Airway remodelling: We have identified three major targets as being of interest for the therapy of airway remodelling in asthma fibrosis and lymphangioleiomyomatosis (LAM) – one involves targeting angiogenesis or new blood vessel formation, another tackles the accumulation of fibrotic proteins in the airway wall in airway disease and the third focuses on the lymphangiogenesis which is abnormal in LAM and could have implications for cancer. These arose out of our CRC funded research and patents have been filed.
Christine Jenkins (WIMR and Concord Hospital), Matthew Peters and Lucy Morgan (Concord Hospital) and Greg King (WIMR and Royal North Shore Hospital) are working with us to access clinical samples from well defined patient groups. Jenny Gamble (Centenary Institute) and Anthony Ashton (Kolling Institute) collaborate on our studies on angiogenesis and Tony Weiss and Ellie Kable at USyd are working with Janette Burgess on extracellular matrix proteins. Paul Foster and Phil Hansbro at Newcastle University are valuable collaborators with whom we can translate our cellular studies into whole animal in vivo investigations and Steve Wilton and Phil Thompson in Western Australia continue to work with us on our genetic studies. Elisabeth Bel (University of Amsterdam, The Netherlands) will work with our group studying mechanisms underlying severe asthma.
Harnessing the power of endogenous anti-inflammatory protein – MKP-1 (Alaina J. Ammit): Asthma is driven by inflammation and one of the major signalling pathways that drive the development of the pro-remodelled phenotype is the mitogen-activated protein kinases (MAPK) superfamily. As the name suggests, MKP-1 is a phosphatase and removes two critical phosphates from MAPK inhibiting its activity. Thus, MKP-1 plays a crucial negative feedback role as an endogenous MAPK deactivator to represses inflammation. But in severe asthma, MKP-1 activity is reduced allowing inflammation to continue unchecked. Thus, our research finds ways to enhance the levels and/or activity of MKP-1 may be exploited as a novel anti-inflammatory strategy in asthma and airway remodelling.
Respiratory viruses: Brian Oliver extended his studies on respiratory viruses collaborating with Euan Tovey (WIMR), Bill Rawlinson (UNSW), Stephen Liggett (University of Maryland, USA) and Nick King (USyd). Thomas Trian (who has returned to Bordeaux after spending three years at the Woolcock) is exploring the mechanisms underlying decreased functionality of beta adrenoceptor agonists which occurs during viral infections in people with asthma.
Lymphangioleiomyomatosis (LAM): We have increased our research effort into this deadly disease of young women with the help of grants from the LAM Australasian Research Alliance (LARA), with money raised by family and friends of sufferers. Markus Weckmann (who has returned to the University of Lübeck, Germany) has extended Sarah Boustany’s observation of a missing fragment of collagen from the lung tissue of LAM patients and has cloned and characterised its properties to find that it inhibits lymphangiogenesis and proliferation of LAM cells. We will continue to examine biological samples obtained from LAM patients participating in a trial of doxycycline at St Vincent’s Hospital, Sydney for content of MMPs and their inhibitors – tissue inhibitors of MMPs or TIMPs. Mike Berridge and James Baty, Malaghan Institute of Medical Research, Wellington, New Zealand are examining the self-renewing properties of LAM cells.
Chronic obstructive pulmonary disease (COPD): David Krimmer, who has recently completed his PhD with Brian Oliver, has developed a model in which he exposes airway cells to cigarette smoke extract (CSE) and examines effects on cytokine and extracellular matrix protein release, to help understand mechanisms underlying smoking induced lung tissue destruction and remodelling. John Whitelock at UNSW is bringing his expertise with the protein perlecan to Brian Oliver’s studies in smoking related lung disease and Ian Adcock at Imperial College, UK is an expert in epigenetics.
Maria Sukkar Pattern-recognition receptors and the pathogenesis of chronic airways disease: Damage to the airway tissue by common environmental exposures such as inhaled allergens (eg. house dust mite) and air pollutants (eg. ozone, tobacco smoke) and respiratory infections are strongly implicated in the inception and progression of asthma and/or COPD in genetically susceptible individuals. Repeated tissue injury, chronic inflammation and abnormal tissue repair lead to structural alterations or ‘remodelling’ of the airway wall, contributing to airflow limitation and variable airflow obstruction. Dr Maria Sukkar leads a research program focused on understanding how the airway tissue ‘senses’ and ‘responds’ to environmental insult; with the aim of targeting these receptors for therapeutic benefit. Her current work is focused on elucidating the role of RAGE (the receptor for advanced glycation end products), a unique pattern recognition receptor involved in the host response to tissue injury, infection and inflammation in chronic airways disease. RAGE recognises and binds to a large repertoire of soluble and cell-associated molecules released/expressed by stressed, injured, inflamed or infected cells and tissues (collectively termed damage-associated molecular patterns or DAMPs) leading to sustained cellular dysfunction. Dr Sukkar is examining the impact of RAGE activation on cellular responses in airway structural cells (epithelial cells, airway smooth muscle cells) in vitro. Through collaborations with Dr Simon Phipps (School of Biomedical Sciences, The University of Queensland) and A/Prof Peter Wark (Centre for Asthma and Respiratory Disease, Hunter Medical Research Institute, The University of Newcastle) she is extending these studies to understand the impact of RAGE activation in animal models of asthma and in patients with chronic airways disease. Current PhD students working on these projects include Md Ashik Ullah, Zaridatul Aini Ibrahim and Sharon Wong.
Airway mechanics is investigated by the smooth muscle mechanics group headed by Brent McParland. We are interested in the mechanisms of increased airway sensitivity and increased ability to narrow. Our philosophy is that structure is strongly linked with function and with changes in airway pathology/structure it is not surprising then that airways from asthmatic and emphysema patients behave abnormally. Since sensitivity relates to clinical symptoms we believe it is important to understand the mechanism of increased sensitivity. Since the airway smooth muscle mass is related to asthma severity, is greatly increased in patients that die with asthma, and there is no evidence for an increase in smooth muscle mass with duration of disease, we believe that an increased smooth muscle mass increases the chances of either fatal or near fatal deaths due to asthma “attacks”. Understanding the role of airway smooth muscle in airway narrow is therefore paramount.
Pulmonary fibrosis/Interstitial Lung Disease (ILD): Tam Corte runs the interstitial lung disease clinic at Royal Prince Alfred Hospital and is helping us identify markers of fibrosis in her patients. Hal Collard (San Francisco) provides us with valuable clinical material for our studies on lung fibrosis.
Thoracic physicians, pathologists and transplant coordinators – Allan Glanville (St Vincent’s Hospital, Sydney); Brian McCaughan and Jocelyn McLean (Royal Prince Alfred Hospital, Sydney); Juliet Burn (Douglass Hanly Moir, Sydney) and pathologists, transplant coordinators and theatre nurses at a number of Sydney hospitals and private practices all contribute to our ability to source tissue, following approval from appropriate ethics committees and signed, informed patient consent.