Asthma (researching causes)

Professor Carol Armour
Professor of Pharmacy
Associate Dean (Career Development), Faculty of Medicine

Dr J. Margaret Hughes
Senior Research Officer, NHMRC

Dr Maria Sukkar
Lecturer, Pharmacy Practice

Research projects

• Airway smooth muscle control of mast cell location: Molecular mechanisms
  We hypothesise that changes in intracellular signalling in airway smooth muscle cells from asthmatics cause their failure to release factor(s) that prevent mast cell chemotaxis and thus mast cell microlocalisation to the muscle in asthma. We hypothesised that altered intracellular signalling in airway smooth muscle (ASM) cells from asthmatics cause their failure to release factor(s) that reduce mast cell (MC) chemotaxis. Thus changes in ASM underlie mast cell localisation to the ASM and cellular abnormalities in asthma. We aim to identify signalling pathways involved in ASM production of factor(s) which inhibit MC chemotaxis to the ASM. we further aim to determine if differences in cell signalling underlie the failure of asthmatic ASM cells to release those inhibitory factor(s).
  In asthma degranulating MC numbers on the ASM are increased and correlate with hyperresponsiveness and severity. Clearly MC-ASM interactions may contribute to the pathogenesis of asthma. To address the first aim, a list of candidate inhibitory factors will be prepared. Differences in protein release by ASM cells from 5-8 asthmatics and non-asthmatics will be explored by protein microarrays and any differences in candidate proteins identified and confirmed by real-time PCR and ELISA and their inhibitory activity tested in chemotaxis assays. To address the second aim, the signalling pathways involved in release of the inhibitory factor(s) by ASM cells from 5-8 non-asthmatic subjects will be determined using activity assays, immunoblotting, specific inhibitors, ELISAs and real-time PCR. Any changes in the signalling pathways leading to inhibitory factor production will then be detected in ASM cells from 5-8 asthmatic subjects. The identification of the endogenous inhibitory factor(s) will provide a key to understanding MC-ASM interactions in the pathogenesis of asthma and how to prevent them.
• Chronic inflammatory airway diseases: The role of immune receptors in driving airway smooth muscle inflammation
  This project will address the role of immune receptors, known as toll-like receptors, in driving airway smooth muscle inflammation in chronic inflammatory airway diseases such as asthma and chronic obstructive pulmonary disease. Asthma and chronic obstructive pulmonary disease (COPD) are characterised by chronic inflammation and remodelling of the airways and while the nature and pattern of inflammation, and the predominant anatomic locations affected are distinct, they share some common features. A critical abnormality is the increase in the amount of airway smooth muscle (ASM) in the airway wall, occurring in proximal airways in asthma and the small airways in COPD. ASM inflammation and remodelling is a key pathogenic factor in chronic inflammatory airways disease. We have uncovered new evidence showing that fibrogenic factors such as the cytokine TGF-b, a well established mediator of ASM remodelling, may drive ASM inflammatory and remodelling responses by inducing oxidant stress in ASM cells. This adds significant weight to evidence of a pathogenic role for oxidative stress in asthma and COPD. Toll-like receptors (TLRs) activate immune and inflammatory responses upon recognition of a broad repertoire of endogenous ‘danger’ molecules produced at sites of tissue damage and inflammation, and thus play a major role in host defence against tissue injury. Importantly, activation of TLRs by endogenous molecules produced at sites of tissue injury and inflammation leads to generation of reactive oxygen species, and as such, these receptors are critically implicated in oxidant-driven inflammation and tissue remodelling in disease. Current research projects available with Dr Maria Sukkar aim to elucidate the role of endogenous ‘danger’ molecules in driving TLR driven ASM inflammation and remodelling.

HDR candidates

• Alkhouri, Hatem
  Doctor of Philosophy (full-time)
  Submit date: July 2011
  "Airway smooth muscle and mast cells in asthma"
  Primary supervisor: Dr Margaret Hughes
  Associate supervisor: Professor Carol Armour

Competitive research grants

• "Corticosteroids, mast cells, airway smooth muscle and remodelling in asthma"
  Hughes, Oliver, Armour
  Asthma Foundation NSW
  $50,000
  2009
• "Expression and function of the damage: Associated protein high-mobility Box-1 (HMGB1) in human airway smooth muscle"
  Sukkar
  Pharmacy Research Trust NSW
  $20,000
  2008 - 2009
• "High mobility group-box 1 and airway smooth muscle synthetic, proliferative and migratory function"
  Sukkar
  Asthma Foundation NSW
  $50,000
  2009
• "Airway smooth muscle control of mast cells in asthma"
  Hughes, Brightling, Ammit, Burgess, Armour
  NHMRC Project Grant # 457457
  $618,000
  2007 - 2009

Recent publications

1. Krimmer DI, Loseli M, Hughes JM, Oliver BGG, Moir L, Hunt NH, Black JL, Burgess JK (2009). CD40 and Ox40L are differentially regulated on asthmatic airway smooth muscle. Allergy 64: 1074-82.
2. Ammit AJ, Burgess JK, Hirst SJ, Hughes JM, Manminder Kaur, JYL, Zuyderduyn S (2008). The Effect of Asthma Therapeutics on Signalling and Transcriptional Regulation of Airway Smooth Muscle Function. In press, Pulmonary Pharmacol & Therapeutics doi:10.1016/j.pupt.2008.10.006.
3. Seidel P, Merfort I, Hughes JM, Oliver B, Tamm M, Roth M (2009). Dimethyl fumarate inhibit the NFkB pathway at multiple levels to limit airway smooth muscle cell cytokine secretion. In press, Amer J Physiol: Lung Cell Mol Physiol doi:10.1152/ajplung.90624.2008.
4. Parmentier P, Quante T, Ramsay EE, Schulz V, Schuster F, Henness S, Allen.C, Ge Q, Armour CL, Ammit AJ (submitted). Corticosteroids inhibit sphingosine 1-phosphate-induced IL-6 secretion from human airway smooth muscle. Am. J. Physiol.