A Life Course Approach to Investigating Asthma Pathogenesis and Progression

Lead Research Organisation: University of Southampton
Department Name: Cancer Sciences

Abstract

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.

Technical Summary

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.

Publications

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Akoto C (2017) Mast cells are permissive for rhinovirus replication: potential implications for asthma exacerbations. in Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology

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Andriotis OG (2014) Nanomechanical assessment of human and murine collagen fibrils via atomic force microscopy cantilever-based nanoindentation. in Journal of the mechanical behavior of biomedical materials

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Andriotis OG (2015) Structure-mechanics relationships of collagen fibrils in the osteogenesis imperfecta mouse model. in Journal of the Royal Society, Interface

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Bachert C (2012) Specific IgE against Staphylococcus aureus enterotoxins: an independent risk factor for asthma. in The Journal of allergy and clinical immunology

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Bhimrao SK (2011) Airway inflammation in atopic patients: a comparison of the upper and lower airways. in Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery

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Blume C (2013) Barrier responses of human bronchial epithelial cells to grass pollen exposure. in The European respiratory journal

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Bondanese VP (2014) Identification of host miRNAs that may limit human rhinovirus replication. in World journal of biological chemistry

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Bousquet J (2014) Birth cohorts in asthma and allergic diseases: report of a NIAID/NHLBI/MeDALL joint workshop. in The Journal of allergy and clinical immunology

 
Description Clinical Research Training Fellowship (MJ)
Amount £219,573 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2013 
End 08/2016
 
Description MRF/Asthma UK Research Grant (HMH)
Amount £291,765 (GBP)
Organisation Medical Research Council (MRC) 
Department Medical Research Foundation
Sector Charity/Non Profit
Country United Kingdom
Start 01/2016 
End 12/2019
 
Description NIHR BRC
Amount £15,000,000 (GBP)
Organisation National Institute for Health Research 
Department NIHR Biomedical Research Centre
Sector Public
Country United Kingdom
Start 04/2017 
End 03/2022
 
Description Non-animal models for asthma
Amount £86,116 (GBP)
Organisation National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2015 
End 05/2016
 
Description Programme Grant
Amount £500,000 (GBP)
Funding ID G0900453 and G0900453-E01/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2009 
End 10/2015
 
Description Project grant
Amount £499,713 (GBP)
Organisation National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2011 
End 06/2013
 
Description research contract
Amount $146,652 (USD)
Organisation Johnson & Johnson 
Sector Private
Country United States
Start 09/2015 
End 03/2016
 
Description CASE PhD studentship 
Organisation Novartis
Country Global 
Sector Private 
PI Contribution A joint PhD student working between Novartis Horsham and University of Southampton
Collaborator Contribution Expertise in epithelial cell models - UoS Expertise in analytical methodologies- Novartis Shared expertise in respiratory diseases
Impact 2 Poster presentations at the American Thoracic Society 2014: Jessica E Donaldson, Betty Shamji, Emily J Swindle, Matt E Edwards, Donna E Davies. Regulation Of Thymic Stromal Lymphopoietin Release From Human Bronchial Fibroblasts By Pro-Inflammatory Cytokines Jessica E Donaldson, Betty Shamji, Emily J Swindle, Matt E Edwards, Donna E Davies. Characterization Of The Thymic Stromal Lymphopoietin Response In Co-Cultures Of Human Bronchial Fibroblasts And Epithelial Cells
Start Year 2011
 
Company Name Synairgen 
Description Respiratory Drug discovery company as spin-out of university of Southampton 
Year Established 2005 
Impact June 2014: Out licencing of inhaled IFN beta for asthma and COPD exacerbations $7.25 million up-front, $225 million milestone payments and 9-16% Royalties on final sales.
 
Company Name Synairgen 
Description Synairgen is a respiratory drug development company 
Year Established 2005 
Impact June 2014: AS Southampton, UK: Synairgen plc (LSE: SNG) today announced a global licence agreement with AstraZeneca for SNG001, a novel, inhaled interferon beta (IFN -beta) in clinical development for treating respiratory tract viral infections in patients with severe asthma. SNG001supports the immune system by correcting a deficiency which makes patients vulnerable to respiratory tract viral infections. Under the terms of the exclusive licence agreement, AstraZeneca will pay Synairgen a $7.25 million up - front fee and potential development, regulatory and commercial milestones of up to $225million. In addition, AstraZeneca will pay tiered royalties ranging from single -digit up to mid - teens on commercial sales. AstraZeneca will be responsible for future development costs. In early 2015, AstraZeneca will commence a Phase II a study in patients with severe asthma building on available clinical data from an initial Phase ll a trial in a broad asthma population. SNG001 also provides the opportunity to expand the clinical programme in other pulmonary diseases including chronic obstructive pulmonary disease (COPD).
Website http://www.synairgen.com/
 
Description Think Tank with CAAT (Europe) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact WE have prepared a white paper on barrier models for the lung, skin and GI tract. Publication by end 2014.

Better understanding of the needs of industry academia and regulatory bodies.
Year(s) Of Engagement Activity 2014
URL http://www.controlledreleasesociety.de/BioBarriers%202014%20-%20Program.pdf