Aberrant cell migration contributes to defective airway epithelial repair in childhood wheeze
Thomas Iosifidis, … , Western Australian Epithelial Research Program (WAERP), Australian Respiratory Epithelium Consortium (AusREC)
Thomas Iosifidis, … , Western Australian Epithelial Research Program (WAERP), Australian Respiratory Epithelium Consortium (AusREC)
Published March 24, 2020
Citation Information: JCI Insight. 2020;5(7):e133125. https://doi.org/10.1172/jci.insight.133125.
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Research Article Cell biology Pulmonology

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

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.

Authors

Thomas Iosifidis, Erika N. Sutanto, Alysia G. Buckley, Laura Coleman, Erin E. Gill, Amy H. Lee, Kak-Ming Ling, Jessica Hillas, Kevin Looi, Luke W. Garratt, Kelly M. Martinovich, Nicole C. Shaw, Samuel T. Montgomery, Elizabeth Kicic-Starcevich, Yuliya V. Karpievitch, Peter Le Souëf, Ingrid A. Laing, Shyan Vijayasekaran, Francis J. Lannigan, Paul J. Rigby, Robert E.W. Hancock, Darryl A. Knight, Stephen M. Stick, Anthony Kicic, Western Australian Epithelial Research Program (WAERP), Australian Respiratory Epithelium Consortium (AusREC)

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Figure 5

Activation of Akt signaling enhances repair of pAEC from children with wheeze and increased integrin α5β1 expression.

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Activation of Akt signaling enhances repair of pAEC from children with w...
pAEC from children with wheeze were treated with different concentrations (0.5, 5, 20 μM) of the specific Akt activator SC79. (A) SC79 treatment resulted in phosphorylation of Akt (serine residue 473), at 12 and 48 hours after treatment. (B) Significant increase of integrin subunit α5 cell membrane expression was observed in pAEC from children with wheeze for all concentrations at 12 hours and 0.5, 5, and 20 μM SC79 at 48 hours. (C) Also, integrin subunit β1 cell membrane expression was increased in pAEC from children with wheeze treated with 0.5, 2, and 5 μM SC79 at 12 and 48 hours. (D) Treatment of pAEC from wheezers with SC79 at the time of scratch wounding resulted in a concentration-dependent increase in closure rates, although DMSO vehicle (0.08% v/v) control was not significantly altered compared with untreated cultures. (E–M) Although treatment of pAEC from wheezers with 0.08% (v/v) DMSO vehicle control had no effect on cell migration (E and F), SC79 treatment enhanced cell migration in a concentration-dependent manner (G–I) by stimulating distance migrated (J), velocity (K), directionality (L), and centrality (yFMI, M). All experiments were completed with pAEC cultures from 6 children with wheeze, and data were represented as either box and whisker (min/max) or dot plots with median ± IQR. Statistical differences between treatment and untreated control (*P < 0.050) or nonwheezing group (#P < 0.050) were determined using 2-way Kruskal-Wallis ANOVA with Dunn’s post hoc test for multiple comparisons. The wound closure (D) and cell migration parameters (J–M) for the untreated wheeze and nonwheeze groups were also presented in Figure 4 and were utilized for baseline response purposes.