Expression of Epidermal Growth Factor and Epidermal Growth Factor Receptor Immunoreactivity in the Asthmatic Human Airway

Abstract

Chronic airway inflammation, one of the pathophysiologic features of bronchial asthma, is suspected to be responsible for irreversible pathological changes of airways, called airway remodeling. To examine the mechanisms of airway remodeling in asthma, we investigated the expression of epidermal growth factor (EGF) and its receptor immunohistochemically in asthmatic human airways. Airway specimens from seven patients with asthma were obtained from autopsied and surgically resected lungs. Control specimens were obtained from lungs of eight subjects without asthma and other pulmonary complications at autopsy. We stained those specimens by the avidin-biotin-peroxidase complex (ABC) method with anti-human polyclonal EGF antibody and monoclonal EGF receptor antibodies. Three different portions of airways-large bronchi (about 1 cm in diameter), small bronchi (about 3 mm in diameter), and peripheral airways (less than 2 mm in diameter)-were examined. The thickness of the bronchial smooth muscle and basement membrane was significantly greater in the asthmatic airways than in controls. Clear immunoreactivities of EGF were widely observed on bronchial epithelium, glands, and smooth muscle in asthmatic airways. In the controls, the bronchial epithelium and the bronchial glands partially expressed faint EGF immunoreactivity. For the EGF receptor, clear immunoreactivities were also observed on bronchial epithelium, glands, smooth muscle, and basement membrane in asthmatic airways. In control airways, only part of the bronchial epithelium and smooth muscle weakly expressed EGF receptor immunoreactivity. These results suggest a possible contribution of EGF to the pathophysiology of bronchial asthma, including airway remodeling.

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

“…Amishima et al (1998) also reported increased expression of EGF and EGFR in asthmatic human airway epithelium compared with their levels in a control population, suggesting that EGF may contribute to the pathophysiology of bronchial asthma. EGF and eosinophilderived TGF-, another natural ligand for the EGFR, have been shown to stimulate MUC5AC mucin gene expression and protein synthesis in a human airway epithelial cell line, and goblet cell metaplasia (Burgel and Nadel, 2004).…”

“…Pretreatment with gefitinib inhibits the activation of EGFR and Akt, reduces the release of Th2 cytokines from airway epithelium, and decreases the recruitment of eosinophils into airway epithelium. In fact, EGFR expression is increased in bronchial epithelium in adult and childhood asthma and there is an increasing number of studies using EGFR to regulate airway inflammation in asthma (Amishima et al, 1998;Polosa et al, 2002;Fedorov et al, 2005). However, it is not well known the mechanisms that EGFR tyrosine kinase inhibitor inhibits 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).…”

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].…”