Epidermal growth factor receptor signalling in the pulmonary immune response - diverging roles in early life and adulthood?
Author(s)
Stoelting, Helen
Type
Thesis
Abstract
Asthma is a chronic heterogeneous airway disease characterised by airway inflammation, hyperresponsiveness and remodelling. Onset of asthma primarily takes place in childhood, an aspect that is underrepresented in mouse models of allergic airway disease (AAD), and results in long-lasting deficits in lung function. Epidermal growth factor receptor (EGFR) is ubiquitously expressed, fulfils both protective and pathogenic functions in various disease contexts and was shown to be upregulated in both children and adults with asthma. The aim of this thesis was to define the role of EGFR signalling in early-life AAD and compare it to adulthood.
Analysis of newly generated and published data in Chapter 3 revealed widespread expression of EGFR and its ligands in the lungs of both developing and adult mice and provided evidence for enhanced EGFR signalling upon allergen exposure.
Manipulation of EGFR signalling in various AAD models in Chapter 4 identified a unique role of this pathway in protecting against airway hyperresponsiveness in early life which was not observed in adulthood.
In-depth analysis of EGFR inhibition during early-life AAD conducted in Chapter 5 established a novel role for EGFR signalling in driving sex differences in early-life AAD by augmenting type 2 immune responses of young female animals.
Finally, Chapter 6 investigated EGFR involvement in respiratory infection, comparing SARS-CoV-2 infection between children and adults by studying paediatric and adult airway epithelial cells. This demonstrated SARS-CoV-2 infection to be indistinguishable between paediatric and adult cells but significantly diminished damage and inflammation compared to infection with Influenza H1N1.
Collectively, these findings demonstrate that EGFR signalling is highly active during AAD but fulfils distinct roles depending on age and sex, underscoring the need to use appropriate models of disease. The pathway may constitute therapeutic targets to preserve lung function
in early life and may protect young females from developing severe disease.
Analysis of newly generated and published data in Chapter 3 revealed widespread expression of EGFR and its ligands in the lungs of both developing and adult mice and provided evidence for enhanced EGFR signalling upon allergen exposure.
Manipulation of EGFR signalling in various AAD models in Chapter 4 identified a unique role of this pathway in protecting against airway hyperresponsiveness in early life which was not observed in adulthood.
In-depth analysis of EGFR inhibition during early-life AAD conducted in Chapter 5 established a novel role for EGFR signalling in driving sex differences in early-life AAD by augmenting type 2 immune responses of young female animals.
Finally, Chapter 6 investigated EGFR involvement in respiratory infection, comparing SARS-CoV-2 infection between children and adults by studying paediatric and adult airway epithelial cells. This demonstrated SARS-CoV-2 infection to be indistinguishable between paediatric and adult cells but significantly diminished damage and inflammation compared to infection with Influenza H1N1.
Collectively, these findings demonstrate that EGFR signalling is highly active during AAD but fulfils distinct roles depending on age and sex, underscoring the need to use appropriate models of disease. The pathway may constitute therapeutic targets to preserve lung function
in early life and may protect young females from developing severe disease.
Version
Open Access
Date Issued
2022-12-09
Date Awarded
01/03/2023
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Lloyd, Clare M
Saglani, Sejal
Sponsor
British Lung Foundation
Grant Number
P76993
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)