Scarring And Angiogenesis In The Airway Wall In Smoking And COPD: Links Between Inflammation And Remodelling
Funder
National Health and Medical Research Council
Funding Amount
$361,614.00
Summary
Smoking damages airways to produce scarring and new blood vessel growth resulting in airway narrowing, so-called COPD. Details of these processes are poorly understood. We will analyse airway biopsies taken from smokers, to dissect out the linkages between airway damage, airway inflammation, structural remodelling, and clinical changes. We will investigate the effects on these processes of: 1) inhaled corticosteroid; and 2) smoking cessation over 3 and 12 months.
Expression And Function Of Fatty Acid Binding Proteins In Asthmatic Airway Epithelium
Funder
National Health and Medical Research Council
Funding Amount
$226,500.00
Summary
Asthma is an inflammatory disease of the lungs that affects over 10% of all Australians. It ranges in severity from mild to life-threatening. Although a number of drugs are currently available for the treatment of asthma, there are many people whose asthma does not respond very well to treatment. We have recently identified a gene called aP2 that is important in the development of asthma. Drugs targeted against this gene may be very useful in the treatment of asthma. In this project, we aim to u ....Asthma is an inflammatory disease of the lungs that affects over 10% of all Australians. It ranges in severity from mild to life-threatening. Although a number of drugs are currently available for the treatment of asthma, there are many people whose asthma does not respond very well to treatment. We have recently identified a gene called aP2 that is important in the development of asthma. Drugs targeted against this gene may be very useful in the treatment of asthma. In this project, we aim to understand how aP2 is turned on during asthma, and how it contributes to disease development. This information will be essential for designing optimal strategies for drug targeting of the aP2 pathway in asthma.Read moreRead less
While many cases of asthma are mild, severe cases require extensive health care resources and are virtually unresponsive to conventional treatment. This project will investigate whether specific compounds released from the airway are able to cause lung damage and airway abnormalities similar to that in severe asthma. We will investigate whether these changes are responsive to conventional therapy and investigate a potential treatment for regaining this responsiveness in severe asthma.
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
Developmental And Cellular Mechanisms Involved In The Pathological Changes To The Epithelium In Asthma.
Funder
National Health and Medical Research Council
Funding Amount
$263,500.00
Summary
A consensus has developed in recent years that asthma involves chronic airway inflammation superimposed upon a background of airway remodelling. If untreated, these processes result in increased airway responsiveness, variable airflow obstruction and ultimately a progressive decline in lung function). Recently the role of the epithelium in the pathogenesis of asthma has been emphasised based upon observations indicating that the epithelium can play an important role in airway inflammation and re ....A consensus has developed in recent years that asthma involves chronic airway inflammation superimposed upon a background of airway remodelling. If untreated, these processes result in increased airway responsiveness, variable airflow obstruction and ultimately a progressive decline in lung function). Recently the role of the epithelium in the pathogenesis of asthma has been emphasised based upon observations indicating that the epithelium can play an important role in airway inflammation and remodelling. However, this paradigm has been developed using data accumulated almost exclusively from studies in adults. Epidemiological studies suggest that airway remodelling might play a less significant role in the majority of childhood asthma since most children with asthma have relatively minor symptoms, minimal disruption of lung function and tend not to have symptoms that persist into adulthood. Clearly the relative importance of inflammation and remodelling and the regulatory mechanisms involved are important factors to understand particularly if new, effective prevention and therapeutic strategies are to be developed. For the first time in children, the proposed project will allow the study of asthma mechanisms using target organ tissue (airway epithelium) from a large unselected population. Primary cell samples recovered by bronchial brushing will be analysed separately and also cultured in order to investigate critical elements of the pathogenesis of asthma. Data collected from symptomatic children can be easily compared with that from healthy controls and also with data from adults to determine age related factors that contribute to asthma. Furthermore, the establishment of a repository of cultured epithelial cells from these children will provide a unique resource that will allow future collaborations with scientists studying a variety of mechanisms in asthma and with the pharmaceutical industry.Read moreRead less
Integrin-growth Factor Interactions In The Development Of Airway Wall Remodelling
Funder
National Health and Medical Research Council
Funding Amount
$405,300.00
Summary
Asthma is a clinically and socio-economically important disease with prevalence in the Australian population of approximately 13% for adults and approaching 25% for children. Currently, glucocorticoids (GCS) are first line prophylactic therapy for the disease. Despite a wide diversity of precipitating factors, the mechanisms underlying its pathogenesis remain unclear. A marked thickening of the airway wall bought about by excessive deposition of extracellular matrix is a prominent pathological f ....Asthma is a clinically and socio-economically important disease with prevalence in the Australian population of approximately 13% for adults and approaching 25% for children. Currently, glucocorticoids (GCS) are first line prophylactic therapy for the disease. Despite a wide diversity of precipitating factors, the mechanisms underlying its pathogenesis remain unclear. A marked thickening of the airway wall bought about by excessive deposition of extracellular matrix is a prominent pathological feature but why this occurs and how it can be prevented is equally unclear. Recent studies have suggested that interactions between cells and the extracellular matrix influence the airways response to inflammation and modulate the effectiveness of currently available therapies. Indeed, there is mounting evidence to suggest that GCS fail to modulate and indeed in some cases even contribute to structural changes in the remodeled airway wall. The aim of this study is to assess the mechanisms by which cells and the extracellular matrix interact to promote remodelling of the airway wall and to determine whether this association influences the responsiveness to traditional asthma therapies.Read moreRead less