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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:143

Article

Inoue, Hideki^1,2  Hattori, Takeshi¹  Zhou, Xiuxia¹  Etling, Emily B.¹  Modena, Brian D.^3,4  Trudeau, John B.¹  Holguin, Fernando⁵  Wenzel, Sally E.¹ 

[1] Univ Pittsburgh, Div Pulm Allergy & Crit Care Med, Dept Med, Pittsburgh, PA 15260 USA

[2] Showa Univ, Dept Med, Div Pulm & Allergy Med, Sch Med, Tokyo, Japan

[3] Scripps Res Inst, Mol & Expt Med, La Jolla, CA USA

[4] Scripps Hlth, Dept Allergy Asthma & Immunol, San Diego, CA USA

[5] Univ Colorado, Sch Med, Div Med Pulm Sci & Crit Care, Aurora, CO USA

关键词: Asthma;    epidermal growth factor receptor;    erythroblastosis oncogene B2;    epithelial cell;    wound repair;    airway inflammation;    cell proliferation;    cyclin D1;    air-liquid interface culture;   

DOI  :  10.1016/j.jaci.2018.11.046

来源: Elsevier

【 摘 要 】

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 [H-3] 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.

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