Aberrant cell migration contributes to defective airway epithelial repair in childhood wheeze.

Thomas Iosifidis,Shyan Vijayasekaran,Laura Coleman,Kelly M Martinovich,Alysia G Buckley,Kevin Looi,Erika N Sutanto,Stephen M Stick,Ingrid A Laing,Peter Le Souëf,Nicole C Shaw,Darryl A Knight,Francis J Lannigan,Yuliya V Karpievitch,Jessica Hillas,Erin E Gill,Kak-Ming Ling,Luke W Garratt,Elizabeth Kicic-Starcevich ,Ahwon Lee ,Samuel Montgomery ,Paul Rigby ,Robert E W Hancock ,Anthony Kicic

doi:10.1172/jci.insight.133125

Abstract

Abnormal wound repair has been observed in the airway epithelium of patients with chronic respiratory diseases, including asthma. 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-school-aged and school-aged wheezing phenotypes, characterized by aberrant migration patterns and reduced integrin α5β1 expression. Next generation sequencing identified the PI3K/Akt pathway as the top upstream transcriptional regulator of integrin α5β1, where Akt activation enhanced repair and integrin α5β1 expression in primary cultures from children with wheeze. Conversely, inhibition of PI3K/Akt signaling in primary cultures from children without wheeze reduced α5β1 expression and attenuated repair. Importantly, the FDA-approved drug celecoxib - and its non-COX2-inhibiting analogue, dimethyl-celecoxib - stimulated the PI3K/Akt-integrin α5β1 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-integrin α5β1 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.

Highlights

300 million individuals suffer from asthma globally [1], and it remains the commonest chronic respiratory disorder in children
Given our transcriptomic analysis and corroboration by prior knowledge (Supplemental Table 7), we explored whether dysregulated signaling via the PI3K/Akt pathway occurs in primary airway epithelial cells (pAEC) from children with wheeze, thereby reducing the expression of integrin subunits α5 and β1 and impairing the capacity of cells to migrate and repair efficiently
Given our previous studies that indicate that exogenous addition of FN improves but does not provide complete restitution of cultures from children with physician-diagnosed asthma [27], we turned our attention to FN-binding integrins

Summary

Introduction

300 million individuals suffer from asthma globally [1], and it remains the commonest chronic respiratory disorder in children. Unresolved airway epithelial restitution following insults, such as viral infection, have been associated with asthma exacerbations [16, 17] and drive chronic airway remodeling [18,19,20,21]. These features are evident in young children with wheeze, not necessarily subsequent to but rather in parallel with airway inflammation [11, 15, 22,23,24,25,26,27], highlighting the potential for early interventions that target the epithelium to modify the recurrence of respiratory wheeze symptoms and disease trajectory

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Conclusion