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.
The Mechanisms Underlying Pneumoviral-induced Angiogenesis Of The Lung And Its Impact On The Asthmatic Response.
Funder
National Health and Medical Research Council
Funding Amount
$564,625.00
Summary
Asthma, is a serious respiratory disease resulting in structural changes to the lung and breathing difficulties, and is often compounded by respiratory viruses. We have shown that viral infection of newborn mice causes the growth of new blood vessels in the lungs (a feature seen in human asthmatics). This project will investigate the mechanisms involved and determine the potential of this feature as a therapeutic target.
In the asthmatic lung structural changes or remodelling occur, which are thought to contribute to the abnormal functioning of the airways. These remodelling events which occur in the asthmatic airway include increased deposition of proteins which form the scaffolding of the airways (the extracellular matrix ECM proteins), and an increased mass of bronchial smooth muscle cells. Many of these critical structural changes are not reversed or prevented with current asthma therapy. Remodelling is an i ....In the asthmatic lung structural changes or remodelling occur, which are thought to contribute to the abnormal functioning of the airways. These remodelling events which occur in the asthmatic airway include increased deposition of proteins which form the scaffolding of the airways (the extracellular matrix ECM proteins), and an increased mass of bronchial smooth muscle cells. Many of these critical structural changes are not reversed or prevented with current asthma therapy. Remodelling is an important process in both the development and progression of asthma. The reason why remodelling occurs in the lungs of people with asthma is not known. It is thought that persistent inflammation drives the remodelling process; however remodelling can perpetuate inflammation, thereby creating a cyclic series of events. Furthermore we have shown that cells from non-asthmatic volunteers which are grown on asthmatic ECM change to become more like cells from asthmatic subjects. Viruses which infect the lungs may play a role in the development of asthma, and in the increased remodelling which is observed. Many common respiratory viruses are capable of infecting lung cells, eg epithelial cells, which evokes an inflammatory response. I will investigate if viral infection can alter the remodelling process, using lung cells isolated from asthmatic and non-asthmatic volunteers. Furthermore, I will assess if current and novel treatments are effective in reducing the remodelling process. We have preliminary evidence that infection of lung epithelial cells with rhinovirus (the common cold virus) alters the amount of ECM deposited by these cells. I hypothesise that this process will be increased in cells from volunteers with asthma compared to non-asthma. As current therapeutics are unlikely to be able to reverse these remodelling events these experiments will enable the development of new therapeutics which can target this important aspect of airway disease.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
The Relationship Between Vascular Remodelling And Mast Cells In Chronic Asthma
Funder
National Health and Medical Research Council
Funding Amount
$353,253.00
Summary
It is known that the airwalls of asthmatics have increased numbers of small blood vessels which can contribute to poor lung function in asthma. The proposed research uses a novel sheep model for chronic asthma to investigate the progressive changes to the blood vessels in the airway walls of asthmatic lungs. The information gained from our sheep model will assist the understanding of blood vessel growth and thus ulitmately help in devising new strategies to treat the effects of asthma.
In the asthmatic lung structural changes, such as increased deposition of proteins which form the scaffolding of the airways (the extracellular matrix proteins), and an increased mass of bronchial smooth muscle cells occur. Many of these critical structural changes are not reversed or prevented with current asthma therapy, thus we need to investigate, by using lung cells and tissues , why they happen and how we can prevent them.
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
Understanding Corticosteroid-sensitive And -insensitive Pathways In Airway Remodelling
Funder
National Health and Medical Research Council
Funding Amount
$299,270.00
Summary
Asthma and chronic obstructive pulmonary disease (COPD) are chronic disorders of the airways affecting millions of people worldwide. Airways become remodelled, or thickened, resulting in airway obstruction and decline in lung function. Approximately 400 asthmatics and 6000 COPD sufferers die in Australia each year. Worryingly, COPD is currently the fourth highest cause of death in Australia and this number is predicted to increase in the future. Unfortunately, the drugs currently available for c ....Asthma and chronic obstructive pulmonary disease (COPD) are chronic disorders of the airways affecting millions of people worldwide. Airways become remodelled, or thickened, resulting in airway obstruction and decline in lung function. Approximately 400 asthmatics and 6000 COPD sufferers die in Australia each year. Worryingly, COPD is currently the fourth highest cause of death in Australia and this number is predicted to increase in the future. Unfortunately, the drugs currently available for combating these diseases have limited success. We need to understand how to control airway remodelling to be able to improve treatments for asthma and COPD. But first we require a greater understanding of the molecular mechanism-s underlying the development of airway remodelling. With this proposal we will increase our knowledge of the mechanistic basis of asthma and COPD and may elucidate novel therapeutic targets for future pharmacological intervention.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
Airway Smooth Muscle Control Of Mast Cells In Asthma
Funder
National Health and Medical Research Council
Funding Amount
$612,696.00
Summary
Around 12% of Australians are asthmatic, with up to 25% of children affected. Thus it is a significant burden for us and our healthcare system. Currently we treat asthma with corticosteroids to reduce airway inflammation, otherwise the inflammation leads to thickened airways with increased amounts of smooth muscle (ASM) that contracts too much and too easily. However more research is needed. Corticosteroids sometimes stop working or have unwanted side effects, especially for children, and we sti ....Around 12% of Australians are asthmatic, with up to 25% of children affected. Thus it is a significant burden for us and our healthcare system. Currently we treat asthma with corticosteroids to reduce airway inflammation, otherwise the inflammation leads to thickened airways with increased amounts of smooth muscle (ASM) that contracts too much and too easily. However more research is needed. Corticosteroids sometimes stop working or have unwanted side effects, especially for children, and we still cannot prevent asthma developing or cure it. We need to know more about the chemical signals which cause the pattern of inflammation that is specific for asthma in order to cure it and prevent it developing. Recently, inflammatory cells called mast cells (MC) have been found in increased numbers in the ASM layer of asthmatics compared with bronchitics or healthy people. MC release mediators that contract the airways, induce mucous secretion and promote further inflammation. We think the effects ASM cells and MC have on each other are central factors in causing physical changes to the airways of asthmatics. In asthmatics we have identified a chemical message (IP10) released in increased amounts by the ASM which attracts MC to it. We also have evidence that ASM from people without asthma release factors that prevent IP10 and similar chemical messages from working on MC. These two exciting findings demonstrate asthmatic ASM is different. We will investigate why asthmatic ASM produces more IP10 and try to prevent each of the steps we identify with drugs that have very specific actions. In addition, we will identify the factors released by non-asthmatic ASM that inhibit IP10 and similar chemical messages from working. The additional knowledge gained by this research may lead to the design of novel treatments to prevent asthma symptoms without side effects and lead to new strategies to prevent asthma developing, especially in children.Read moreRead less