Original Articles: Mechanisms of Allergy
Expression of c-erbB receptors and ligands in the bronchial epithelium of asthmatic subjects,☆☆

https://doi.org/10.1067/mai.2002.120274Get rights and content

Abstract

Background: The c-erbB family of receptor tyrosine kinases act in a combinatorial fashion to regulate cell behavior. Disturbances in this system have been associated with neoplastic and inflammatory diseases. Objectives: Although expression of the epidermal growth factor receptor (EGFR; c-erbB1) is increased in the bronchial epithelium in asthma, there is no information on expression of other members of the c-erbB receptor and ligand family that can modulate EGFR function. Methods: Immunohistochemistry was used to compare expression of EGFR, c-erbB2, c-erbB3, epidermal growth factor, heparin-binding epidermal growth factor–like growth factor, and transforming growth factor α in bronchial biopsy specimens from normal and asthmatic subjects. Scrape-wounded monolayers of 16HBE 14o cells were used as an in vitro model of damage and repair. Changes in EGFR, c-erbB2, and c-erbB3 distribution were measured by means of immunocytochemistry, whereas tyrosine phosphorylation was measured by means of immunoprecipitation and Western blotting. Results: Although epithelial staining for the EGFR was significantly increased in asthmatic epithelium (P < .001), there was no difference in staining for the other receptors and ligands studied. In scrape-wounded epithelial monolayers, tyrosine phosphorylation of EGFR, c-erbB2, and c-erbB3 occurred immediately after damage; however, only EGFR showed a change in expression in response to damage. Conclusions: Even though EGFR levels are increased in asthma, this is not linked to changes in expression of its activating ligands or other c-erbB receptors. Because bronchial epithelial cells respond to physical damage through activation of several c-erbB family members, the shift in favor of increased EGFR levels in asthma may lead to altered epithelial function by influencing the number and type of heterodimeric signaling complexes, assuming sufficient ligand availability. (J Allergy Clin Immunol 2002;109:75-81.)

Section snippets

Patient characterization and fiberoptic bronchoscopy

Ten control subjects without asthma (8 men) with a mean ± SEM age of 26.0 ± 1.8 years and 13 subjects with mild-to-severe asthma (9 men) with a mean ± SEM age of 37.2 ± 2.4 years participated in this study. Asthmatic subjects had a mean ± SEM percent predicted FEV1 of 76.9% ± 6.3%, and their geometric mean PC20 histamine was 0.94 mg/mL (range, 0.12-8.33 mg/mL). All were taking inhaled bronchodilators, and 9 of them were taking steroids. All subjects studied were nonsmokers and had not

Analysis of c-erbB receptor and ligand expression in asthmatic epithelium

c-erbB receptor and ligand expression was analyzed in sections of bronchial biopsy specimens that were obtained by means of fiberoptic bronchoscopy from normal (n = 10) or asthmatic subjects (n = 13). Immunohistochemical analysis of biopsy specimens of normal airway mucosa revealed positive epithelial staining for EGFR, c-erbB2, and c-erbB3 receptors. This was associated with cell membranes and confined to the lateral junctions between columnar epithelial cells and their junctions with basal

Discussion

Combinatorial c-erbB receptor interactions leading to signal diversification and modulation of cellular responses is the focus of intense research activity in many areas of biology.9 Because EGFR, c-erbB2, and c-erbB3 are coexpressed in the bronchial epithelium, we postulated that differential expression of these receptors regulates responses to stress or injury in asthma. Using a model of mechanical damage to human bronchial epithelial cells in vitro, which may reflect some of the physical

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  • Cited by (0)

    Supported by the Medical Research Council (No. G8604034) and Asthma Allergy and Inflammation Research (AAIR) and by an ECC Marie Curie Award (ERB4001GT965839) to R. Polosa.

    ☆☆

    Reprint requests: Donna Davies, PhD, Medical Specialties RCMB (810), D Level Centre Block, Southampton General Hospital, Southampton, SO16 6YD, United Kingdom.

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