Epidermal growth factor receptor in airway remodeling during allergic airway disease – divergent roles during early life and adulthood?
H. Stölting, S. A. Walker, M. C. Zarcone, F. Puttur, S. Saglani, C. M. Lloyd
National Heart and Lung Institute, Imperial College London - London (United Kingdom)
Airway remodelling is a key pathological feature of paediatric and adult asthma, but the underlying mechanisms remain poorly understood. However, their elucidation is crucial, since lung function deficits established in children with asthma persist into adulthood. Epidermal growth factor receptor (EGFR) was shown to be overexpressed in paediatric and adult asthmatics. In addition, several in vivo studies using rodent models of allergic airway disease (AAD) have described a role for EGFR signalling in driving impaired lung function and airway remodelling in adult animals. Here, we aimed to study the role of EGFR in early life AAD.
Bronchial epithelial cells from non-asthmatic children cultured at air-liquid interface were shown to exhibit high mRNA levels for EGFR and its ligands. Exposure of these cells to the allergen house dust mite induced EGFR activation dose-dependently, as measured by Y1068 phosphorylation. qPCR analysis of flow-sorted murine lung cell populations during postnatal development similarly showed high EGFR expression in murine lung epithelial cells from neonatal and adult mice, and lung epithelial EGFR expression was confirmed by flow cytometry. Finally, a pharmacological inhibitor was used to block EGFR signalling in a neonatal model of AAD. Preliminary findings indicate that EGFR inhibition in neonatal mice resulted in worsened lung function, as measured by a 2-fold increase in airway resistance (AUC), without affecting overall inflammation, a finding we did not observe in a corresponding adult AAD model.
These results indicate that EGFR is present in lungs at all stages of life and that, in contrast to its widely described pathogenic contribution to airway remodelling of adult animals, signalling through EGFR may play a protective role during early life AAD.