Our Laboratory investigates the mechanisms and treatment of airway wall remodelling in asthma and other airway disorders. Airway smooth muscle growth and differentiation are central to this remodelling process. Cryptopharma funds studies on potential new anti-asthma and anti-inflammatory agents related to 2-methoxyestradiol (2-MEO) that inhibit mesenchymal cell proliferation.
Air Liquid Interface Epithilial Culture
The Immunopharmacology laboratory is investigating the determinants of glucocorticoid sensitivity in structural cells of the airway including in epithelial cells. We have recently reported that TGF-beta induces glucocorticoid resistance in two epithelial cell lines, BEAS-2B and A549. Current work is examining responses of primary epithelial cells from small and large airways that are differentiated in an Air Liquid Interface (ALI) culture to produce an organotypic multilayer cell population that comprises basal cells, mucous-producing goblet cells and ciliated cells. The beating cilia in the 100x phase contrast image shown can be seen as shimmering in the high frame rate looping movie showing above.
The immunopharmacology laboratory has a number of potential PhD projects and the laboratory head, Professor Stewart would be pleased to discuss these in detail. Briefly, the main interest is in the remodelling of tissue during chronic inflammation an its potential for targeting by anti-inflammatory agents with actions complementary to those of glucocorticoids. We are particularly interested in understanding the influence of changes in the extracellular matrix on the efficacy of anti-inflammatory agents. Projects using animal models and those using human cell culture-based approaches are available. The laboratory has broad technical competence and applies state-of-the-art approaches to better understand tissue remodelling in airway, lung and other inflammatory diseases.
Airway Smooth Muscle
Airway smooth muscle can be stimulated to proliferate by a range of factors identified in the inflamed airways of asthmatics, including epidermal growth factor, basic fibroblast growth factor and thrombin. These growth factors increase levels of the key regulatory protein in the cell-cycle, cyclin D1, by increasing gene transcription and decreasing protein breakdown. Further definition of the pathways regulating cyclin D1 levels in airway smooth muscle may lead to identification of new pharmacological targets for regulation of excessive airway smooth muscle proliferation.
Anti-remodelling activity of currently used and potential anti-asthma agents
b2-adrenoceptor agonists including salbutamol inhibit DNA synthesis by arresting cell cycle progression late in G1 near the restriction point of the cell cycle, as do glucocorticoids. However, b2-agonists and other agents which increase cAMP reduce cyclin D1 protein levels by influencing its proteasome-dependent degradation, whereas glucocorticoids reduce levels by reducing mitogen-stimulated increases in cyclin D1 mRNA. Our recent work suggests that the extracellular matrix component collagen, induces resistance to some anti-remodelling actions of glucocorticoids.
The extracellular matrix is expanded in fibrotic tissues. However, the ECM is not merely providing filler between cells, but also has a wide-ranging impact on cell function. Our studies are examining the impact of ECM components on the efficacy of anti-remodelling agents on fibrogenic activities of fibroblasts.
There is great interest in understanding the mechanisms that regulate sensitivity to anti-inflammatory glucocorticoids in chronic inflammatory conditions such as asthma. We have recently identified transforming growth factor b as a key mediator of steroid resistance. Current research is targetting the pathways that mediate this action of TGF-b to reveal strategies for the development of steroid-sensitising agents.
Collaborations between our group and the School of Chemistry with Profs Spencer Williams and Mark Rizacassa are well-established and productive. Our goal is to discover and develop non-steroidal highly selective anti-remodelling and anti-inflammatory agents.
Dr Connie Xia, NHMRC Peter Doherty Research Fellow
Dr Philippe LaChapelle, Visiting Respiratory Fellow
Ms Shenna Langenbach, Senior Research Assistant
Ms Trudi Harris, Senior Research Assistant
Ms Meina Li, PhD Student
Ms Danica Radojicic, PhD Student
Mr Asres Mitke, PhD Student
Mr Fernando Guzman, PhD Student
Ms Asmaa Radwan, PhD Student
Ms Qianyu Chen, PhD Student
Mr Yanqi Wu, PhD Student
Ms Yan Tu, PhD Student
Ms Aakriti Sharma, BSc Hons student
Therapeutic Technologies Hallmark Research Initiative
ARC-ITTC in personalised therapeutic technologies
Lung Health Research Centre
Professor Alastair Stewart
Dr Maria Bellesis
Dr Susan Northfield
The University of Melbourne
Dr Jon Mangum, Department of Pharmacology & Therapeutics,
Dr Graham Mackay, Department of Pharmacology & Therapeutics
Professor Peter Lee, Biomedical Engineering
Dr Sarah Londrigan, Microbiology and Immunology, Peter Doherty institute,
Dr David Simpson, School of Physics, The University of Melbourne
Professor Lloyd Hollenberg, School of Physics, The University of Melbourne
Professor Spencer Williams, School of Chemistry, The University of Melbourne
Professor Jo Douglass, Clinical immunology and Allergy, Royal Melbourne Hospital
Associate Professor Glen Westall, AIRMed, Alfred Hospital
Dr Jin-Ah Park, Harvard TH Chan School of Public Health, USA
Professor Martina Schmidt, University of Groningen, The Netherlands
Dr Michael Schuliga, University Newcastle, NSW
- Bonacci JV, Schuliga M, Harris T, Stewart AG. Collagen impairs glucocorticoid actions in airway smooth muscle through integrin signalling. Br J Pharmacol 2006; 149(4): 365-73.
- Sutherland TE, Schuliga M, Harris T, Eckhardt BL, Anderson RA, Quan L, Stewart AG. 2-methoxyestradiol is an estrogen receptor agonist that supports tumor growth in murine xenograft models of breast cancer. Clinical Cancer Research 2005; 11: 1722-1732.
- Xia YC, Radwan A, Keenan CR, Langenbach SY, Li M, Radojicic D, Londrigan SL, Gualano RC, Stewart AG. Glucocorticoid insensitivity in virally infected airway epithelial cells is dependent on transforming growth factor- β activity. PLOS Pathogens http://dx.doi.org/10.1371/journal.ppat.1006138.
- Stewart AG. Translational Pharmacology. Frontiers in Pharmacology – Translational Pharmacology doi: 10.3389/fphar.2017.00008
- Krishnan R, Park JA, Seow CY, Lee PVS, Stewart AG. Cellular biomechanics in drug screening and evaluation: Mechanopharmacology. Trends in Pharmacological Sciences 2016; 37:87-100.
- Salem S, Harris T, Shiueh Lian JM , Li MYS, Keenan CR, Schuliga MJ, Stewart AG. Transforming growth factor-β impairs glucocorticoid activity in the A549 lung adenocarcinoma cell line. Br J Pharmacol 2012; 166: 2036-2048.
Faculty Research Themes
School Research Themes
For further information about this research, please contact the research group leader.