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Therapies focusing on repairing vulnerable airways, particularly in early life, present a potentially novel treatment strategy. We report defective lower airway epithelial cell repair to strongly associate with common pre\u2013school-aged and school-aged wheezing phenotypes, characterized by aberrant migration patterns and reduced integrin \u03b15\u03b21 expression. Next generation sequencing identified the PI3K\/Akt pathway as the top upstream transcriptional regulator of integrin \u03b15\u03b21, where Akt activation enhanced repair and integrin \u03b15\u03b21 expression in primary cultures from children with wheeze. Conversely, inhibition of PI3K\/Akt signaling in primary cultures from children without wheeze reduced \u03b15\u03b21 expression and attenuated repair. Importantly, the FDA-approved drug celecoxib \u2014 and its non\u2013COX2-inhibiting analogue, dimethyl-celecoxib \u2014 stimulated the PI3K\/Akt\u2013integrin \u03b15\u03b21 axis and restored airway epithelial repair in cells from children with wheeze. When compared with published clinical data sets, the identified transcriptomic signature was also associated with viral-induced wheeze exacerbations highlighting the clinical potential of such therapy. Collectively, these results identify airway epithelial restitution via targeting the PI3K\u2013integrin \u03b15\u03b21 axis as a potentially novel therapeutic avenue for childhood wheeze and asthma. We propose that the next step in the therapeutic development process should be a proof-of-concept clinical trial, since relevant animal models to test the crucial underlying premise are unavailable.<\/jats:p>","DOI":"10.1172\/jci.insight.133125","type":"journal-article","created":{"date-parts":[[2020,3,24]],"date-time":"2020-03-24T12:01:03Z","timestamp":1585051263000},"source":"Crossref","is-referenced-by-count":34,"title":["Aberrant cell migration contributes to defective airway epithelial repair in childhood wheeze"],"prefix":"10.1172","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8462-5865","authenticated-orcid":true,"given":"Thomas","family":"Iosifidis","sequence":"first","affiliation":[{"name":"Division of Pediatrics and"},{"name":"Centre for Cell Therapy and Regenerative Medicine, School of Medicine, University of Western Australia, Nedlands, Western Australia, Australia."},{"name":"Telethon Kids Institute Respiratory Research Centre, Perth, Western Australia, 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