This application will allow me to restructure my work to provide sufficient time to do full justice to the current and planned commitments of our Respiratory Research Group. Our research programme includes the immunopathology of chronic airway diseases; the epidemiology of respiratory disease (TAHS); clinical physiology technology to service these studies; respiratory clinical pharmacology; microbe-host interactions in CF and COPD; and EBM in chronic respiratory disease self-management .
Investigating The Effects Of Macrolides On Excessive Synthesis And Secretion Of Airway Mucins Using Novel Ex Vivo And In Vivo Approaches
Funder
National Health and Medical Research Council
Funding Amount
$520,821.00
Summary
Many people have difficulty breathing because the airway tubes that move air in and out of their lungs are blocked by excessive amounts of sticky mucus. Our project will use new techniques developed in our laboratories to investigate whether a group of medicines called “macrolides” can prevent the excessive production and release of mucus in the airways, and thus be beneficial in treating asthma, and potentially other lung diseases.
Mechanisms Of Airway Narrowing In Eosinophilic And Non-eosinophilic Asthma
Funder
National Health and Medical Research Council
Funding Amount
$500,593.00
Summary
Asthma is associated with excessive airway narrowing, increased thickness of the airway wall and inflammation, most typically with eosinophils. However, 50% of cases have few eosinophils and respond less well to current treatments. This project will examine differences in airway structure between patients with or without eosinophils, using post-mortem tissue, as part of an international research collaboration.
Mannitol In The Assessment Of Bronchial Responsiveness In Airway Disease
Funder
National Health and Medical Research Council
Funding Amount
$365,250.00
Summary
The airways of people with asthma respond by narrowing too easily and too much to a wide range of stimuli. The tests most commonly used to measure airway responsiveness in asthma are the pharmacological agents methacholine and histamine. When inhaled, they act directly on bronchial muscle causing it to contract and hence the airways to narrow. We have developed a non-pharmacological test using a dry powder of a sugar - mannitol. When inhaled, mannitol causes narrowing of the airways in asthmatic ....The airways of people with asthma respond by narrowing too easily and too much to a wide range of stimuli. The tests most commonly used to measure airway responsiveness in asthma are the pharmacological agents methacholine and histamine. When inhaled, they act directly on bronchial muscle causing it to contract and hence the airways to narrow. We have developed a non-pharmacological test using a dry powder of a sugar - mannitol. When inhaled, mannitol causes narrowing of the airways in asthmatics but little or no effect in healthy subjects. Many asthmatics respond to mannitol even when they have few symptoms of asthma. Mannitol causes the airways to narrow 'indirectly' by causing the release of substances from inflammatory cells in the airways (e.g. histamine, leukotrienes and prostaglandins) that cause the muscle to contract. After the inflammation has cleared, either by treatment with inhaled steroids or spontaneously, the response to mannitol is close to healthy subjects. Thus the response to mannitol depends on the presence of inflammation and loss of responsiveness means resolution of inflammation. The significance of this is that the mannitol test may be used as an 'inflammometer'. It would be important if airway responsiveness to mannitol could be used to identify individuals with airway diseases other than asthma, (chronic bronchitis, and chronic obstructive lung disease) who could benefit from treatment with inhaled steroids. This would be significant as there is currently no test to identify those individuals and there are unwanted effects from using steroids. Further, it may be possible to use mannitol to identify individuals with other inflammatory diseases who may be at risk of developing asthma. Some people with asthma, chronic bronchitis and chronic obstructive lung disease have increased levels of oxidative stress. We wish to identify those people and to measure change after treatment with steroids.Read moreRead less
The Effect Of Heterogeneity And Airway Closure On Distensibility Measurements In Asthma
Funder
National Health and Medical Research Council
Funding Amount
$35,085.00
Summary
Long term asthma can result in stiffening of the airways, which cannot currently be measured with standard lung function tests. A new non-invasive technique, using sound, has been shown to measure airway stiffness, but this may be adversely influenced by other respiratory changes that occur with asthma (airway closure, heterogeneity). We are investigating the effects of these confounding factors to fully characterise this novel technique, so that it can be used in the clinical environment.
Assessment Of Airway Smooth Muscle Hypertrophy In Asthma And Chronic Obstructive Pulmonary Disease (COPD)
Funder
National Health and Medical Research Council
Funding Amount
$298,055.00
Summary
Asthma and chronic obstructive pulmonary disease (COPD) are common in the Australian community. The cause of asthma is unknown and although COPD is most often due to smoking cigarettes it remains unknown why it develops only in some smokers and in some non-smokers. The pathology of asthma and COPD includes increased thickness of the airway smooth muscle layer. In asthma this is associated with relatively normal airway lumen size and intermittent, excessive airway narrowing whereas in COPD it is ....Asthma and chronic obstructive pulmonary disease (COPD) are common in the Australian community. The cause of asthma is unknown and although COPD is most often due to smoking cigarettes it remains unknown why it develops only in some smokers and in some non-smokers. The pathology of asthma and COPD includes increased thickness of the airway smooth muscle layer. In asthma this is associated with relatively normal airway lumen size and intermittent, excessive airway narrowing whereas in COPD it is associated with fixed narrowing of the airway lumens. The increased smooth muscle layer might result from more or bigger smooth muscle cells or from more connective tissue (matrix) between the muscle cells. This project aims to determine which of these 3 factors causes the increased thickness of the smooth muscle layer in asthma and COPD. We hypothesise that in asthma there are more muscle cells and more matrix, and that in COPD there is only more matrix. These differences would account for the different behaviour of the airways in asthma and COPD. Currently there is no useful or practical method to measure the amount of matrix in the airway wall, especially in the smooth muscle. This project will study the amount of matrix and muscle in very thin airway sections (< 1 m) from a large number of cases of asthma and COPD to allow, for the first time, accurate assessment of the fractions of matrix and muscle in the smooth muscle layer, since they barely overlap on these thin sections. The results of this study are important because they will: differentiate between mechanisms of increased thickness of the airway smooth muscle layer in asthma and COPD and therefore identify different prevention and treatment strategies; help to develop a method of monitoring airway remodeling in airway diseases that can be applied to bronchial biopsies.Read moreRead less
Cytokines Regulating Airway Inflammation, Remodelling And Hyper-reactivity In Chronic Asthma
Funder
National Health and Medical Research Council
Funding Amount
$329,500.00
Summary
This project examines a new approach to treatment of asthma, based on immunisation against the body's own chemical signals. The investigators will also be continuing studies on how twitchy airways develop in asthma, the mechanisms by which scarring of the airway walls progresses, and the signals that trigger inflammation of the airways. These studies will use a much-improved mouse model of the disease. In this experimental model, which was developed by the investigators, sensitised mice are chro ....This project examines a new approach to treatment of asthma, based on immunisation against the body's own chemical signals. The investigators will also be continuing studies on how twitchy airways develop in asthma, the mechanisms by which scarring of the airway walls progresses, and the signals that trigger inflammation of the airways. These studies will use a much-improved mouse model of the disease. In this experimental model, which was developed by the investigators, sensitised mice are chronically exposed to low concentrations of aerosolised egg white protein. The proposed studies will involve comparisons with animals that are immunised against certain inflammation-related molecules, as well as with mice that are genetically deficient in their ability to produce such molecules. The results of these studies may help in the development of methods for long-term suppression of the changes that develop in the airways of asthmatics.Read moreRead less
Targeting Remodelling In Chronic Obstructive Pulmonary Disease (COPD), Chronic Asthma And Idiopathic Pulmonary Fibrosis (IPF)
Funder
National Health and Medical Research Council
Funding Amount
$386,634.00
Summary
Lung diseases (emphysema, asthma & pulmonary fibrosis) are major burdens on Australian community and economy. Airway remodelling/wounding is a key feature of all these diseases. Patients experience severe breathlessness seriously impacting quality of life and frequently leading to death. We will assess the potential of new targets (including IL-33), & therapy in suppressing wounding in experimental models. This may lead to a new treatment to reverse or prevent lung diseases.
Clinical And Physiological Features Of Obstructive Sleep Apnoea Phenotypes
Funder
National Health and Medical Research Council
Funding Amount
$117,331.00
Summary
Obstructive sleep apnoea has variable causes and clinical effects in different patient groups. My research will quantify the contribution of various physiological processes to the development of upper airway obstruction in different sub-types of sleep apnoea and to determine how this affects clinical presentation. I will be measuring a number of physiological parameters, and finding out how sleep apnoea manifests in terms of symptomatology and adverse health effects.