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
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.
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
Novel Candidate Genes, Lung Function And Allergic Airways Disease
Funder
National Health and Medical Research Council
Funding Amount
$581,892.00
Summary
We propose to study airway remodelling (structural changes to the airway) and in asthma using human samples and rodent models of asthma. We are particularly interested in investigating the role of trefoil peptide 2 and relaxin, two genes identified as determining lung function. To do this we need to understand the mechanisms of airway remodelling and its impact on disease severity in the patient. A strength of this study is availability of samples from a large study of human asthma.
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.
Does The Pattern Of Ventilation Distribution Predict Airway Hyperresponsiveness?
Funder
National Health and Medical Research Council
Funding Amount
$256,973.00
Summary
The tendency for airways to narrow too easily when stimulated is called airway hyperresponsiveness (AHR). AHR is an important feature of asthma, but it also occurs in other diseases, such as chronic obstructive pulmonary disease (COPD) - an airway disease caused by smoking, and cystic fibrosis. People who have AHR have more severe respiratory disease, regardless of which disease they have, and are more likely to develop poor lung function in old age and to be hospitalised or die from their disea ....The tendency for airways to narrow too easily when stimulated is called airway hyperresponsiveness (AHR). AHR is an important feature of asthma, but it also occurs in other diseases, such as chronic obstructive pulmonary disease (COPD) - an airway disease caused by smoking, and cystic fibrosis. People who have AHR have more severe respiratory disease, regardless of which disease they have, and are more likely to develop poor lung function in old age and to be hospitalised or die from their disease. If we can understand the causes of AHR we will have a better understanding of why some people with respiratory disease have poor outcomes. We have recently discovered that, in asthma, there is a very close relationship between AHR and the uneven distribution of air within the lungs. We believe that structural changes in the airways that cause this uneven distribution make the airways prone to AHR. This raises the possibility that factors that cause uneven ventilation in other respiratory diseases might also predispose the airways to AHR. If this is true, it suggests that there is a single physiological basis for AHR in a range of different diseases, and would allow us to focus research more closely on the causes of uneven ventilation. In this project we will measure the relationship between AHR and uneven ventilation in people with asthma, COPD or cystic fibrosis. The study is important because older people with asthma, particularly those with permanently narrowed airways, are likely to have more structural changes in their airways than young asthmatics, whereas people with COPD and cystic fibrosis have a different pattern of both structural changes and airway inflammation from that in asthma. The study will tell us whether there is a consistent relationship between AHR and uneven ventilation. If so, this would be extremely strong evidence that the factors that cause uneven ventilation contribute to AHR, and will point the way to studies of new treatments.Read moreRead less
Intrinsic Response Of Airways To Cyclical Dilation And Elongation In Breathing
Funder
National Health and Medical Research Council
Funding Amount
$355,014.00
Summary
Variations in lung pressures during breathing produce cyclical expansion of the airway tubes. These respiratory movements provide one of the most powerful protective mechanisms for the lung. The protective mechanism fails in asthma so that cyclical expansion of the airway tubes can make breathing more difficult. Current belief is that protective and harmful effects of lung expansion occur by either relaxation or contraction of the muscles lining the airway tubes. Findings from this laboratory su ....Variations in lung pressures during breathing produce cyclical expansion of the airway tubes. These respiratory movements provide one of the most powerful protective mechanisms for the lung. The protective mechanism fails in asthma so that cyclical expansion of the airway tubes can make breathing more difficult. Current belief is that protective and harmful effects of lung expansion occur by either relaxation or contraction of the muscles lining the airway tubes. Findings from this laboratory suggest that the above dogma needs reconsideration. The project will utilize a novel model of the lung to enable us to determine the mechanisms producing both the protective effect, and in asthmatics the harmful effects of cyclical lung expansion. Once the part of the lung that 'fails' in this aspect of asthma has been detected then therapeutic strategies can be put in place to reverse the defect.Read moreRead less
Mechanisms Of Protease-activated Receptor-2-mediated Bronchoprotection
Funder
National Health and Medical Research Council
Funding Amount
$354,758.00
Summary
The incidence of asthma continues to increase globally, yet there have been few real therapeutic advances. Our research, however, has recently uncovered a novel mechanism that protects the airways from inflammatory diseases like asthma. We have found that the layer of cells that line the airways - the epithelium - acts as a detector of early inflammatory events and releases anti-inflammatory substances. The lungs achieve this level of protection via 'sensor' molecules called receptors which are ....The incidence of asthma continues to increase globally, yet there have been few real therapeutic advances. Our research, however, has recently uncovered a novel mechanism that protects the airways from inflammatory diseases like asthma. We have found that the layer of cells that line the airways - the epithelium - acts as a detector of early inflammatory events and releases anti-inflammatory substances. The lungs achieve this level of protection via 'sensor' molecules called receptors which are located in the epithelium. In the case of our discovery, these receptors are called protease-activated receptors (PARs) to highlight the unique manner in which they are turned on or activated by enzymes called proteases. We have discovered that the epithelium of the lungs stores these enzymes and probably releases them during the inital stages of infection. Once released, these enzymes are detected by PARs on epithelial cells which then release substances that inhibit multiple inflammatory pathways. This mechanism protects the airways from effects that make breathing difficult, as in asthma. We have confirmed that this system provides protection in the airways of intact animals. The purpose of this projects outlined in this application is to examine the effects of activating one PAR, PAR2, on several processes in the lung, in order to characterise the individual events and processes that underlie the protective response. These studies will enable us to determine whether synthetic compounds that activate PAR2 are potential novel compounds for the treatment of diseases like asthma.Read moreRead less
Response Of Human Airways To Deep Inflation In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$281,037.00
Summary
The trachea and bronchi contain muscle that when it contracts narrows the air passages and makes it harder to breath. In healthy people taking a deep breath relaxes this airway muscle and improved breathing. However, in people who suffer from asthma and chronic airflow obstruction deep breaths do not have the normal relaxing actions on airway contraction. This study will use lung removed as part of surgery for lung cancer to study how the relaxing actions of deep breathing work in human airways.