Prostanoid receptors as targets for asthma and COPD therapy

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

Abstract

Asthma is an inflammatory disease of the lung that affects a large percentage of the population in the Western world and represents a huge health care burden and is characterised by chest tightness and breathing difficulties. There are 5.2 million asthma sufferers in the UK, 1.1 million children (1 in 10) and 4.1 million adults (1 in 12). On average, 1400 people die from asthma each year, and asthma now costs the NHS an average of #889 million per year. The Global Burden of Disease studies ranked COPD as the 6th commonest cause of death worldwide in 1990 and this has now risen to 4th. In the UK COPD now causes about 30,000 deaths a year and mortality is almost double the European average, with COPD killing more women than breast cancer last year.Inflammation is believed to be central to the development and symptoms of asthma and COPD. A naturally occurring chemical in the body can open the airways and reduce the inflammation through interactions with one or more of a family of proteins. Unfortunately, this chemical also causes cough. The aim of this study is to try to determine which of the proteins are involved in the beneficial responses and which in the detrimental cough response of the chemical. The hope is that this work may lead to the discovery of a novel drug which could selectively target the beneficial processes leading to the production of a therapy that could help these patients who suffer from these debilitating diseases.

Technical Summary

In the clinic, patients with asthma and COPD are treated with either beta-agonists to induce bronchodilatation, or steroids to control the underlying airway inflammation observed in this disease. The prostanoid, PGE2 has been reported to induce bronchodilatation in animals and humans, and confers certain advantages over existing bronchodilators due to its anti-inflammatory potential. However, PGE2 also causes airway irritancy and cough. Prostanoids act at G-protein coupled receptors, of which five main classes have been identified. The EP-receptor also exists in four subtypes. PGE2 relaxes smooth muscle (possibly via activation of the EP2 receptor) and is anti-inflammatory (receptor not known). Furthermore, the receptor that induces cough has not been characterised. It is, therefore, possible that the EP-receptor subtype mediating irritancy and cough differs from that mediating bronchodilatation and anti-inflammatory effects. The current proposal aims to classify the receptor(s) through which prostanoids act to stimulate airway vagal sensory nerves, nerves that are instrumental in orchestrating the cough reflex. In addition, we also aim to investigate the receptors involved in evoking the anti-inflammatory effects attributed to prostanoids under both normal and disease conditions. This work may highlight a bronchodilator and anti-inflammatory agonist devoid of side-effects that may be formulated as an anti-asthma/COPD therapy.

Publications

10 25 50
 
Description ERS/BTS Cough Task Force
Geographic Reach Asia 
Policy Influence Type Membership of a guidance committee
 
Description BBSRC DTP Studentship
Amount £90,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2012 
End 09/2015
 
Description BBSRC studentship obtained with the Integrative Mammalian physiol/pharmacol centre
Amount £65,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start  
 
Description MICA-Investigation into the Mechanisms that drive Cough in Health and Disease
Amount £663,782 (GBP)
Funding ID MR/K020293/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 05/2013 
End 04/2016
 
Description MRC 3+1 MRes/PhD Student -Awarded to Centre Integrative Physiology/Pharmacology Centre
Amount £70,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start  
 
Description MRC PhD Studentship
Amount £65,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start  
 
Description The role of TRP receptors in various immune responses/airway disease
Amount £409,991 (GBP)
Organisation F. Hoffmann-La Roche AG 
Sector Private
Country Global
Start  
 
Description Wellcome Trust Project Grant (Effect of theophylline on sensory nerve activity and the cough reflex: novel anti-tussive therapy)
Amount £365,541 (GBP)
Funding ID 089301/Z/09/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Title Characterisation and assay development of human vagal nerve preparation as in vitro assay for cough 
Description These tissue based assays inform about mechanistic information regarding the control of human respiratory reflexes. 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2008 
Provided To Others? Yes  
Impact These tissue based assays inform about mechanistic information regarding the control of human respiratory reflexes. Allows clinicians to better interpret in vivo clinical trial data. Collaboration and joint publications with 2 cough clinicians. 
URL http://www.ncbi.nlm.nih.gov/pubmed/18695648
 
Title Developed methodologies to record activity in single afferent units innervating the lung 
Description Single fibre recordings. This method can be used to determine nerve impulse recordings from single fibres arising in the jugular and nodose ganglia and innervating the lung. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact This technology has been adpated and optimised from Johns Hopkins, USA and has now been set up for the first time in the UK. 
 
Description Collaboration - Hull 
Organisation Hull York Medical School
Country United Kingdom 
Sector Academic/University 
PI Contribution We contributed by providing a major intellectual contribution in the developing the project hypothesis, desigining and performing the majority of the pre-clinical studies. We also wrote the paper which was accepted by the American Journal of Respiratory and Critical Care Medicine (highest IF respiratory journal)
Collaborator Contribution A collaborative study was initiated and as part of this a clinical study was undertaken in Hull to evaluate the tussive potential of an environmental challenge agent.
Impact PMID: 19818366
Start Year 2007
 
Description Collaboration - Manchester 
Organisation University of Manchester
Department School of Medicine Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution Based on this research we have formed a collaboration to carry out a clinical study to evaluate the tussive potential of Prostaglandin E2 in normal volunteers and in patients with asthma, COPD, smokers and idiopathic cough.
Collaborator Contribution Provided clinical expertise in follow up studies.
Impact Ethical approval is in place and the clinical study has been completed. Abstract to be presented at ATS, BPS and BTS 2011/12.
Start Year 2008
 
Description GSK pharmacological tools 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution We performed all the experiments that contributed to subsequent publications.
Collaborator Contribution GSK provided selective agonists and antagonists
Impact These compounds have resulted in the publication of several abstracts, a journal article (PMID: 19729667) and a review (PMID: 19830488, PMID: 19818366)
Start Year 2006
 
Description Merck pharmacological tools 
Organisation Merck
Country Germany 
Sector Private 
PI Contribution We performed the in vitro and in vivo experiments carried out with this compound that contributed to the subsequent publications
Collaborator Contribution Merck supplied a selective EP3 antagonist L826266 and also analysed some samples from our in vivo study
Impact These compounds have resulted in the publication of several abstracts, a journal article (PMID: 19729667) and a review (PMID: 19830488, PMID: 19818366)
Start Year 2007
 
Description ONO pharamcological tools 
Organisation Ono Pharmaceutical
Country Japan 
Sector Private 
PI Contribution We performed all the experiments that contributed to a subsequent publication.
Collaborator Contribution ONO pharmaceuticals provided pharmacological agonists and antagonists to support our research and genetically modified mice
Impact Obtaining these compounds and prostanoid receptor knockout mice enabled us to write a successful grant application to fund this project and has resulted in the publication of several abstracts, a journal article (PMID: 19729667) and review articles (PMID: 19830488 and PMID: 19818366)
 
Description Roche pharmacological tools 
Organisation F. Hoffmann-La Roche AG
Country Global 
Sector Private 
PI Contribution We performed all the experiments that contributed to subsequent publications.
Collaborator Contribution Roche provided a selective IP antagonist for use in these studies
Impact The availablilty of this compound has resulted in the publication of several abstracts, a journal article (PMID: 19729667) and a review (PMID: 19830488 and PMID: 19818366 )
Start Year 2006
 
Company Name IR Pharma 
Description http://www.irpharma.co.uk/ 
Year Established 2010 
Impact CRO in the pre clinical respiratory arena. Enabled by the expertise and knowledge base within the Respiratory Pharmacology Group. Funded in part by Imperial College Innovations
Website http://www.irpharma.co.uk/
 
Description HEFCE Medical Sciences Summer School 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Schools
Results and Impact Chance to debate isues around the use of animals in research

Excellent feedback from schools that took part
Year(s) Of Engagement Activity 2010
 
Description Big Bang Fair 
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 Demonstrating experiments to the public on a stand.

The same person was asked to oparticipate in other events
Year(s) Of Engagement Activity 2013
 
Description Britiah Pharmacological Society youtube 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact One of our PhD students filmed a veideo about how LABA's work in asthmatics as part of a series 'How do drugs work' for the British Pharmacological Society.

Additional invitations to participate in media and outreach events
Year(s) Of Engagement Activity 2013
URL http://www.youtube.com/watch?v=j-EOGJECjXY
 
Description Lecture for Trainees (Meidcal, BSc, PhD, Nurses, University Hospital of South Manchester) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact More than 150 nurses, clinicians, BSc, PhD students, patients, pharma attended. I gave a plenary talk and judged a young scientist prize.
Respiratory Forum, University of South Manchester, Wythenshawe, 10th October 2012.

The conference was successful and will run again next year. Evaluation sheets distributed at the meeting established that the audience felt that the activity was worthwhile.
Year(s) Of Engagement Activity 2012
 
Description Patient Involvement (Manchester) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Out clinical collaborators (MRC grant partners on this award) in Manchester hold an event each year to keep chronic cough patients up to date with the work they are doing in their clinic and through our research to find a cure for chronic cough. Combat my Cough is an opportunity to listen to and talk to the research team, but also for you to meet and talk to other sufferers with the condition.

http://www.combatmycough.com/#!events/c1k9b
Year(s) Of Engagement Activity 2015,2016
URL http://www.combatmycough.com/#!events/c1k9b
 
Description Press Release 2 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Our data regarding the role of reflexes in the late asthmatic response following allergen challenge has been published (and was highlighted by the media (21841185) (http://www.bbc.co.uk/news/health-14504186).

Invitations to discuss the research with various pharma companies.
Inclusion in WP6 of the Severe asthma IMI initiative.
Year(s) Of Engagement Activity 2011
URL http://www.bbc.co.uk/news/health-14504186
 
Description Press release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact We wrote a press release, in collaboration with Imperial College Press office following the publication that the TRPA1 is involved in the cough response to environmental irritants (PMID: 19729665).

The press release was published in several different websites and newspapers (including the MRC website, Daily Mail). Links to these are shown below. We also had over 10 patients contact us by telephone for advice following this breakthrough. http://www.mrc.ac.uk/Newspublications/News/MRC006506 http://www.dailymail.co.uk/health/article-1230125/A-cure-coughing-offing.html http://www.dailyindia.com/show/346080.php http://www.news-medical.net/news/20091124/Scientists-identify-factors-behind-chronic-coughing.aspx http://www.medicalnewstoday.com/articles/172027.php http://www.sciencedaily.com/releases/2009/11/091123094126.htm?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+sciencedaily+(ScienceDaily%3A+Latest+Science+News) http://www.sflorg.com/comm_center/unv_medical/p951_231.html
Year(s) Of Engagement Activity 2009
URL http://www.dailymail.co.uk/health/article-1230125/
 
Description Talk at the Dana Centre (Science Museum Outreach Centre) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact The lay public were allowed to ask the panel any questions regarding asthma, its disgnosis, treatment and research efforts in this area.

This event has sparked other public engagment events.
Year(s) Of Engagement Activity 2010
URL http://www.danacentre.org.uk/events/2010/11/19/598