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Outcome Of Childhood Asthma In Adult Life And The Interaction With COPD
Funder
National Health and Medical Research Council
Funding Amount
$503,549.00
Summary
The Melbourne Study of Childhood Asthma (MESCA) is the longest, most comprehensive follow-up study of childhood asthma. The members were recruited in 1964 at the age of 7 and they have been reviewed at ages 10, 14, 21, 28, 35 and 42 years of age with a retention rate of 87% of survivors at the most recent follow-up. To date, the MESCA study has provided comprehensive data on the outcome of childhood asthma through to their adult years and has been particularly influential in establishing approac ....The Melbourne Study of Childhood Asthma (MESCA) is the longest, most comprehensive follow-up study of childhood asthma. The members were recruited in 1964 at the age of 7 and they have been reviewed at ages 10, 14, 21, 28, 35 and 42 years of age with a retention rate of 87% of survivors at the most recent follow-up. To date, the MESCA study has provided comprehensive data on the outcome of childhood asthma through to their adult years and has been particularly influential in establishing approaches to treatment of paediatric asthma nationally and internationally. The results of the study have been published widely over the years and cited extensively. The members of this cohort turn 50 in 2007 and will be invited to participate in a further review to reassess their clinical outcome to examine the relationship between long standing asthma and the development of COPD. Those members of the cohort who have had asthma persisting through their adult years have a degree of fixed obstruction on their tests of lung function and are potentially at risk of developing COPD. Some are at increased risk as approximately 30% of the members are regular smokers. In this review, at age 59 years, there is an excellent opportunity to examine the interaction of asthma and COPD and to compare the inflammatory processes between those who have continuing asthma, those whose asthma has resolved and in each group examine the effect of smoking. We will also look at a numbers of genetic markers associated with COPD to identify those who are more susceptible to the development of COPD. A second area of interest is the components of the immune system that influence asthma.. In an earlier study we identified one component of the immune system, known as the T cell system, that had returned to normal in those whose asthma had resolved. In this review, we plan to examine the T cell system in detail to understand what mechanisms may be responsible for resolution of childhood 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.
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
We will conduct a survey of respiratory symptoms, lung function, smoking status, occupational exposures, and other risk factors among 3200 people aged 40 years and over living in five Australian communities: Melbourne, Sydney, Tasmania, Busselton (WA), and the Kimberley region (WA). In the Kimberley we will survey 400 Aboriginal people and 400 non-Aboriginal people. We will use a survey methodology that has been developed by an international expert panel and has been implemented in many other co ....We will conduct a survey of respiratory symptoms, lung function, smoking status, occupational exposures, and other risk factors among 3200 people aged 40 years and over living in five Australian communities: Melbourne, Sydney, Tasmania, Busselton (WA), and the Kimberley region (WA). In the Kimberley we will survey 400 Aboriginal people and 400 non-Aboriginal people. We will use a survey methodology that has been developed by an international expert panel and has been implemented in many other countries (in North and South America, Asia, and Europe). This study will provide the first nationally-representative information on the burden of chronic obstructive pulmonary disease (COPD) and the opportunities for health gain by improving the management of this illness. In Australia, COPD is a relatively silent and under-recognised disease but nevertheless is the third most important contributor to the burden of disease and the third leading cause of hospital admission as well as being the underlying cause of 4.2% of all deaths. The information we will collect is needed to form a basis for prevention and disease management interventions to reduce the burden of COPD, particularly among population sub-groups who are disproportionately affected, either due to greater exposure to risk factors (mainly tobacco smoking and occupation), greater susceptibility, under-recognition and under-diagnosis, or inadequate disease management. Importantly, the study will serve to raise awareness about the hazards of smoking for all Australians. By identifying target groups, prevalent exposures and management deficiencies, it will lead the way towards policy-relevant randomised controlled trials testing community-based interventions to prevent COPD and-or manage it more effectively. The information collected will help advance knowledge of the prevalence, burden and treatment of COPD that will be relevant to communities throughout the world.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
Macrophages, Sugars And Innate Immunity In Chronic Lung Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$413,150.00
Summary
This project is about a new idea to treat severe asthma, chronic obstructive lung disease (COPD) and sudden worsening of these diseases (exacerbations). Asthma and COPD are very common. Asthma afflicts approximately 10 % of all Australians and kills approximately 700 annually. COPD will be the third most common cause of death worldwide by 2010 (WHO) and costs more that $ AUS 10 Billion annually. The highest risk of death and greatest costs are associated with severe asthma and exacerbations. Our ....This project is about a new idea to treat severe asthma, chronic obstructive lung disease (COPD) and sudden worsening of these diseases (exacerbations). Asthma and COPD are very common. Asthma afflicts approximately 10 % of all Australians and kills approximately 700 annually. COPD will be the third most common cause of death worldwide by 2010 (WHO) and costs more that $ AUS 10 Billion annually. The highest risk of death and greatest costs are associated with severe asthma and exacerbations. Our idea, which is based on extensive animal data, is that these diseases can be treated by blocking the activity of proteins that allow a cell called the lung macrophage to grow, become activated, proliferate and survive. These proteins are called CSF-1 and GM-CSF and they belong to a larger class of proteins called colony stimulating factors (CSFs) Macrophages are important because they can rapidly respond to bacteria, viruses and fungi that can infect the lungs of asthma and COPD patients. Infections cause exacerbations. Normally, macrophages release a number of molecules called mediators that rouse a strong defensive reaction- a process called innate immunity. For example macrophages signal for a cell type called the neutrophil, which is a very efficient bacteria killer, to flood into the lung. However, these same cells can cause serious lung damage if the response is too strong or persistent. Macrophages and neutrophils need CSFs to work properly so blocking CSFs prevents lung damage. Although we now already know that blocking CSFs can prevent and reverse lung inflammation we still need to know a great deal more in order to know if this approach will be useful to treat people in the future. Our project is therefore all about understanding the fine detail of how CSFs can damage the lung. The importance of the project is that our work may lead to entirely new, and much more effective, treatments for people suffering from asthma and COPD.Read moreRead less
Modulation Of Asthmatic Airway Inflammation By Activation Of Epithelial Proteinase Activated Receptors
Funder
National Health and Medical Research Council
Funding Amount
$188,912.00
Summary
Children and adults feel the symptoms of asthma because their airways close up too easily. We have discovered a new mechanism that the healthy lung uses to keep airways open. The epithelial cells which line the airway release an enzyme that cuts of a small part of another protein, called a PAR receptor, that sits on the same cell. When this happens the epithelial cell releases relaxing substances from their lower surface. The relaxing substances keep the airways open. This grant application is d ....Children and adults feel the symptoms of asthma because their airways close up too easily. We have discovered a new mechanism that the healthy lung uses to keep airways open. The epithelial cells which line the airway release an enzyme that cuts of a small part of another protein, called a PAR receptor, that sits on the same cell. When this happens the epithelial cell releases relaxing substances from their lower surface. The relaxing substances keep the airways open. This grant application is designed to test whether the relaxing system also stops the airways from developing inflammation. If the relaxing system does this we will be able to use the knowlege we have that lets us activate the PAR receptors artificially to design new types of drugs. These drugs would be better than existing asthma drugs because they would prevent inflammation and relax the airways at the same time. These drugs could also be useful in other lung diseases such as chronic bronchitis.Read moreRead less
Asthma, Lung Function, Snoring And Passive Smoking In Busselton
Funder
National Health and Medical Research Council
Funding Amount
$115,110.00
Summary
Respiratory diseases such as asthma, chronic obstructive airway disease, and sleep apnoea are common in the community, and asthma is becoming more and more common. These diseases are a major cause of morbidity, lost time from work, use of health and community resources and death. Using information collected by the Busselton Health Studies between 1966 and 2000, we will investigate some new epidemiological aspects of respiratory diseases. Some of the questions we will examine are: * How much more ....Respiratory diseases such as asthma, chronic obstructive airway disease, and sleep apnoea are common in the community, and asthma is becoming more and more common. These diseases are a major cause of morbidity, lost time from work, use of health and community resources and death. Using information collected by the Busselton Health Studies between 1966 and 2000, we will investigate some new epidemiological aspects of respiratory diseases. Some of the questions we will examine are: * How much more common has asthma become in the Busselton population? Has the increase been more pronounced in some groups than in others (eg younger people)? Have other respiratory diseases also become more common? * Is decline in FEV1 over time a more useful measure of lung health than a single FEV1 measurement? How is decline in FEV1 related to age and other factors such as asthma, smoking, chronic respiratory diseases and hay fever? * Do the following put people at increased risk of sleep apnoea: overweight, recent weight gain, smoking, heavy alcohol intake, respiratory illness, cardiovascular disease and use of sedatives? * Do non-smoking spouses of smokers suffer more respiratory illness than spouses of non-smokers? We expect that results from this study will increase our understanding of the causes and progression of respiratory diseases, and may eventually point to ways of reducing the burden of these diseases in the community. Since all the information needed has already been collected in the course of earlier health surveys, this study will be particularly cost-effective.Read moreRead less
THE CHANGING PREVALENCE OF ASTHMA AND CHRONIC OBSTRUCTIVE AIRWAY DISEASE IN AUSTRALIA
Funder
National Health and Medical Research Council
Funding Amount
$737,817.00
Summary
Respiratory illnesses are common with asthma symptoms affecting up to 15% of adults and 30% of children in the Australian community. Chronic obstructive pulmonary disease (COPD) is also common. The term encompasses emphysema and bronchitis and is mainly due to cigarette smoking. Although COPD is less common than asthma it causes more persistent disability especially in older people. Asthma is associated with faster decline in lung function with age and may also ultimately cause COPD. A diagnosis ....Respiratory illnesses are common with asthma symptoms affecting up to 15% of adults and 30% of children in the Australian community. Chronic obstructive pulmonary disease (COPD) is also common. The term encompasses emphysema and bronchitis and is mainly due to cigarette smoking. Although COPD is less common than asthma it causes more persistent disability especially in older people. Asthma is associated with faster decline in lung function with age and may also ultimately cause COPD. A diagnosis of asthma has become more common especially in children although this may be due to increased awareness and available treatments. Less is known about changes in the prevalence of asthma and COPD in adults over the last 10 years. These airway diseases are associated with inflammation in the airways and changes in airway structure. Tests of lung function and airway responsiveness have been used repeatedly in Busselton a coastal town in the south west of Western Australia since 1966 to provide information on changes in airway structure (calibre). Recently non invasive tests that can provide evidence of inflammation have been developed. Although treatment of asthma can control symptoms and improve lung function, airway inflammation tends to persist. The extent to which inflammation and abnormal structure are present in the airways of people in the community who do not complain of respiratory symptoms is not known. This study will determine if the frequency of asthma and COPD are actually increasing in the population of Busselton in comparison to previous estimates over the past 35 years. It will determine the degree to which unrecognised airway inflammation is present in the community and the best ways of detecting it. The results of the study will help to look for causes of asthma, determine how big a problem airway inflammation is in the community, and how it relates to abnormal airway structure, lung function, airway responsiveness and respiratory symptoms.Read moreRead less
Airway Inflammation In Asthma And Chronic Obstructive Pulmonary Disease
Funder
National Health and Medical Research Council
Funding Amount
$390,509.00
Summary
In chronic diseases of the airway such as asthma and airway narrowing due to cigarette smoking - chronic obstructive pulmonary disease (COPD), the airways show inflammation (increased numbers of cells and their products) and remodelling (increased thickness and scarring) which persist for many years, possibly indefinitely. The exact mechanisms by which inflammation persists in the airway wall in asthma and COPD are unknown. We and others have shown that greater numbers of memory T-lymphocytes (T ....In chronic diseases of the airway such as asthma and airway narrowing due to cigarette smoking - chronic obstructive pulmonary disease (COPD), the airways show inflammation (increased numbers of cells and their products) and remodelling (increased thickness and scarring) which persist for many years, possibly indefinitely. The exact mechanisms by which inflammation persists in the airway wall in asthma and COPD are unknown. We and others have shown that greater numbers of memory T-lymphocytes (T-cells) are present in the airway wall in asthma and COPD. T-cells orchestrate the processes involved in inflammation. We have hypothesised that the persistence of airway inflammation in asthma and COPD results from the proliferation of memory T-cells within the airway wall. Unlike na ve T-cells, memory T-cells have previously been stimulated and can easily be activated to proliferate and promote inflammation by other cells which are fixed in the airway. Data from our current work examining this process suggests that, although cells fixed in the airway such as fibroblasts and macrophages are activated in asthma and COPD and may activate T-cells, they do not seem to be causing T-cell proliferation. We now wish to extend these studies by determinimg if memory T- lymphocytes are proliferating in the airway wall within aggregations of lymphoid cells which act like lymph nodes and promote T-cell growth. To do this we will compare the number of these aggregations and the types of T-cells they contain in mild and severe cases of asthma and COPD with those in normal subjects. This work will provide new knowledge to help understand the mechanisms for the persistance of airway inflammation in asthma and COPD and may thereby also provide a focus for effective treatments of these condition.Read moreRead less