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
Abnormal Smooth Muscle Behaviour In Asthma: Toward An In Vivo Test
Funder
National Health and Medical Research Council
Funding Amount
$196,527.00
Summary
In order to understand asthma better, and to improve our ability both to prevent and to treat the disease, we need to understand why the airways of people with asthma narrow too easily and too much. Airway hyperresponsiveness is almost certainly a downstream consequence of several different abnormalities. Airway inflammation, resulting from an allergic reaction in the airways, probably plays a major role. It is also likely that the smooth muscle in the airways contributes to airway narrowing, bu ....In order to understand asthma better, and to improve our ability both to prevent and to treat the disease, we need to understand why the airways of people with asthma narrow too easily and too much. Airway hyperresponsiveness is almost certainly a downstream consequence of several different abnormalities. Airway inflammation, resulting from an allergic reaction in the airways, probably plays a major role. It is also likely that the smooth muscle in the airways contributes to airway narrowing, but at present we have no way to measure airway behaviour in the living human. In this project we will examine the response of the airways to a deep breath, to determine if this is an indicator of smooth muscle behaviour. When the airways are narrowed, taking a deep breath stretches them and helps to overcome the narrowing. It is well known that this stretching mechanism is impaired in asthma, probably as a result of inflammatory changes to the airway wall. What is less well known is that after the airway has been stretched by a deep breath, it re-narrows, and there is new evidence that the rate of re-narrowing is increased in asthma. Based on our knowledge of how the smooth muscle behaves in the organ bath, and of the types of abnormal behaviour found in muscle from allergic and some asthmatic people, it seems likely that the rate of airway re-narrowing following a deep breath is an indicator of smooth muscle behaviour. This hypothesis has not been tested before. If we can establish that the rate of re-narrowing is an indicator of smooth muscle behaviour, we can then determine if abnormal muscle behaviour occurs in asthma, and examine the factors associated with abnormal muscle behaviour. This will improve our understanding of the basic abnormalities in asthma, and facilitate studies to see if this test can predict who is at risk from developing asthma. Evidence that smooth muscle behaviour is abnormal in asthma may suggest new directions for drug therapy.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.
Airway Wall Thickness And Heterogeneity Are Key Determinants Of Asthmatic Airway Function.
Funder
National Health and Medical Research Council
Funding Amount
$207,509.00
Summary
Asthma is a common disease which is typified by excessive narrowing of the airways in response to stimuli that are trivial to non-asthmatic individuals. However, little is known about what causes asthmatic airways to be able to narrow so excessively. In this study, we will be looking at the importance of thickening of the airway walls in relation to excessive airway narrowing in asthmatics. We will also look to see how patchy the airway narrowing is in asthmatics and how this relates to excessiv ....Asthma is a common disease which is typified by excessive narrowing of the airways in response to stimuli that are trivial to non-asthmatic individuals. However, little is known about what causes asthmatic airways to be able to narrow so excessively. In this study, we will be looking at the importance of thickening of the airway walls in relation to excessive airway narrowing in asthmatics. We will also look to see how patchy the airway narrowing is in asthmatics and how this relates to excessive airway narrowing that occurs in severe asthmatic attacks. We will therefore be studying asthmatics of varying degrees of disease severity as well as those admitted to hospital because of acute severe attacks of asthma, and comparing them with a group of non-asthmatic subjects.Read moreRead less
The breathing difficulty experienced by asthmatics occurs because of excessive narrowing in the bronchial tubes or airways. These airways are normally held open by the pressures in the chest during breathing. It is possible that the excessive airway narrowing in asthma occurs because these pressures are no longer effective. This may be due to changes in the airway stiffness which occurs during asthma. The project will involve experts Canada and Australia who have developed new techniques which a ....The breathing difficulty experienced by asthmatics occurs because of excessive narrowing in the bronchial tubes or airways. These airways are normally held open by the pressures in the chest during breathing. It is possible that the excessive airway narrowing in asthma occurs because these pressures are no longer effective. This may be due to changes in the airway stiffness which occurs during asthma. The project will involve experts Canada and Australia who have developed new techniques which allow the airways to be seen so that these changes can be measured.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
Hyperplasia And Hypertrophy Of Airway Smooth Muscle In Asthma
Funder
National Health and Medical Research Council
Funding Amount
$286,250.00
Summary
Asthma is common in Australia with significant morbidity and it is the 6th Australian National Health Priority. Examination of the airways in asthma shows increased thickness of the airway wall (remodeling), and inflammation. Most long-term asthma treatment is currently focussed on treating inflammation. Since the contribution of smooth muscle to remodeling and excessive airway narrowing is crucial and may be largely independent of airway inflammation, new treatments aimed at the smooth muscle a ....Asthma is common in Australia with significant morbidity and it is the 6th Australian National Health Priority. Examination of the airways in asthma shows increased thickness of the airway wall (remodeling), and inflammation. Most long-term asthma treatment is currently focussed on treating inflammation. Since the contribution of smooth muscle to remodeling and excessive airway narrowing is crucial and may be largely independent of airway inflammation, new treatments aimed at the smooth muscle are needed. Treatments must be based on knowledge of the factors which result in more smooth muscle - hypertrophy (enlargement of cells), hyperplasia (more cells) or deposition of proteins (extracellular matrix) between the muscle cells. Matrix is produced by airway myofibroblasts which are more numerous in asthma. These various contributing factors have different signals that can be targeted for treatment, however, information regarding their relative importance is scant. We propose to examine cases of mild and severe asthma using archived tissue blocks in a multi-centre collaborative study using stereological techniques not previously applied to the airway in man. This study is important because it will: 1. Yield new data regarding the degree to which hyperplasia, hypertrophy and increased extracellular matrix vary in the airways; 2. Provide direction for the development of treatments of increased smooth muscle in asthma; 3. Provide relevance and direction to animal and tissue studies of airway smooth muscle; 4. Yield new information on the number of myofibroblasts in mild and severe asthma; 5. Yield new information on the effects of corticosteroids on smooth muscle, extracellular matrix and myofibroblasts in severe, fatal asthma, and 6. Relate increased smooth muscle to increased extracellular matrix, numbers of myofibroblasts and other airway wall dimensions including those close to the airway surface. These may be used to monitor airway pathology in asthma.Read moreRead less
How Do Thick Airway Walls Affect Airway Hyperresponsiveness In Asthma?
Funder
National Health and Medical Research Council
Funding Amount
$382,538.00
Summary
Asthmatic airways narrow too easily, a characteristic called airway hyperresponsiveness (AHR). To understand the cause of asthma we need to understand the cause of AHR. Thickened airway walls could amplify airway narrowing and increase AHR. However, thick airway walls are also stiff, and stiff walls could reduce narrowing and AHR. This project will examine the relationships between AHR and airway wall thickness and stiffness during and after treatment that reduces airway wall thickness.