GSE117489
Leading edge airway epithelial cell responses to in vitro wounding
The airway epithelium of asthmatics is characterized by intrinsically abnormal wound repair that may contribute to disease pathobiology. In this study, we show that in asthma, the airway epithelial cells at the leading edge of a wound display aberrant migration patterns, reduced expression of a5 and ß1 integrin subunits at baseline and during wound repair, resulting in dysregulated cell migration and an inability to fully repair. Transcriptional profiling identified the PI3K/Akt signaling pathway as the top upstream transcriptional regulator of integrin a5ß1. Significantly, activation of Akt signaling enhanced airway epithelial repair in cultures derived from asthmatic children via upregulation of a5 and ß1 integrin subunits. Conversely, inhibition of the PI3K/Akt signaling pathway in airway epithelial cultures from non-asthmatic children attenuated epithelial repair and reduced a5 and ß1 integrin expression. Importantly, the FDA-approved drug celecoxib, and its non-COX2 inhibitory analogue dimethyl-celecoxib, also stimulated the PI3K/Akt/integrin a5ß1 axis and restored airway epithelial repair in cells from asthmatics. Thus, targeting the PI3K/Akt pathway may represent a novel therapeutic avenue for asthma. Overall design: Examination of baseline and wound healing response differences in primary airway epithelial cell cultures from 4 non-asthmatic and 6 asthmatic children