Respiratory Pharmacology Laboratory
Research
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| Cell Photo: Scanning electron micrograph of collagen gel seeded with airway smooth muscle cell showing cell-matrix interactions | Airway Photo: Phase-contrast image of mouse lung slice showing small airway in situ |
Current research in the Respiratory Pharmacology laboratory focuses on the role of the peroxisome proliferator-activated receptor gamma (PPARgamma), a ligand-activated transcription factor, in the regulation of changes in lung structure and function that occur during the development of asthma and lung fibrosis (Ward and Tan, 2007). We have previously established that the PPARgamma ligand, rosiglitazone inhibits cell proliferation and the release of mediators of inflammation from human airway smooth muscle cells (Ward et al., 2004) and also reduces airways hyperresponsiveness in a mouse model of asthma (Ward et al., 2006). These findings underpinned successful grant applications for our current funding from NHMRC and Asthma Victoria to extend this work, exploring the potential therapeutic actions of PPARgamma ligands in chronic lung diseases.
Our research capacity has broadened through the development of key local and international collaborations. A recent joint publication with the Immunopharmacology group headed by Professor Stewart utilising unique biopsy samples from the Melbourne Epidemiological Study of Childhood Asthma has contributed to critical debate on mechanisms contributing to airway remodelling in asthma (Ward et al., 2008). We are also exploring the potential of airway smooth muscle cells to remodel collagen gels in vitro to assess profibrotic interactions between the cells and the surrounding extracellular matrix (Burgess et al., 2008).
An ongoing collaboration to synthesise novel drugs to target PPARgamma, with Dr Hutton at the Bio21 Institute, forms the basis for the current PhD project being undertaken by Xiahui Tan, examining their antifibrotic effects in fibroblasts and epithelial cells. Recent Honours projects examining PPARgamma ligand regulation of airway smooth muscle contractile functions in a mouse model of chronic allergic airways disease with Dr Bailey, Dr Royce and A/Professor Tang have identified rosiglitazone as a novel bronchodilator. With Dr Snibson, we are now assessing rosiglitazone’s actions in a sheep model using house dust mite as a relevant allergen to human asthma. Additional exciting new avenues of research will utilise a lung slice model developed by our collaborator Professor Sanderson at the University of Massachusetts and recently established in our laboratory. This novel technique is being used to examine airway contractility and calcium signalling in small airways – a forgotten target for the treatment of asthma.
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Key References
Clarke, D.L., Dakshinamurti, S., Larsson, A.-K., Ward, J.E. & Yamasaki, A. (2008). Lipid metabolites as regulators of airway smooth muscle function. Pulmonary Pharmacology and Experimental Therapeutics Dec 25. [Epub ahead of print].
Burgess, J.K., Ceresa, C., Johnson, S., Kanabar, V., Moir L.M., Nguyen, T.T., Oliver, B.G., Schuliga, M. & Ward, J.E. (2008). Tissue and matrix influences on airway smooth muscle function. Pulmonary Pharmacology and Experimental Therapeutics Dec 24. [Epub ahead of print].
Ward, J.E., Harris, T., Bamford, T., Mast, A., Pain, M.C.F., Robertson, C., Smallwood, D., Tran, T., Wilson, J.W. & Stewart, A.G. (2008). Proliferation is not increased in airway myofibroblasts isolated from asthmatics. European Respiratory Journal 32:362-71.
Ward, J.E. & Tan, X. (2007). Peroxisome proliferator activated receptor ligands as regulators of airway inflammation and remodelling in chronic lung disease. PPAR Research 2007:14983.
Ward, J.E., Fernandes, D.J., Taylor, C.C., Bonacci, J.V., Quan, L. & Stewart, A.G. (2006) The PPARgamma ligand, rosiglitazone, reduces airways hyperresponsiveness in a murine model of allergen-induced inflammation. Pulmonary Pharmacology and Experimental Therapeutics, 19:39-46.
Ward, J.E., Gould, H., Harris, T., Bonacci, J. & Stewart, A.G (2004). PPARgamma ligands 15-deoxyD12,14-prostaglandin J2 and rosiglitazone have different mechanisms for their anti-proliferative effects in human airway smooth muscle. British Journal of Pharmacology 144:517-525.
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