A Life Course Approach to Investigating Asthma Pathogenesis and Progression

Asthma is the commonest chronic lung disease in the UK. It affects all age groups and significantly impacts on quality of life, schooling and work. For most it requires lifelong treatment with drugs and uncertainty, due to the variable nature of the disease. Little is known how factors initiate the disease in early life or impact over the life course of the disease. This programme is centred on studying the life course of asthma, focusing on underlying mechanisms that may lead to disease persistence and progression and how different environmental factors exert influence.
Our research focuses on the human asthma and involves sampling the airways to evaluate on-going tissue events and to obtain airway cells that can be studied in the laboratory under different conditions of exposure. We believe that the airways lining (epithelium) plays a major role in interacting with the environment and, in asthma, expresses signals that promote abnormal inflammation within the airways and induce structural changes (scarring) that alters their flexibility. We have called this dynamic interaction between the epithelium and the deeper airway wall structures the Epithelial Mesenchymal Trophic Unit (EMTU). Our research focuses on understanding how this EMTU is activated in asthma of differing severity and stages of disease. Recognising that most asthma has its origin in the first few years of life, undergoes major changes during childhood and adolescence in which over half ?grow out? of their diseases and adopts characteristics of becoming irreversible in some adults, we have constructed our 5 year programme in 3 stages: (i) In young children at the onset of disease we will use our cell culture systems in the presence and absence of virus, allergen and tobacco smoke exposure to seek differences in the way the epithelium communicates with underlying cells in the EMTU; ii) In teenagers from our Isle of Wight cohort, that has been extensively characterised in relationship to asthma from birth to the age of 18 years, we will assess activation of the EMTU in those with persistent asthma and those who have ?grown out? of asthma; and (iii) In adults with established asthma we determine how the scarring affects the stiffness of the airway wall and whether repeated airway narrowing contributes to and can account for the loss of treatment response in such asthmatics.
This research will identify much needed new targets in disease prevention and treatment high up in the causal disease pathways.

Asthma is an inflammatory disorder of the airways which undergo distinct structural and functional changes leading to variable airflow obstruction. It is amongst the commonest chronic conditions in Western countries affecting 1 in 7 children and 1 in 12 adults. Despite massive investment in research, few new treatments have emerged, current treatment being aimed at suppressing inflammation and symptoms without influencing the underlying causes. The purpose of this programme is to take a life-course view of asthma, the development of sub-phenotypes and their progression over time by combining epidemiological with functional and mechanistic studies in vivo and in vitro. Fundamental to our approach is the recognition that the disease begins most frequently in the first few years, involves multiple interacting environmental stimuli (including viruses, allergens and pollutants) and has a variable natural history. Our programme places the airway epithelium and its communication with the underlying mesenchyme (Epithelial Mesenchymal Trophic Unit) at the centre of asthma. To test this, we will study three age groups: (i) young children at the onset of disease focussing on the role of multiple insults on a susceptible epithelium; ii) teenagers from our Isle of Wight cohort that has been extensively phenotyped for asthma from birth to 18 years seeking evidence for persistent activation of the EMTU; and (iii) adults with established asthma focussing on disease chronicity due to structural changes driven by the EMTU.
Using biopsies and epithelial brushings from well phenotyped subjects we will apply our culture systems of epithelial monolayer, differentiated epithelium, epithelium seeded with dendritic cells and epithelium grown over (myo)fibroblasts to recapitulate the EMTU using airway cells from groups (i) and (ii). Cultures will be exposed to rhinovirus and smoke extract as the most important early life exposures linked to asthma onset, and effects on barrier function, allergen penetration and innate immunity assessed. In adults, airway wall remodelling dominates more chronic asthma. We will use endobronchial fibrepotic fluorecence microscopy combined with IHC, atomic force microscopy (stiffness) and helium ion microscopy (ultrastructure) and relate these to collagen type and cross-linking. Because remodelling is a response to repeated distortion of the airways, we will examine the effect of cyclical strain on the EMTU using cells from well phenotyped patients with differing degrees disease severity and remodelling.
This integrated programme brings together epidemiological and disease cohorts with detailed phenotyping and mechanistic studies to reveal new high level targets fundamental to disease pathogenesis and progression.