Background: Emerging evidence suggests significant transcriptomic overlap between upper and lower airways, and prior work has shown a dysregulated response to injury in the lower airway of children with wheeze. However, there is little data that directly compares functionality between these two regions.

Objective: Here, we hypothesized that dysregulated epithelial repair is observed in upper and lower airways of children with and without wheeze.

Methods: Upper airway epithelial cell (AEC) cultures were established from children with asymptomatic recurrent wheeze (n=22), acute wheeze exacerbations (n=29) or without wheeze (n=29). Of these, matched upper and lower AEC cultures were established from children with and without wheeze (n?6). Scratch wound and cell migration assays were performed, and therapeutic efficacy of celecoxib and dimethyl-celecoxib to enhance repair was determined.

Results: Matched upper and lower AEC from children with asymptomatic wheeze displayed reduced repair response compared to non-wheeze counterparts. Upper AEC from children with acute wheeze showed a variable repair response where children with a poor repair ?vulnerable epithelium? endotype had a shorter time to next exacerbation and higher number of exacerbations relative to full repair counterparts. Defective upper AEC repair associated with rhinitis and sibling asthma. Aberrant cell migration was observed in upper AEC from children with wheeze. Celecoxib and dimethyl-celecoxib enhanced upper AEC repair and migration.

Conclusion: This study provides evidence of functional surrogacy, specifically airway repair responses, and highlights a novel vulnerable epithelium endotype in children with wheeze that is therapeutically targetable.