Role of Oxidative and Nitrative Stress and Histone De-acetylation in Rhinovirus Induced Acute Exacerbations of COPD

Lead Research Organisation: Imperial College London
Department Name: National Heart and Lung Institute

Abstract

Chronic obstructive pulmonary disease (COPD) or smokers? lung is a growing problem and already one of the commonest causes of death and disability in the UK. COPD accounts for over #800 million in direct healthcare costs. Seventy percent of these costs are related to acute attacks. Acute attacks are also dreaded by COPD sufferers, as they lead to severe breathlessness, prolonged hospitalisation or death. Current therapies are not good at either treatment or prevention of acute attacks. New approaches to therapy are therefore urgently needed. COPD is associated with inflammation in the lung, which gets worse as the disease progresses. Acute attacks also involve inflammation in the lung but how this occurs is very poorly understood. Most acute attacks are caused by common cold viruses, which ?go to the chest?. We plan to carry out detailed studies of virus induced acute attacks of COPD, to understand the molecules switching on inflammation in the lung during these attacks. By identifying the molecules that increase lung inflammation during these attacks, we should be able to identify targets for the development of new therapies for both prevention and treatment of acute attack of COPD. So doing would greatly reduce distress suffered by COPD patients, as well as reducing mortality and health care costs.

Technical Summary

Respiratory viral infections are detected in 40-60% of exacerbations of COPD and 2/3 of patients report common cold symptoms preceding exacerbation. Rhinoviruses (RV) are the major virus type identified. Existing treatments are poorly effective at treating or preventing COPD exacerbations. New treatments are urgently required to reduce the associated morbidity, mortality and health care costs. To identify targets for the development of new treatments, understanding of the molecular mechanisms of COPD exacerbations is required.
Inflammatory gene transcription is up-regulated by acetylation and down-regulated by deactylation of histones. Stable COPD is associated with increased oxidative/nitrative stress, degradation of histone deacetylase-2 (HDAC2), transcription factor activation, resulting in airway inflammation. Rhinovirus infection of epithelial cells rapidly induces oxidative stress and inflammatory gene transcription.
We hypothesize that (i) RV infection of epithelial cells and macrophages in vitro induces oxidative/nitrative stress leading to nitration of HDAC2 and its degradation - this results in increased acetylation of histones and of specific transcription factors leading to enhanced inflammatory gene transcription (ii) these pathways are all up-regulated in COPD patients compared to control subjects on RV infection in vivo and are related to increased airway inflammation, virus load, respiratory symptoms and reductions in lung function.
RV experimental infection in asthma provides a model of virus-induced asthma exacerbations allowing investigation under controlled conditions of the molecular mechanisms of asthma exacerbations. We have developed an experimental RV infection model in moderate COPD patients and have shown it is safe and induces lower respiratory symptoms and reductions in lung function typical of COPD exacerbations.
We propose an experimental infection study in moderate COPD patients and age/smoking matched non-obstructed control volunteers to investigate the molecular mechanisms of COPD exacerbations with the aim of identifying targets for the development of new therapies. Lower respiratory tract sampling will be carried out at baseline, intensively during exacerbation, through recovery and at 6 weeks. These in vivo studies will be complemented by in vitro studies investigating molecular mechanisms of RV induction of inflammation in bronchial epithelial cells and macrophages. Molecular targets identified by the in vitro studies will then be confirmed and related to airway inflammation, virus load, respiratory symtpoms and lung function in vivo. Finally we will investigate pharmacologic/genetic inhibition of key regulatory molecules in vitro to identify novel targets for development of new therapies for acute exacerbations of COPD.

Publications

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Mallia P (2018) Role of airway glucose in bacterial infections in patients with chronic obstructive pulmonary disease. in The Journal of allergy and clinical immunology

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Molyneaux PL (2014) The role of bacteria in the pathogenesis and progression of idiopathic pulmonary fibrosis. in American journal of respiratory and critical care medicine

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Molyneaux PL (2013) Outgrowth of the bacterial airway microbiome after rhinovirus exacerbation of chronic obstructive pulmonary disease. in American journal of respiratory and critical care medicine

 
Title Human model of rhinovirus induced exacerbation of COPD 
Description Human model of rhinovirus induced exacerbation of COPD 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2009 
Provided To Others? Yes  
Impact Will be used in PoC study for new treatment approach in 2010 
 
Description Associate Prof Fred Wong 
Organisation National University of Singapore
Country Singapore 
Sector Academic/University 
PI Contribution ongoing collaboration
Collaborator Contribution ongoing collaboration
Impact ongoing collaboration
 
Description GlaxoSmithKline 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution Molecular mechanisms of inhibition by fluticasone, salmeterol and the combination of rhinovirus induction of pro-inflammatory molecules.
Collaborator Contribution Molecular mechanisms of inhibition by fluticasone, salmeterol and the combination of rhinovirus induction of pro-inflammatory molecules.
Impact ...
 
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 Pfizer 
Organisation Pfizer Ltd
Country United Kingdom 
Sector Private 
PI Contribution Development of an experimental model of rhinovirus induced COPD exacerbations.
Collaborator Contribution Development of an experimental model of rhinovirus induced COPD exacerbations.
Impact ...
 
Description Prof Alberto Papi, University of Ferrara at S.Anna University Hospital 
Organisation University of Ferrara
Country Italy 
Sector Academic/University 
PI Contribution ongoing collaboration
Collaborator Contribution ongoing collaboration
Impact ongoing collaboration
 
Description Prof Dallas Swallow, UCL 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution ongoing collaboration
Collaborator Contribution ongoing collaboration
Impact ongoing collaboration
 
Description Prof Ian Sabroe, Sheffield 
Organisation University of Sheffield
Country United Kingdom 
Sector Academic/University 
PI Contribution ongoing collaboration
Collaborator Contribution ongoing collaboration
Impact ongoing collaboration
 
Description Prof Jane Mitchell, Imperial College London 
Organisation Imperial College London
Department National Heart & Lung Institute (NHLI)
Country United Kingdom 
Sector Academic/University 
PI Contribution ongoing collaboration
Collaborator Contribution ongoing collaboration
Impact ongoing collaboration
 
Description Prof Jonathan Grigg, QMUL 
Organisation Queen Mary University of London
Department Blizard Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution ongoing collaboration
Collaborator Contribution ongoing collaboration
Impact ongoing collaboration
 
Description Prof Renaud Louis, Belgium 
Organisation University of Liege
Department Department of Pneumology
Country Belgium 
Sector Academic/University 
PI Contribution ongoing collaboration
Collaborator Contribution ongoing collaboration
Impact ongoing collaboration
 
Description American Thoracic Society 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Lecture Viruses and Asthmatic Airways
Year(s) Of Engagement Activity 2015
 
Description MRC Centenary Celebration (Science Festival & Open Week, June 2013) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact The Centre took part in the MRC Centenary Celebrations on 15th-16th June 2013 (Science Festival at the Science Museum) and on 20th June 2013, when we organised a day-time event as part of the Centenary Open Week.


Some outcomes of our Open Day event on 20th June 2013 by the Observation Point in London's South Bank:

• 12ft inflatable lungs from The Roy Castle Lung Cancer Foundation were probably our most significant model for the Open Week event. Centre scientists worked in shifts, presenting the anatomy and function of normal lungs and also spoke of lung diseases
• Asthma themed sand sculptures on the banks of Thames were of great interest. MRC Centenary hash tag #100mrc was also drawn in sand
• The desk size balloon model of lungs demonstrated how lungs work in a healthy individual and what happens in the lungs of asthmatics
• Members of the public were introduced to most common allergens at home ('Allergen House' poster game with magnetic allergens). Allergens such as dustmites and mold were placed in rooms where one would most likely encounter them. Afterwards scientists corrected the answers and explained the reasons why
• We ran an interactive game of Respiratory Olympics where peoples' lung capacities were measured using a spirometer. Men and women competed in different categories and the biggest lung capacity in each category won a prize, which was a pair of tickets to the Open East Festival (the first official opening of the Olympic Park since the 2012 Olympics)
• Overall we felt that our event was very well received, judging by the footfall and the fact that we did not experience many quiet moments. We felt that people were interested in our work and found our research of great significance

Other information:

• Collaboration and interaction with our partners (MRC, Asthma UK, Imperial and King's Colleges) as well as the other London based MRC Centres
• The Biomedical Research Centre (BRC) and the British Society for Immunology (BSI)
• Great learning exposure and enthusiasm for the Centre trainees (students and Post Docs)
• Our Open Day event was attended by Dr. Alfred William Frankland, one of the early pioneers of allergen immunotherapy
• Asthma UK Visit on12th Nov 2013 to the Centre Headquarters. Asthma UK have since requested further events for patients and donors. There are likely to be some as yet unknown impacts.
Year(s) Of Engagement Activity 2013
URL http://www.centenary.mrc.ac.uk/