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 4

Inhibition of Akt signaling abrogates pAEC repair and integrin expression.

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Inhibition of Akt signaling abrogates pAEC repair and integrin expressio...
pAEC from children without wheeze were treated with different concentrations (0.01, 0.1, 1 μM) of the specific Akt inhibitor MK2206. (A) MK2206 inhibited phosphorylation of Akt (serine residue 473) at 12 and 48 hours after treatment. (B and C) Inhibition of Akt in pAEC from children without wheeze resulted in significant reduction of integrin subunit α5 (B) cell membrane expression in a concentration-dependent manner at 12 and 48 hours after MK2206 treatment. Although no differences were observed in cell membrane integrin subunit β1 at 12 hours following Akt inhibition an increase was seen at 48 hours following treatment compared to vehicle control (C). (D) Treatment of pAEC cultures from nonwheezing children with MK2206 at the time of scratch wounding resulted in a concentration-dependent reduction in closure rates, although DMSO vehicle (0.05% v/v) control was not significantly altered compared with untreated cultures. (E–M) Although treatment of pAEC from nonwheezing children with 0.05% (v/v) DMSO vehicle control had no effect on cell migration (E and F), MK2206 treatment attenuated cell migration in a concentration-dependent manner (G–I) by inhibiting distance migrated (J), velocity (K), directionality (L), and centrality (yFMI, M). All experiments were completed with pAEC cultures from 6 children without 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 wheezing group (#P < 0.050) were determined using 2-way Kruskal-Wallis ANOVA with Dunn’s post hoc test for multiple comparisons.