Involvement of the epidermal growth factor receptor in epithelial repair in asthma

Abstract

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-beta2 was also measured. Scrape wounding increased release of TGF-beta2 from epithelial monolayers and EGF had no additional stimulatory effect. However, when repair was retarded with AG1478, the amount of TGF-beta2 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.

Potential use of an anticancer drug gefinitib, an EGFR inhibitor, on allergic airway inflammation

“…For example, EGFR plays an essential role in airway inflammation, reflecting epithelial damage and activation, and its expression increases in proportion to the severity of the asthma (Amishima et al, 1998;Puddicombe et al, 2000;Burgel and Nadel, 2004;Wong, 2005). EGFR is a 170-kDa membrane glycoprotein which is activated by multiple ligands including EGF, TGF-, heparin binding (HB)-EGF, amphiregulin, -cellulin, and epiregulin.…”

“…On ligand binding, EGFR homodimerise or heterodimerise, thereby inducing intrinsic kinase activities that initiate intracellular signal transduction cascades including the Ras/Raf/MAPK pathway, the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, and the STAT pathway (Bogdan and Klambt, 2001). The degree of EGFR expression reflects the epithelial damage and activation, and increases in proportion to asthma severity (Amishima et al, 1998;Puddicombe et al, 2000;Burgel and Nadel, 2004;Wong, 2005). Activated EGFR also has an essential role in mucin production in airway epithelium (Takeyama et al, , 2001Nadel, 2001;Nadel and Burgel, 2001).…”

DUOX1 mediates persistent epithelial EGFR activation, mucous cell metaplasia, and airway remodeling during allergic asthma

“…One well-recognized feature of epithelial alterations in the asthmatic airway is the increased expression of the EGFR and several of its ligands, leading to increased and corticosteroid-insensitive EGFR activation (6)(7)(8)(9)(10). Epithelial EGFR activation contributes to several important features of asthma, including the activation of a chronic wound response within the airways characterized by airway remodeling, mucous metaplasia, and neutrophilic inflammation (11)(12)(13).…”

EGF receptor activation during allergic sensitization affects IL‐6‐induced T‐cell influx to airways in a rat model of asthma

“…However, the EGFR signaling pathway is implicated in airway biology and EGFR is expressed by many cell types in the lung, including smooth muscle cells, endothelium, fibroblasts and epithelium [3,4]. Human asthmatic airways show increased EGFR immunoreactivity in airway epithelium, glands, and smooth muscle [5] and EGFR activation has been reported to promote epithelial repair and to induce mucin production and remodeling of airway tissues [6,7]. We previously reported that multiple OVA challenges increased protein expression of the EGFR ligand, heparin-binding EGF-like growth factor (HB-EGF) in airway epithelium in Brown Norway (BN) rats [4].…”