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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\u2013driven (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.<\/jats:p>","DOI":"10.1172\/jci.insight.94888","type":"journal-article","created":{"date-parts":[[2018,1,24]],"date-time":"2018-01-24T11:00:56Z","timestamp":1516791656000},"source":"Crossref","is-referenced-by-count":38,"title":["A pathophysiological role of PDE3 in allergic airway inflammation"],"prefix":"10.1172","volume":"3","author":[{"given":"Jan","family":"Beute","sequence":"first","affiliation":[{"name":"Department of Pulmonary Medicine, Erasmus MC, \u2018s-Gravendijkwal, Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Lukkes","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Erasmus MC, \u2018s-Gravendijkwal, Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewout P.","family":"Koekoek","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Erasmus MC, \u2018s-Gravendijkwal, Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hedwika","family":"Nastiti","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Erasmus MC, \u2018s-Gravendijkwal, Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keerthana","family":"Ganesh","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Erasmus MC, \u2018s-Gravendijkwal, Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjolein J.W.","family":"de Bruijn","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Erasmus MC, \u2018s-Gravendijkwal, Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Hockman","sequence":"additional","affiliation":[{"name":"Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menno","family":"van Nimwegen","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Erasmus MC, \u2018s-Gravendijkwal, Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gert-Jan","family":"Braunstahl","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, Franciscus Gasthuis, Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis","family":"Boon","sequence":"additional","affiliation":[{"name":"Epirus Biopharmaceuticals Netherlands Yalelaan, Utrecht, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart N.","family":"Lambrecht","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Erasmus MC, \u2018s-Gravendijkwal, Rotterdam, Netherlands."},{"name":"VIB Center for Inflammation Research, Ghent University, Ghent, Belgium."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vince C.","family":"Manganiello","sequence":"additional","affiliation":[{"name":"Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudi W.","family":"Hendriks","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Erasmus MC, \u2018s-Gravendijkwal, Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"KleinJan","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Erasmus MC, \u2018s-Gravendijkwal, Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2018,1,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nri2254"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2014.08.042"},{"key":"B3","unstructured":"Asthma Death Rate Per 100,000 Age Standardize. 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