Asthma
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2005 – 2008 Dr Hadwen Trust Research Grant: Pathobiology of airway smooth muscle from asthmaticsDr SJ Hirst, Dr VA Snetkov and Prof T LeeKing’s College London |
Dr Stuart Hirst was a Reader in Cell Pharmacology in the Department of Asthma, Allergy and Respiratory Science at King’s College London during this grant. He is now a researcher at Monash University, Australia.
Dr Vladimir A Snetkov is a Senior Research Fellow and Prof Tak H Lee is Head of the Division of Asthma, Allergy and Respiratory Science, King’s College London.
Asthma rates are soaring worldwide, especially in children, although the reasons for this remain unclear. Asthma now affects 5.2 million people in the UK and is responsible for 1,300 deaths each year. It costs the NHS an average of £730 million per year and causes the loss of 17 million working days annually.
Animals are widely used in asthma research, but important species differences between the lungs and airways of humans, rats, mice and other animals, mean that there are marked variations between findings in animal experiments and humans with asthma. Moreover, none of the animals commonly used in asthma research (guinea pigs, rabbits, rats and mice) naturally exhibit an asthma-like syndrome.
One of the aims of this project was to improve access to airway tissue from human volunteers with and without asthma using endobronchial biopsy to supersede the use of animals and resected human lung tissue. Airway tissue from resected human lung usually involves patients with a history of smoking and other lung diseases, which makes the relevance to asthma and healthy airway dubious. Similarly, animal studies have produced conflicting results.
A clinical research forum had been set up at by the researchers at King’s College to forge closer links with clinical scientists, enabling a regular supply of airway smooth muscle (ASM) tissue from biopsies for research. The Dr Hadwen Trust provided essential funding for endobronchoscopy costs and cell culture equipment, to facilitate human cell-based studies. Developing techniques for culturing ASM cells and establishing the systematic use of these cells as a research tool will help to replace the use of animals.
A further goal of this project was to elucidate the specific features of calcium handling in ASM cells that underlie airway hyper-responsiveness in asthmatic patients (see progress report below). Our grant enabled studies of airway smooth muscle cells from patient biopsies that have shed light on the changes that underlie airway remodelling in asthma, including alterations in calcium handling [1-3], induction of angiogenesis [4-5] and hypersecretory responses [6]. There has been much interest in this work from other scientists and collaborative studies are now being planned with other research groups internationally.
References
- Mahn K, Hirst SJ, McVicker CG et al (2006). Calcium signalling in asthmatic airway smooth muscle is abnormal. Proc Am Thoracic Soc 3:A772 (Abstr).
- Mahn K, Hirst SJ, Karner LC et al (2007). Calcium buffering is delayed in asthmatic airway smooth muscle. Proc Am Thoracic Soc A523 (Abst).
- Mahn K, Hirst SJ, Ying S et al (2009) Diminished sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) expression contributes to airway remodelling in bronchial asthma. PNAS 106: 10775-10780
- Simcock DE, Kanabar V, Clarke GW et al (2008). Induction of angiogenesis by airway smooth muscle from patients with asthma. Crit Care Med 178:460-468
- Simcock DE, Kanabar V, Clarke GW et al (2007). Pro-angiogenic activity in bronchoalveolar lavage fluid from asthmatics. Am J Respir Crit Care Med 176:146-153.
- Chan V, Burgess JK, Ratoff JC et al (2006). Extracellular matrix regulates enhanced eotaxin expression in asthmatic airway smooth muscle cells. Am J Resp Crit Care Med 174:370-385.