The Mechanisms of Inflammation and Immunity in COPD and Their Relationship to Exacerbations and Disease Progression

Lead Research Organisation: University of Nottingham
Department Name: Division of Respiratory Medicine

Abstract

COPD (which used to be called chronic bronchitis and emphysema) is a common disease which causes considerable difficulty to sufferers. The pharmaceutical industry has been relatively unsuccessful in bringing new treatments to the marketplace for COPD, with many products failing when they are first given to patients because they do not have the effects that were predicted from studies in animals. A way of circumventing this problem is to test new potential medicines in cells and tissues obtained from COPD sufferers and develop laboratory models of COPD using these cells to predict more accurately the approaches that are likely to succeed in patients. Many patients with COPD have progressive changes in their airways and airspaces which are currently unresponsive to any of the current COPD medicines. By understanding how these processes develop, we will identify new pathways that the medicines of tomorrow can target. We will also gain information on molecules that we can measure in patients that will accurately predict whether a patients airways or airspaces are getting destroyed.

Technical Summary

COPD is characterised by extensive lung remodelling for which there is currently no effective treatment. The co-existence of airways fibrosis and emphysema in COPD points to both pro-fibrotic and tissue destructive mechanisms being operative at the same time, which could be explained by differences in fibroblast function between the airways and parenchyma. The main insults underlying the cycle of tissue damage and frustrated repair that fails to result in restitution of tissue integrity are oxidative stress and infection. We propose that the effect of these is channelled through the epithelium to the underlying mesenchymal cells, resulting in tissue fibrosis in the airways and alveolar destruction.
In a step change for translational research and drug development, this workpackage brings together leading academic respiratory research groups and pharmaceutical companies to address the widely perceived key unmet needs in COPD: 1) understanding the mechanisms of injury and repair, 2) validated human lung tissue models for the ex vivo study of COPD pathogenesis, 3) pre-clinical proof of efficacy of drugs in development and 4) biomarkers which assist drug development.
Our hypothesis is that lung epithelial damage, caused by a combination of exogenous and endogenous radical oxygen species and virus infections, drives remodelling in COPD, with varying degrees of fibrosis and destruction in the airway and parenchymal compartments depending on the relative involvement of TGF? and metalloproteases. We will apply our validated lung ex vivo models using samples from deeply characterised COPD patients and controls, enabling integration of clinical and experimental data that should help focus drug development to appropriate COPD phenotypes. We will use bronchial and alveolar epithelial cultures alone or co-cultures with fibroblasts or smooth muscle cells, progressing to whole tissue explant (biopsy, wedge resection, dissected small airways); applying disease-relevant stimuli, including oxidants and viruses, we will study disease mechanisms, looking for differences between the airways and lung parenchyma. We will extend our pilot observations of carbonyl-modified proteins which act as auto-antigens and induce auto-antibodies in correlation with COPD severity and study their destructive role. Progressing from simple, single cell type (high-throughput) models to complex tissue explants, we will provide proof of efficacy for an array of tool compounds from pharma. The focused and well integrated approach that we are applying should deliver within 2-3 years a step change in the understanding of remodelling mechanisms in COPD and an advance in drug development through provision of proof of concept for novel drugs.

Publications

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Alipoor SD (2016) Exosomes and Exosomal miRNA in Respiratory Diseases. in Mediators of inflammation

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Alipoor SD (2016) The roles of miRNAs as potential biomarkers in lung diseases. in European journal of pharmacology

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Bigler J (2017) A Severe Asthma Disease Signature from Gene Expression Profiling of Peripheral Blood from U-BIOPRED Cohorts in American Journal of Respiratory and Critical Care Medicine

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Bousquet J (2017) Building Bridges for Innovation in Ageing: Synergies between Action Groups of the EIP on AHA. in The journal of nutrition, health & aging

 
Description COPDMAP 
Organisation Association of the British Pharmaceutical Industry
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Member of workpage 3
Collaborator Contribution Investigation of the innate immune responses of BECs from COPD patients to rhinovirus infection
Impact Investigation of innate immune dysfunction of airway epithelial cells and the association with responses to oxidative stress.
Start Year 2011
 
Description Models of PAH 
Organisation University of Newcastle
Country Australia 
Sector Academic/University 
PI Contribution Introduced collaborators to concept of COPD-associated PAH and will be performing bioinformatic analysis of samples.
Collaborator Contribution Looking at smoking model and others for evidence of PAH to provide models of COPD-associated PAH. Partners will be validating changes in vascular remodelling and cardiovascular parameters
Impact No outcomes to date as still validating models
Start Year 2016
 
Description IGNITE event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Day of interactive events to educate public
Year(s) Of Engagement Activity 2016,2017,2018
 
Description Mayfest/Wonder University of Nottingham 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Open day where research presented
Year(s) Of Engagement Activity 2015,2016,2017
 
Description Presentation at American Thoracic Society accepted 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Research findings will be presented

Will disseminate findings, stimulate discussion
Year(s) Of Engagement Activity 2015,2016,2017,2018