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
Increased Airway Smooth Muscle Mass As An Independent Determinant Of Asthma Pathogenesis And Severity
Funder
National Health and Medical Research Council
Funding Amount
$409,966.00
Summary
Asthma is a major health burden to the community. The most common form of the disease is allergic asthma and it is thought that allergic inflammation drives associated airway abnormalities including increased airway smooth muscle (ASM) mass. This study tests a new hypothesis that airway abnormalities and allergy have separate origins but combine to produce allergic asthma, and it’s the individuals with the greatest amount of ASM who develop clinically severe asthma.
Heterogeneity Of Airway Smooth Muscle Remodelling In Asthma
Funder
National Health and Medical Research Council
Funding Amount
$623,078.00
Summary
Increased smooth muscle in the airways causes excessive narrowing and asthma symptoms. The distribution of the increased muscle in the lung varies between people with asthma and may determine how severe the asthma is and what treatments are best. This project will use tissues from many cases of asthma to map this distribution and will use laser scanning in the airways to develop a test to safely examine the smooth muscle in living people, in order to better treat or prevent asthma.
Functional And Structural Relationships Of The Peripheral Airways In Chronic Asthma
Funder
National Health and Medical Research Council
Funding Amount
$318,917.00
Summary
It is now considered that airway wall thickening (airway remodeling), a consequence of persistent airway inflammation in asthmatics, significantly contributes to the symptoms and risk of death from asthma. Despite recent advances in the field, there are still many clinically relevant questions that have not been addressed. Some important issues still to be elucidated are: What is the precise sequence of tissue changes in remodeling? Which components of remodeling are reversible in the absence of ....It is now considered that airway wall thickening (airway remodeling), a consequence of persistent airway inflammation in asthmatics, significantly contributes to the symptoms and risk of death from asthma. Despite recent advances in the field, there are still many clinically relevant questions that have not been addressed. Some important issues still to be elucidated are: What is the precise sequence of tissue changes in remodeling? Which components of remodeling are reversible in the absence of allergen provocation? At what point does airway remodeling become irreversible? Does early intervention with anti-inflammatory medication have long term benefits in terms of reducing long-term remodeling? As there have been few appropriate models for addressing these types of remodeling issues, we propose to utilise a large animal model for chronic asthma to address these questions. One of the main focuses of this proposal is to identify biomarkers or functional indices of the different stages of remodelling. The sheep model is well placed to achieve these objectives given that the structure, physiology and asthma pathophysiology of sheep airways is similar to human airways. The novel experimental design is to expose four spatially separate lung regions (segments) in individual sheep with different durations of repeated weekly doses of HDM. The strength of the proposal is that lung function and structure of challenged segments from successive stages of remodeling can be assessed in one sheep. A separate experiment will examine how lung structure and function return to normal in chronically HDM-treated lung segments over successive months after exposure to HDM ceases. It is expected that information gained from this research will lead to a greater fundamental understanding of disease mechanisms in chronic asthma. This will increase the chances of improving current treatments, and allows for new strategies to be devised for treating asthma more effectively.Read moreRead less
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
The Role Of Glutathione Transferase P1 In Regulating Allergic Airways Disease
Funder
National Health and Medical Research Council
Funding Amount
$436,882.00
Summary
Recent studies have shown that a single amino acid change in an enzyme called glutathione tranferase Pi (GSTP)1 protects against the likelihood of developing asthma. This enzyme is found in the cells that line the airways and detoxifies harmful chemicals such as those found in pollutants and cigarette smoke. The aim of our study is to understand how GSTP1 protects against the development of asthma.