The epidermal growth factor receptor mediates allergic airway remodelling in the rat

Abstract

The chronicity of bronchial asthma is attributed to persistent airway inflammation and to a variety of structural changes, or remodelling, that includes smooth muscle and goblet cell hyperplasia.To investigate the mechanisms of airway remodelling, the current authors used an established allergen (ovalbumin; OVA)-driven rodent model (the Brown Norway rat).Brown Norway rats were sensitised to OVA and challenged three times at 5-day intervals to evoke airway remodelling. The effects of an epidermal growth factor (EGF) receptor inhibitor, AG1478, and a cysteinyl leukotriene-1 receptor antagonist, montelukast, on epithelial and airway smooth muscle (ASM) cell proliferation in vivo in response to repeated OVA challenge were tested. Three challenges with leukotriene (LT)D 4 were given, to examine their effects on remodelling with and without AG1478 pretreatment.OVA challenges caused ASM hyperplasia, with an increase in mass, epithelial cell proliferation and goblet cell proliferation. AG1478 prevented the changes, as did montelukast. Multiple OVA challenges increased heparin-binding EGF-like growth factor but not EGF expression by airway epithelium. LTD 4 reproduced the changes in remodelling induced by OVA and this was blocked by AG1478.Allergen-induced airway epithelial and airway smooth muscle remodelling is mediated by cysteinyl leukotrienes via the cysteinyl leukotriene-1 receptor with downstream effects on the epidermal growth factor receptor axis.KEYWORDS: Allergy, inflammation, lung, signal transduction A sthmatic airways often show extensive and complex remodelling [1][2][3][4]. The growth of smooth muscle has the potential to have the most significant pathophysiological consequences through excessive airway narrowing and airway hyperresponsiveness [5,6]. Increase in airway smooth muscle (ASM) in the airways has been associated with the severity of asthma [3,7], and when present in excess in the large airways is associated with mortality [8]. It is known that hyperplasia of smooth muscle in animal models [9][10][11] and both hyperplasia and hypertrophy in airway specimens from human subjects [12,13] contribute to the increase in ASM mass. It has also been proposed that migration of subepithelial myofibroblasts may add to the tissue mass [7].The mechanism of the growth response of muscle is quite uncertain, although several descriptive studies of growth factor expression in human airway tissues have been reported [14][15][16] and many growth factors have been demonstrated to have mitogenic effects on ASM in culture [17][18][19][20]. Cysteinyl (cys)-leukotrienes (LTs) are known to be involved in allergen-induced ASM cell proliferation in vivo [21,22] but in vitro these substances are weak mitogens for ASM [23,24]. In the sensitised mouse, cys-LT 1 receptor (cys-LT 1 R) antagonism prevents an increase in ASM thickening after repeated allergen challenge [25,26]. It is possible that the effects of cys-LTs in vivo are indirect and mediated by altering the expression of or potentiating the effects of tyrosi...

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

“…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]. The inhibition of the tyrosine kinase signaling cascade might have therapeutic effects in asthma [8].…”

“…A recent publication has suggested a role for amphiregulin, an EGFR ligand, in Th2-cell differentiation in the mouse [15]. Therefore, it is possible that EGFR signaling may be important during the sensitization phase of the immune response to allergen and may affect airway inflammation and airway responsiveness by altering the function of immune cells including lymphocytes.The BN rat model of asthma has been widely used [4,16] as it develops high levels of IgE upon sensitization [17] and has typical Th2 inflammation, early-and late-phase airway responses and AHR after allergen challenge [18]. In the current study, we hypothesized that the inhibition of EGFR signaling by the selective EGFR-TK inhibitor AG1478 given at the time of allergic sensitization was capable of modulating immune reactions in the BN rat.…”

“…AG1478 inhibits the proliferation of lung fibroblasts in vitro and has protective effects against bleomycin and vanadium pentoxide-induced pulmonary fibrosis [10,11]. Recently, we demonstrated that AG1478 prevented allergeninduced airway epithelial and airway smooth muscle remodeling mediated by cysteinyl leukotrienes in BN rats [4]. Furthermore, it has been reported that AG1478 given just prior to allergen challenge reduces eosinophil inflammation and MUC5AC protein expression in BAL and airway hyperresponsiveness (AHR) in OVA-sensitized, challenged mice [12].…”

“…The importance of the EGFR axis in cancer has best been studied in breast malignancies. 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].…”

“…growth factor (HB-EGF) in airway epithelium in Brown Norway (BN) rats [4]. The inhibition of the tyrosine kinase signaling cascade might have therapeutic effects in asthma [8].…”