Professor MacNee & Professor Donaldson
Prof William MacNee (Professor/ PI)
Prof Ken Donaldson (Professor/ PI)
W.Macnee@ed.ac.uk
Ken.Donaldson@ed.ac.uk
ELEGI (The Edinburgh Lung and the Environment Group Initiative) Colt Laboratory
Group Members
Dr Ellen Drost (Senior Post-doctoral Research Fellow)
Dr Roberto Rabinovich (Clinical Fellow)
Craig Poland (Colt Foundation Postgraduate Fellow)
Irene Mc Guinnes (Research Assistant)
Jen McLeish (Research Assistant)
Fiona Murphy (Postgraduate student)
Jen Raftis (Postgraduate Student)
Dr Wan-Seob Cho (Post-doctoral Research Fellow)
Dr Santiago Giavedoni (Clinical Fellow)
Dr Jing Bai (Clinical Fellow)
Andrew Deans (Research Nurse)
Plain English Summary
Research in the ELEGI labs is related to the smoker's disease, Chronic Obstructive Pulmonary Disease (COPD) and allied research on the toxicology of inhaled particles. Both COPD and particle effects have similar underlying pathological processes which include inflammation and oxidative stress This has formed the basis of research to assess features of COPD that we could potentially measure to more specifically identify different subgroups of the disease to facilitate more tailored treatment in this heterogeneous disease. This is achieved using non-invasive assessment of the increased spaces in the lungs that occurs in COPD, using medical imaging called CT scanning. In addition, measurements of the lungs have shown that thicker bronchial tube walls are associated with acute episodes (exacerbations) of COPD and also a high body mass index (BMI). COPD has now been shown to affect organs other than the lungs. Indeed many more COPD patients die from cardiovascular events, such as strokes or heart attacks, than from respiratory-related events. Hence, we have been assessing the mechanisms behind such cardiovascular events in COPD patients. These studies have shown that COPD patients have increased blood vessel stiffness. We are also investigating the mechanisms relating to the skeletal muscle wasting and dysfunction that occurs in a proportion of COPD patients. These studies involve examining muscle from patients with COPD and determining the underlying damage.
Particles from traffic pollution and workplace dusts are a huge source of illness and death worldwide. The general populations affected include those with airways disease (such as asthma and COPD) and those with cardiovascular disease, whilst workers in dusty trades suffer from lung scarring and cancer. Our research aims to understand what properties harmful dusts possess, coupled with studies to determine the cellular and molecular mechanisms whereby disease arises in exposed tissues. This should allow us eventually to design safe particles and predict, from their physicochemical structure, how dangerous new particles are likely to be and to intervene in disease processes in those who are accidentally exposed. The research involves toxicological approaches with well-defined samples of particles in well-validated test systems. The cardiovascular research is multi-disciplinary, involving researchers from cardiovascular sciences and a number of models for effects on atherosclerosis and clot formation and endothelial dysfunction. Studies on carbon nanotubes have shown that they can behave like asbestos, having a long, thin shape and resisting breakage in the lungs.
Aims
To carry out research into the mechanisms of lung disease caused by inhaled pollutants towards improving diagnosis and treatment in COPD and optimising risk assessment and limiting disease progression in diseases caused by occupational and environmental particle exposures.
Background
The Edinburgh Lung and the Environment Group Initiative (ELEGI) Colt Laboratory is a laboratory carrying out research into the mechanisms of adverse health effects of air pollutants on the lungs. ELEGI was founded upon established collaborations between the Respiratory Medicine Unit of the University of Edinburgh, The School of Life Sciences, Napier University and the Institute of Occupational Medicine, Edinburgh with the financial support of the Colt Foundation. The purpose of the ELEGI initiative is to combine multi-disciplinary expertise in clinical science, cell and molecular biology and mathematical modelling, to address the problems of inhaled air pollutants and lung disease.
Chronic Obstructive Pulmonary Disease (COPD)
COPD, the chronic inflammatory lung disease caused by cigarette smoking and other noxious dusts and gases, is a major focus of research in ELEGI and we have been centred on the role of oxidative stress. A number of grants, including a large one from the National Institutes of Health (USA), have allowed us to study biomarkers for monitoring COPD phenotype and progression.
Computed Tomography Scanning
Research is also ongoing on the use of CT scanning to image COPD. CT scanning is being utilised for two purposes: for the measurement of airways dimensions to validate against established techniques; and to characterise different pathological (airways disease, small airways disease or emphysema) phenotypes and determine disease severity.
Systemic Effects
Systemic inflammation and oxidative stress have been implicated in the pathogenesis of most of the systemic effects of COPD including, muscle wasting and skeletal muscle dysfunction and cardiovascular disease endothelial dysfunction.
Inflammation and oxidative stress may have adverse systemic vascular effects in COPD by causing endothelial dysfunction. The endothelium plays a vital role in the control of blood flow, coagulation, fibrinolysis and inflammation. Failure of the endothelium to respond appropriately is believed to be a crucial factor in promoting acute coronary events. Having demonstrated that cigarette smoking and inhaled environmental particulate matter cause endothelial dysfunction (see below), we are exploring the link between cardiovascular disease and COPD, and the mechanisms involved.
Systemic inflammation and oxidative stress may also be the cause, or consequence, of skeletal muscle dysfunction. Muscle dysfunction in COPD is characterised by anatomic and functional changes and contributes significantly to limited exercise capacity, reduced quality of life and increased mortality. We are undertaking mechanistic investigations to establish the (dys)regulation of muscle injury/regeneration responsible for muscle wasting in stable and acute exacerbations of COPD. We are also assessing the impact of pulmonary rehabilitation during exacerbations on skeletal muscle wasting and quality of life.
The overall aim of the COPD research is to understand the regulation of inflammation and the role of oxidative stress in COPD, to use biomarkers to define disease phenotypes and to develop therapeutic interventions that are based on these understandings.
Particles
Workplace and ambient particles We have studied the pulmonary response to inhaled particles of all sorts and in the recent past we have studied cigarette smoke, PM10, crystalline silica, welding fume, diesel exhaust particles, volcanic ash, asbestos, man-made vitreous fibres and London Underground dust. The overall aims of the particle research are:- 1) to better understand the cellular and molecular mechanisms that lead from exposure to inflammation and lung disease; this will hold out the prospect of improved therapeutic modalities; 2) to improve understanding of the factors that make dusts and particles harmful; this will allow more refined measurement of exposure and so improve risk management.
Combustion-derived nanoparticles and the cardiovascular system Recently we have focused on the cardiovascular consequences of particle inhalation. This has coalesced around a British Heart Foundation programme grant led by Prof David Newby of Edinburgh University and of which Ken Donaldson and Bill MacNee are co-applicants. In the first studies we have used diesel particles as model combustion-derived nanoparticles and studied effects on the vascular system and in coronary artery disease. Professor David Newby from Cardiovascular Sciences provides the key cardiology expertise and leadership of the project and Dr Jeremy Langrish is responsible for carrying out the studies. Dr Nick Mills, University Institute for Cardiovascular Science is a key collaborator and his initial studies showed. These studies are carried out in collaboration with Dr Flemming Cassee in Eindhoven, Netherlands and Professor Thomas Sandstrom and Dr Anders Blomberg in Umea, Sweden who provide key exposure and clinical skills.
Manufactured Nanoparticles The development of new manufactured nanoparticles in the nanotechnology industry has produced a new class of potential hazards. The ELEGI lab is a world leader in assessing the hazards associated with these types of particles. We are part of the Safety of Nanoparticles Inter-disciplinary Research Centre (SnIRC), which is run from the Institute of Occupational Medicine. We are forma collaborates with the National Nanotoxicology Research Centre in the Health Protection Agency, led by Prof Robert Maynard. The hazards of manufactured nanoparticles are being addressed in research funded by the MRC, Colt Foundation, European Union Framework 7 and UK Department of Health.
Models
In ELEGI we have a wide range of models to study oxidative stress and inflammation in COPD and in the effects of particles and have the ability to test hypotheses and potential therapeutic modalities in experimental and clinical studies.
Sources of Funding
Recently funding has been obtained from:
MRC
NIH
European Union Framework 7
Department of Health
The Scottish Executive
The Chief Scientist Office
British Lung Foundation
NERC
Colt Foundation
Unilever
Chest Heart and Stroke Scotland
Recent Publications
COPD
MacNee W. Accelerated lung aging: a novel pathogenic mechanism of chronic obstructive pulmonary disease (COPD). Biochem Soc Trans. 2009 Aug;37(Pt 4):819-23. Review.
Maclay JD, McAllister DA, Mills NL, Paterson FP, Ludlam CA, Drost EM, Newby DE, Macnee W. Vascular dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009 Sep 15;180(6):513-20. Epub 2009 Jun 19.
Mair G, Miller JJ, McAllister D, Maclay J, Connell M, Murchison JT, MacNee W. Computed tomographic emphysema distribution: relationship to clinical features in a cohort of smokers. Eur Respir J. 2009 Mar;33(3):536-42. Epub 2008 Oct 1.
Mills, N. L., Miller, J. J., Anand, A., Robinson, S. D., Frazer, G. A., Anderson, D., Breen, L., Wilkinson, I. B., McEniery, C. M., Donaldson, K., Newby, D. E., and Macnee, W. (2008). Increased arterial stiffness in patients with chronic obstructive pulmonary disease: a mechanism for increased cardiovascular risk. Thorax 63, 306-311.
Szulakowski, P., A. J. Crowther, L. A. Jimenez, K. Donaldson, R. Mayer, T. B. Leonard, W. MacNee, and E. M. Drost. 2006. The effect of smoking on the transcriptional regulation of lung inflammation in patients with chronic obstructive pulmonary disease. Am J Respir.Crit Care Med 174:41-50.
McAllister DA, Maclay JD, Mills NL, Mair G, Miller J, Anderson D, Newby DE, Murchison JT, Macnee W. 2007. Arterial stiffness is independently associated with emphysema severity in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 176:1208-14.
Bathoorn, E., Kerstjens, H., Postma, D., Timens, W., and MacNee, W. (2008). Airways inflammation and treatment during acute exacerbations of COPD. Int.J.Chron.Obstruct.Pulmon.Dis. 3, 217-229.
Mair, G., Miller, J. J., McAllister, D., Maclay, J., Connell, M., Murchison, J. T., and Macnee, W. (2008). CT emphysema distribution : relationship to clinical features in a cohort of smokers. Eur.Respir.J. (electronic version on the web prior to publication)
Particles
Miller, M. R., Borthwick, S. J., Shaw, C. A., McLean, S. G., McClure, D., Mills, N. L., Duffin, R., Donaldson, K., Megson, I. L., Hadoke, P. W., and Newby, D. E. (2009). Direct impairment of vascular function by diesel exhaust particulate through reduced bioavailability of endothelium-derived nitric oxide induced by superoxide free radicals. Environ Health Perspect. 117, 611-616.
Mills, N. L., Tornqvist, H., Gonzalez, M. C., Vink, E., Robinson, S. D., Soderberg, S., Boon, N. A., Donaldson, K., Sandstrom, T., Blomberg, A., and Newby, D. E. 2007. Ischemic and thrombotic effects of dilute diesel-exhaust inhalation in men with coronary heart disease. N.Engl.J.Med. 357, 1075-1082.
Lu, S., Duffin, R., Poland, C., Daly, P., Murphy, F., Drost, E., Macnee, W., Stone, V., and Donaldson, K. (2009). Efficacy of simple short-term in vitro assays for predicting the potential of metal oxide nanoparticles to cause pulmonary inflammation. Environ Health Perspect. 117, 241-247.
Donaldson, K., Borm, P. J., Oberdorster, G., Pinkerton, K. E., Stone, V., and Tran, C. L. (2008). Concordance between in vitro and in vivo dosimetry in the proinflammatory effects of low-toxicity, low-solubility particles: the key role of the proximal alveolar region. Inhal.Toxicol. 20, 53-62.
Poland CA, Duffin R, Kinloch I, Maynard A, Wallace WA, Seaton A, Stone V, Brown S, Macnee W, Donaldson K. 2008. Carbon nanotubes introduced into the abdominal cavity of mice show asbestos-like pathogenicity in a pilot study. Nat Nanotechnol. l;3:423-428.