Immunopharmacology

Project Details

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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.

PhD Projects

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.

Fibrosis

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.

Steroid resistance

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.

2-Methoxyestradiol

2-MEO is a metabolite of estradiol with low affinity for the estrogen receptor. 2-MEO is anti-angiogenic and reduces the proliferation of a number of different cell types by inhibiting the function of tubulin during formation of the mitotic spindle. 2-MEO arrests G1 progression that decreases entry of cells into S-phase of the cell cycle. Initial pre-clinical studies from other laboratories support the utility of this compound in regulating aspects of tumour growth.  However, we have identified a lack of anti-tumour action in vivo in mouse models of human breast tumour, and 2-MEO has estrogenic activity that could accelerate tumour growth in some circumstances.  Structure activity relationships amongst 2MEO analogues have the potential to provide new insights into the molecular targets of action of 2MEO.

Medicinal Chemistry

Collaborations between our group and the Research School of Chemistry at ANU have been developed. Our goal is to develop non-steroidal nuclear hormone receptor ligands having selectivity and efficacy as anti-remodelling agents.

Researchers

Dr Michael Schuliga, Senior Research Fellow
Shenna Langenbach, Research Assistant
Ms Nuha Al-Zaubai, PhD Student
Ms Ebony Fietz, PhD Student
Ms Christine Keenan, PhD Student
Ms Thippadey Khau, PhD Student
Mr Francis Shand, PhD Student
Dr Saad Salem, PhD Student
Ms Yan Tu, PhD Student

photo of Immunopharmacology staff

Collaborators

A/Prof Tony Hughes, Department of Pharmacology & Therapeutics, The University of Melbourne
Dr Graham Mackay, Department of Pharmacology & Therapeutics, The University of Melbourne
A/Prof James Ziogas, Department of Pharmacology & Therapeutics, The University of Melbourne
Dr Blanca Camaretti-Mercado, University of Chicago
Professor Martin Banwell, Research School of Chemistry, ANU, Australia
Dr Robin Anderson, Peter MacCallum Cancer Research Institute, Australia
Prof Eric Morand, Monash Medical Centre, Australia
A/Prof Robert Medcalf, Department of Medicine, Monash University
Dr Yuan Yang, Monash University
Professor Martin Banwell, Research School of Chemistry, ANU, Australia
Dr Robin Anderson, Peter MacCallum Cancer Research Institute, Australia
Prof Eric Morand, Monash Medical Centre, Australia
A/Prof Robert Medcalf, Department of Medicine, Monash University
Dr Yuan Yang Monash University

Funding

NHMRC
CASS foundation
Asthma foundation of Victoria

Research Publications

  • 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.
  • Hughes RA, Harris T, Altmann E, McAllister D, Vlahos R, Robertson A, Cushman M, Wang Z and Stewart AG. 2-Methoxyestradiol and analogs as novel antiproliferative agents: Analysis of three-dimensional quantitative structure-activity relationships for DNA synthesis inhibition and estrogen receptor binding.  Mol Pharmacol 2002;61: 1053-69.
  • Konopka TE, Barker JB, Bamford TL, Guida E, Anderson RL and Stewart AG.  Nitric oxide synthase II gene disruption: implications for tumour growth and vascular endothelial growth factor production.  Cancer Res 2001;61: 3182-3187.
  • Hirst SJ, Martin JG, Bonacci JV, Chan V, Fixman ED, hamid Q, Herszberg B, Lavoie J-P, McVicker CG, Moir LM, Nguyen TT, Peng Q, Ramos-Barbon D, Stewart AG. Proliferative aspects of airway smooth muscle.  Journal of Allergy and Clinical Immunology 2004; 114: S2-S17.
  • Shepherd MC, Harris T, Schuliga M, Neylon CB, Brightling C, Bradding P, Stewart AG.   Intermediate conductance calcium-activated potassium channels are expressed in human airway smooth muscle cells and regulate proliferation.  Am J Resp Cell Mol Biol 2007; 37(5): 525-31.
  • Stewart AG, Bonacci JV, Quan L.  Factors controlling airway smooth muscle proliferation in asthma.  Current Allergy Reports 2004; 4: 109-15.
  • 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.
  • Tara E, Sutherland Robin L. Anderson, Richard A. Hughes, Emile Altmann, Michael Schuliga, James Ziogas & Alastair G. Stewart.  2-Methoxyestradiol - a unique blend of activities generates a new class  of anti-tumour/anti-inflammatory agents.  Drug Discovery Today, 12: 577-584.

Research Group

Lung Health Research Centre



Faculty Research Themes

Infection and Immunology

School Research Themes

Cardio-Respiratory, Infection & Immunity



Key Contact

For further information about this research, please contact the research group leader.

Department / Centre

Pharmacology and Therapeutics