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JCI Insight. 2020 Mar 24. pii: 133125. doi: 10.1172/jci.insight.133125. [Epub ahead of print]

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

Author information

1
Department of Respiratory Medicine, Telethon Kids Institute, Perth, Australia.
2
Centre of Microscopy, Characterisation and Analysis, The University of Western Australia, Perth, Australia.
3
Center for Microbial Diseases Research, The University of British Columbia, Vancouver, Canada.
4
Division of Paediatrics, The University of Western Australia, Perth, Australia.
5
School of Medicine, Notre Dame University, Fremantle, Australia.
6
Center for Microbial Diseases Research, University of British Columbia, Vancouver, Canada.
7
School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia.
8
Department of Respiratory Medicine, Perth Children's Hospital, Perth, Australia.
9
Department of Respiratory Medicine, Princess Margaret Hospital for Children, Perth, Australia.

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 an extremely novel treatment strategy. We report defective lower airway epithelial cell repair to strongly associate with common pre-school and school-aged wheezing phenotypes, characterised by aberrant migration patterns and reduced α5β1 integrin expression. Next generation sequencing identified the PI3K/Akt pathway as the top upstream transcriptional regulator of α5β1 integrin, where Akt activation enhanced repair and α5β1 integrin 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 datasets 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/Akt-integrin axis as a 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.

KEYWORDS:

Asthma; Cell Biology; Cell migration/adhesion; Integrins; Pulmonology

PMID:
32208383
DOI:
10.1172/jci.insight.133125
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