Dysfunctional ErbB2, an EGF receptor family member, hinders repair of airway epithelial cells from asthmatic patients

• Published in: Journal of allergy and clinical immunology Vol. 143; no. 6; pp. 2075 - 2085.e10
• Main Authors: Inoue, Hideki, Hattori, Takeshi, Zhou, Xiuxia, Etling, Emily B., Modena, Brian D., Trudeau, John B., Holguin, Fernando, Wenzel, Sally E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-06-2019; Elsevier Limited
• Subjects: Activation; Adult; Age; air-liquid interface culture; airway inflammation; Asthma; Asthma - immunology; Asthma - pathology; Cell growth; Cell proliferation; Cells, Cultured; Cyclin D1; Demographics; Enzyme inhibitors; Epidermal growth factor; epidermal growth factor receptor; Epigenetics; epithelial cell; Epithelial cells; Epithelial Cells - immunology; Epithelial Cells - pathology; Epithelium; ErbB-2 protein; erythroblastosis oncogene B2; Female; Fibroblast growth factor 2; Gene expression; Genomes; Humans; Kinases; Male; Middle Aged; mRNA; Pathogenesis; Protein-tyrosine kinase; Receptor, ErbB-2 - immunology; Respiratory tract; Studies; Therapeutic applications; Thymidine; Values; Wound Healing; wound repair; Wounding; Young Adult; airway inflammation; air-liquid interface culture; Feno; tErbB2; wound repair; cell proliferation; ErbB2; EGF; epidermal growth factor receptor; qRT-PCR; IQR; epithelial cell; WC; ROI; EGFR; Asthma; CCND1; pErbB2; HAEC; cyclin D1; HC; ALI; erythroblastosis oncogene B2
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2018.11.046

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.
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.
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.
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.
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.
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