Dysfunctional ErbB2, an EGF receptor family member, hinders repair of airway epithelial cells from asthmatic patients - 06/06/19
Abstract |
Background |
Genetic and genomic data increasingly point to the airway epithelium as critical to asthma pathogenesis. Epithelial growth factor (EGF) family members play a fundamental role in epithelial differentiation, proliferation, and repair. Although expression of erythroblastosis oncogene B2 (ErbB2) mRNA, an EGF family receptor, was reported to be lower in asthmatic patients, little is understood about its functional role.
Objective |
We sought to determine whether decreased ErbB2 activation in freshly isolated human airway epithelial cells (HAECs) from asthmatic patients associated with impaired wound closure in vitro.
Methods |
An in vitro scratch-wound model of air-liquid interface cultured and freshly isolated HAECs were compared between HAECs from healthy control subjects (HCs) and asthmatic patients in relation to ErbB2.
Results |
Freshly brushed HAECs from asthmatic patients had impaired ErbB2 activation compared with those from HCs. In an in vitro scratch-wound model, HAECs from asthmatic patients showed delayed wound closure compared with HAECs from HCs. Cell proliferation, as assessed based on [3H] thymidine incorporation after wounding, and expression or activation of ErbB2 and cyclin D1 at the leading edge of the wound were lower in HAECs from asthmatic patients and HCs. A selective ErbB2 tyrosine kinase inhibitor, mubritinib, impaired wound closure and decreased cyclin D1 expression in healthy HAECs, with less effect on cells from asthmatic patients, supporting diminished activity in asthmatic patients.
Conclusion |
These results implicate a primary defect in the ErbB2 pathway as constraining epithelial repair processes in asthmatic patients. Restoration of homeostatic ErbB2 function should be considered a novel asthma therapeutic target.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Asthma, epidermal growth factor receptor, erythroblastosis oncogene B2, epithelial cell, wound repair, airway inflammation, cell proliferation, cyclin D1, air-liquid interface culture
Abbreviations used : ALI, CCND1, EGF, EGFR, ErbB2, Feno, HAEC, HC, IQR, pErbB2, qRT-PCR, ROI, tErbB2, %WC
Plan
| Supported by the National Institutes of Health (NIH; HL069174, HL064937, AI40600, PO1 AI106684, and RR024153 to S.E.W.), the National Heart, Lung, and Blood Institute (NHLBI; 5U10 HL109152-05 to S.E.W.), a generous donation from the Dellenback Family (to S.E.W.), the Japanese Society of Allergology Fellowship (to H.I.), a Sanjyukai Fellowship (to H.I.), and a Banyu Fellowship (to T.H.). |
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| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 143 - N° 6
P. 2075 - juin 2019 Retour au numéro
Article précédent
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