IKK-2 inhibition: A novel approach for treating steroid-resistant lung inflammation precipitated by cigarette smoking?

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

Abstract

Chronic obstructive pulmonary disease is an inflammatory disease of the lung that affects a large percentage of the population around the world and represents a huge health care burden. It is characterised by breathing difficulties (e.g. shortness of breath) that progressively worsens with age and is associated with a history of smoking cigarettes. It is believed that there are currently 600 million people living with the disease worldwide and every hour COPD is estimated to kill 250 people. COPD has now become a greater drain on health resources than asthma, and exceeds the healthcare spending on asthma by some three-fold in industrialised countries. These costs will escalate further as the prevalence of COPD is predicted to increase throughout the world over the next 20 yrs. 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. Unfortunately, there are no treatments for patients that can slow the progressive nature of the disease. Inflammation is believed to be central to the development and symptoms of COPD. There is an enzyme in cells that is involved in controlling the level of inflammation in the lung. Blocking the function of this enzyme may reduce the inflammation and slow the progression of the disease. The aim of this study is to try to determine whether blocking this enzyme?s function will reduce lung inflammation associated with COPD. The hope is that this work may lead to the discovery of a novel drug which could selectively target this enzyme leading to a useful therapy that could help these patients who suffer from this debilitating disease.

Technical Summary

Chronic obstructive pulmonary disease (COPD) is a smoking-related lung disease characterised by airway inflammation and airflow obstruction that kills 250 people every hour around the world. The chronic inflammation is believed to cause structural changes to the lung that lead to reduced lung function, disability and death. The inflammation is largely steroid-insensitive and currently, no therapies are available to reduce the inflammation or delay disease progression. Steroids work principally by inhibiting the activation of NF-kB, a transcription factor that controls pro-inflammatory gene expression. In COPD patients, it is believed that there are modifications in the steroid receptor complex that reduces its ability to repress NF-kB function. Thus, alternative strategies aimed at inhibiting NF-kB activation may abrogate the inflammation associated with COPD. One approach is to inhibit IKK-2, a kinase that is involved in the release of NF-kB from its inhibitor complex in the cytoplasm. This allows NF-kB to translocate to the nucleus and trigger gene expression. Our current proposal aims to assess whether IKK-2 inhibition can attenuate cigarette smoking-related lung inflammation. First, we intend to develop models of cigarette smoke-induced (steroid-insensitive) inflammation in mice. Next, we plan to test IKK-2 small molecule inhibitors, IKK-2 conditional knockout mice and siRNA oligonucleotides directed against IKK-2 in these animal models and assess the changes in inflammation. Finally, we aim to translate these findings by examining these same tool inhibitors in human cell models related to COPD inflammation, including using inflammatory cells isolated directly from the lungs COPD patients. This work would result in us developing what is considered to be the most relevant animal model for COPD (unique among UK academic groups) and may highlight IKK-2 inhibition as a novel approach for the treatment of COPD.

Publications

10 25 50
 
Description Our work is being used to teach Medical students (BSc), graduate students and professional courses for reseacrhers as well as clinicians
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact Our work has revealed potential molecular mechanisms that regulate the inflammation induced by cigarette smoke exposure. This work has identified potential druggable targets to treat chronic obstructive pulmonary disease.
 
Description Presentations at International Respiratory and Inflammation Meetings
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Presentations at National Pharmacology and Respiratory meetings
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Wellcome Trust Project grant (Increasing aerobic capacity: A novel approach for treating the inflammatory and physiological damage precipitated by cigarette smoking)
Amount £120,000 (GBP)
Funding ID 088284/Z/09/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2009 
End 10/2010
 
Description IKK-2 conditional knockout mice and proprietary compounds 
Organisation Pfizer Ltd
Department Respiratory Pfizer
Country United Kingdom 
Sector Private 
PI Contribution Pfizer have provided these mice
Collaborator Contribution Provision of IKK-2 knockout mice and proprietary compounds
Impact The generation of data which will led to the publication of a manuscript-listed in publication section
Start Year 2009
 
Description Link between chronic respiratory disease and cardiovascular complications 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution We have provided samples from our lung disease smoke exposure models to our collaborators for them to look at disease relevant biomarkers
Collaborator Contribution Experiments to evaluate cardiovascular danger signals in our models
Impact Abstracts will be submitted and grants to fund future work are in preparation
Start Year 2013
 
Description Lung ageing and DNA damage at telomeres 
Organisation Newcastle University
Country United Kingdom 
Sector Academic/University 
PI Contribution we provided carefully phenotyped samples from our murine models of smoke exposure to our collaborators
Collaborator Contribution Collaborators have assessed ageing dependent biomarkers. Paper is under consideration at Thorax
Impact Paper under consideration at Thorax
Start Year 2014
 
Description Mechanisms involved in smoking-induced inflammation 
Organisation F. Hoffmann-La Roche AG
Country Global 
Sector Private 
PI Contribution Testing novel hypotheses related to chronic lung diseases using models developed during this porject.
Collaborator Contribution Access to pharmacological tools, pharmacokinetic support, molecular tools (gene chips), and bioinformatic support
Impact Abstracts submitted to International Meetings (e.g. American Thoracic Society)
Start Year 2010
 
Description The role of IL-1beta and IL-18 signalling pathways in disease exacerbations 
Organisation Manchester University NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution Hypothesis to be tested, preliminary data and sample analyses
Collaborator Contribution We will obtain human clinical samples wich we can use tovalidate our hypothesis genrated in animal models
Impact Clinical sample generation underway. Multi-disciplinary linking basic science with clinical medicine
Start Year 2011
 
Description 'Breathless' event at the Dana 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 Outreach talk regarding the use of animals in medical research.

Very good discussions and feedback from participants
Year(s) Of Engagement Activity 2010
 
Description Chelsea Academy Visit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Talk to 6th form students regarding the use of animals in medical research.

Good discussions and feedback from students and teachers.
Year(s) Of Engagement Activity 2011
 
Description Contribution to an Imperial College outreach event 
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 Schools
Results and Impact Approximately 60 students attended a science outreach open day.
Our group led a discussion related to the use of animals in research

Schools noted that the students had enjoyed the trip and that this may influence career decisions to go into a scientific related career in the future.
Year(s) Of Engagement Activity 2010
 
Description HEFCE Medical Sciences summer school held at Imperial College. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Debate with 6th form students.

Good feedback from students and lots of discussion after the activity
Year(s) Of Engagement Activity 2010
 
Description Henry Compton School Visit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Two talks to 14-16 year olds regarding the use of animals in medical research.

Good discussions and feedback from the students after the talk.
Year(s) Of Engagement Activity 2011
 
Description Imperial College - Non-science students 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Talk to MSc Science Communication students

Lots of questions and good feedback from participants
Year(s) Of Engagement Activity 2010
 
Description School visit - Kingston 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Presented to students about our work investigating the effects of cigarette smoking on lung health and about the environment in a research laboratory.

We had several discussions with students and staff after the presentation.
Year(s) Of Engagement Activity 2008
 
Description South Camden Community School Visit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Talk to 6th form students about the use of animals in medical research

Good feedback from the students and instructors
Year(s) Of Engagement Activity 2010
 
Description Tiffin Girl's School Visit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Talk to 6th form students from Tiffin and Tiffin Girl's regarding the use of animals in medical research.

Very good discussions and questions from the students. Good feedback from instructors, too.
Year(s) Of Engagement Activity 2011