Department of Pharmacology

Respiratory Research Group


Dr Ross Vlahos BSc(Hons), PhD (Melb)
Head, Respiratory Research Group
Department of Pharmaocology
University of Melbourne
Email: rossv@unimelb.edu.au
Phone: +61 3 8344 4221

The major focus of Dr Vlahos’ laboratory is the mechanisms that underpin induction and progression of Chronic Obstructive Pulmonary Disease (COPD). COPD is a major incurable global health burden and will become the third largest cause of death in the world by 2020.  It is believed that an exaggerated inflammatory response to cigarette smoke where macrophages, neutrophils and lymphocytes are prominent leads to oxidative stress, emphysema, small airway fibrosis, mucus hyper secretion and progressive airflow limitation. Dr Vlahos has developed a number of preclinical models of COPD to identify the cellular and molecular mechanisms underlying COPD.  The significance of this will be the identification of novel therapeutic agents for the treatment of COPD.

Oxidative Stress and COPD

Oxidative stress plays a major role in COPD because cigarette smoke contains more than 1014 oxidants per puff, many of which are relatively long-lived.  These oxidants give rise to Reactive Oxygen Species (ROS), which are a family of highly reactive molecules that are generated enzymatically by various cells in the lung in response to a variety of chemical and physical agents.  These ROS cause tissue damage and activate signal transduction pathways leading to inflammation.  Given the important role of oxidative stress and ROS in COPD, Dr Vlahos’ is focussing on the role of novel anti-oxidants as therapeutic options for COPD.

Macrophages and COPD

Studies have highlighted that macrophages play a pivotal role in the pathophysiology of COPD and can account for most of the known features of the disease.  It is now clear from models of lung inflammation that different macrophage subpopulations exist in the inflamed lung.  Research in Dr Vlahos’ laboratory is focussing on the importance of these macrophage subpopulations in COPD. In addition, since the biology and activation of macrophages is fundamentally influenced by Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF), he is exploring the therapeutic utility of anti-GM-CSF in COPD.

Interleukin-17A in Lung Disease

Interleukin-17 A (IL-17A) is a newly discovered pro-inflammatory cytokine that has rapidly emerged as a major player in lung diseases including asthma and cystic fibrosis.  IL-17A induces the release of secondary, pro-inflammatory chemokines and growth factors in most mesenchymal cells leading, in turn, to the recruitment and accumulation of neutrophils at the site of inflammation in the lung.  In addition, recent studies have shown that IL-17A mediates the accumulation of macrophages during allergen-induced airway inflammation and that IL-17A exerts its effects by acting directly on airway macrophages by promoting their recruitment and survival. The current dogma is that IL-17A is produced predominantly by a specific subset of T helper (h) cells (CD4 cells) termed Th17 cells, which is phenotypically and functionally distinct from Th-1 and Th-2 cells and from T regulatory cells. However, we have evidence to suggest that cell types other than Th17 can also produce IL-17A .  Studies in Dr Vlahos’ laboratory are investigating whether IL-17A may be a novel target that can be exploited therapeutically to slow or prevent cigarette smoke-induced lung inflammation and emphysema.

Oxidative Stress and Influenza Infections

Influenza A virus infection has claimed millions of lives worldwide and continues to impose a major economic burden on health care systems. Co-ordinated efforts to control this infection are problematic due to (i) resistance to anti-virals, (ii) the requirement for strain-specific vaccination and (iii) the ongoing threat of new pandemic strains of virus. Thus, new pharmacological strategies that ameliorate influenza viral lung disease are urgently required. Recent studies provide compelling evidence that immune cells such as macrophages, neutrophils and T lymphocytes, which are critical for efficient viral clearance, initiate and exacerbate lung inflammation and pathology following infection. An understanding of the mechanisms by which the various inflammatory cell types of the immune system cause such inflammation and pathology may reveal novel targets for pharmacological modulation of host immune responses. An emerging paradigm in this regard is the significant contribution of ROS.  Immune cell ROS can be toxic and capable of inducing significant injury to surrounding lung tissue when produced in excess. Moreover ROS are likely to promote the characteristic ‘cytokine storm’ of influenza A pandemic strains. Therefore, Dr Vlahos is currently exploring whether inhibition of ROS production by immune cells may have therapeutic potential for control of influenza A virus-induced lung disease.

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Key Publications

  1. Vlahos, R., Stambas, J., Bozinovski, S., Drummond, G. & Selemidis, S. (2011)  Inhibition of Nox2 oxidase activity ameliorates influenza A virus-induced lung inflammation.  PLoS Pathogens, Feb 3; 7(2):e1001271.
  2. Vlahos, R., Stambas, J. & Selemidis, S. (2011)  Suppressing ROS production for influenza A virus therapy.  Invited opinion piece for Trends in Pharmacological Sciences.
  3. Bozinovski, S., Vlahos, R., Zhang, Y., Lah, L.C., Seow, H.J., Mansell, A. & Anderson, G.P (2011)  Carbonylation caused by cigarette smoke extract is associated with defective macrophage immunity.  American Journal of Respiratory Cell and Molecular Biology, Aug; 45(2):229-236.
  4. Lenzo, J.C., Turner, A.L., Cook, A.D., Vlahos, R., Anderson, G.P., Reynolds, E.C. & Hamilton, J.A. (2011) Control of macrophage lineage populations by CSF-1R and GM-CSF in  homeostasis and inflammation. Immunology & Cell Biology Jul 5.
  5. Ruwanpura, S.M., McLeod, L., Miller, A., Jones, J., Bozinovski, S., Vlahos, R., Ernst, M., Armes, J., Bardin, P.G., Anderson, G.P. & Jenkins, B.J.  (2011)  Interleukin-6 promotes pulmonary emphysema associated with apoptosis in mice.  American Journal of Respiratory Cell and Molecular Biology, Feb 17 [Epub ahead of print].
  6. Vlahos, R., Bozinovski, S., Chan, J.S., Ivanov, S., Linden, A., Hamilton, J.A. & Anderson, G.P. (2010)  Neutralizing GM-CSF inhibits cigarette smoke-induced lung inflammation.  American Journal of Respiratory and Critical Care Medicine, 182 (1), 34-40.
  7. Duong, C., Seow, H.J., Bozinovski, S., Crack, P.J., Anderson, G.P. & Vlahos, R. (2010)  Glutathione peroxidase-1 protects against cigarette smoke-induced lung inflammation in mice.  American Journal of Physiology – Lung Cellular and Molecular Physiology, 299 (3), L425-L433.
  8. Prause, O., Ivanov, S., Bozinovski, S., Vlahos, R., Sjöstrand, M., Anderson, G.P. & Lindén, A. (2009)  IL-17-producing T Lymphocytes in Lung Tissue and in the Bronchoalveolar Space after Exposure to Endotoxin from Escherichia coli in vivo - Effects of Anti-Inflammatory Pharmacotherapy.  Pulmonary Pharmacology & Therapeutics, Jun, 22(3), 199-207.
  9. Gualano, R.C., Hansen, M.J., Vlahos, R., Jones, J.E., Park-Jones, R.A., Deliyannis, G., Turner, S.J., Duca, K.A. & Anderson, G.P. (2008)  Cigarette smoke worsens lung inflammation and impairs resolution of influenza infection in mice.  Respiratory Research, July 15; 9 (1); 53.
  10. Bozinovski, S., Hutchinson, A., Thompson, M., Macgregor, L., Black, J., Giannakis, E., Karlsson, A.S., Silverstrini, R., Smallwood, D., Vlahos, R., Irving, L., & Anderson, G.P. (2008)  Serum Amyloid A is a biomarker of acute exacerbations of COPD.  American Journal of Respiratory and Critical Care Medicine, 177(3), 269-78.
  11. Ivanov, S.N., Bozinovski, S., Bossios, A., Valadi, H., Vlahos, R., Malmhall, C., Sjostrand, M., Kolls, J.K., Anderson, G.P. & Linden, A.  (2007)  Functional relevance of the IL-23 – IL-17 axis in intact lungs in vivo.  American Journal of Respiratory Cell and Molecular Biology, 36 (4), 442-451.
  12. Vlahos, R., Bozinovski, S., Hamilton, J.A. & Anderson, G.P. (2006)  Therapeutic potential of treating COPD by neutralising GM-CSF.  Invited review for Pharmacology & Therapeutics, 112 (1), 106-115.
  13. Vlahos, R., Bozinovski, S., Jones, J.E., Powell, J., Gras, J., Lilja, A., Hansen, M.J., Gualano, R.C., Irving, L, & Anderson, G.P. (2006)  Differential protease, innate immunity and NFkB induction profiles during lung inflammation induced by sub-chronic cigarette smoke exposure in mice.  American Journal of Physiology - Lung Cellular & Molecular Physiology, 290(5), L931-L945.
  14. Vlahos, R., Bozinovski, S., Gualano, R.C., Ernst, M. & Anderson, G.P. (2006) Modelling COPD in mice. Pulmonary Pharmacology & Therapeutics, 19 (1), 12-17.
  15. Bozinovski, S., Jones, J.E., Vlahos, R., Hamilton, J.A. & Anderson, GP. (2002)  GM-CSF regulates lung innate immunity to LPS through Akt/Erk activation of NFkappa B and AP-1 in vivo.  Journal of Biological Chemistry, Nov 8 277(45), 42808-14.

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Recent Funding:

 

 

 

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