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School of Medicine, Division of Respiratory Cell and Molecular Biology, Southampton General Hospital, Southampton, SO16 6YD, U.K.
1Correspondence: Medical Specialties Level D, Centre Block (810), Southampton General Hospital, Tremona Rd., Southampton SO16 6YD, U.K. E-mail donnad{at}soton.ac.uk
Epithelial damage and airway remodeling are consistent features of bronchial asthma and are correlated with disease chronicity, severity, and bronchial hyperreactivity. To examine the mechanisms that control bronchial epithelial repair, we investigated expression of the epidermal growth factor receptor (c-erbB1, EGFR) in asthmatic bronchial mucosa and studied repair responses in vitro. In biopsies from asthmatic subjects, areas of epithelial damage were frequently observed and exhibited strong EGFR immunostaining. EGFR expression was also high in morphologically intact asthmatic epithelium. Using image analysis, EGFR immunoreactivity (% of total epithelial area, median (range) was found to increase from 9.4 (4.1–20.4) in normal subjects (n=10) to 18.4 (9.3–28.9) in mild asthmatics (P<0.01, n=13) and 25.4 (15.4–31.8) in severe asthmatics (P<0.00, n=5). Epithelial EGFR immunoreactivity remained elevated in patients treated with corticosteroids and was positively correlated with subepithelial reticular membrane thickening. Using 16HBE 14o- bronchial epithelial cells, we found that EGF accelerated repair of scrape-wounded monolayers and that the EGFR-selective inhibitor, tyrphostin AG1478, inhibited both EGF-stimulated and basal wound closure whereas dexamethasone was without effect. Intrinsic activation of the EGFR was confirmed by analysis of tyrosine phosphorylated proteins, which revealed a rapid, damage-induced phosphorylation of the EGFR, irrespective of the presence of exogenous EGF. To assess the relationship between EGFR-mediated repair and tissue remodeling, release of the profibrogenic mediator TGF-ß2 was also measured. Scrape wounding increased release of TGF-ß2 from epithelial monolayers and EGF had no additional stimulatory effect. However, when repair was retarded with AG1478, the amount of TGF-ß2 increased significantly. These data indicate that the EGFR may play an important role in bronchial epithelial repair in asthma and that impairment of this function may augment airway remodeling.—Puddicombe, S. M., Polosa, R., Richter, A., Krishna, M. T., Howarth, P. H., Holgate, S. T., Davies, D. E. Involvement of the epidermal growth factor receptor in epithelial repair in asthma.
Key Words: phosphorylation • tyrphostin • remodeling • TGF-ß • c-erbB1
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