and Nastiti, Hedwika and Ganesh, Keerthana and de Bruijn, Marjolein JW and Hockman, Steve and van Nimwegen, Menno and Braunstahl, Gert-Jan and Boon, Louis and Lambrecht, Bart and Manganiello, Vince C and Hendriks, Rudi W and Kleinjan, Alex}},
  issn         = {{2379-3708}},
  journal      = {{JCI INSIGHT}},
  keywords     = {{OBSTRUCTIVE PULMONARY-DISEASE,CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES,L-SELECTIN EXPRESSION,CHRONIC HEART-FAILURE,BROWN-NORWAY RATS,EPITHELIAL-CELLS,GENE-EXPRESSION,IN-VITRO,T-CELLS,ASTHMA}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{16}},
  title        = {{A pathophysiological role of PDE3 in allergic airway inflammation}},
  url          = {{http://doi.org/10.1172/jci.insight.94888}},
  volume       = {{3}},
  year         = {{2018}},
}
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