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
Influence Of Endothelin And Protease-activated Receptors On Eosinophil Trafficking In The Airways Of Allergic Mice
Funder
National Health and Medical Research Council
Funding Amount
$376,980.00
Summary
Asthma is a chronic inflammatory lung disease. This disease affects about 10% of the population, although its incidence in primary school-age children is as high as 30% in some cities. People suffering from asthma have very responsive (hyperresponsive) airways to substances which are usually innocuous. Many asthmatics are allergic to substances such as pollens, animal dander and house dust, which causes the airways of the asthma sufferer narrow, making breathing more difficult. The airways of as ....Asthma is a chronic inflammatory lung disease. This disease affects about 10% of the population, although its incidence in primary school-age children is as high as 30% in some cities. People suffering from asthma have very responsive (hyperresponsive) airways to substances which are usually innocuous. Many asthmatics are allergic to substances such as pollens, animal dander and house dust, which causes the airways of the asthma sufferer narrow, making breathing more difficult. The airways of asthma sufferers also become inflamed and the resulting swelling of the airways and excess formation of mucous makes breathing difficult. Inflamed asthmatic airways contain large numbers of cells called eosinophils, which move from the blood into the airways. Substances released from the eosinophils are thought to damage the airways and cause airways hyperresponsiveness. We have developed a mouse model of allergic inflammation which has many of the hallmark features of asthma, including high numbers of eosinophils and hyperresponsive airways. We have recently shown that these effects are inhibited by treatment of allergic mice with a drug called SB217242. SB217242 inhibits the actions of endothelin, a peptide that is produced in elevated amounts in the airways of asthma sufferers and which may produce many of the effects associated with asthma. We wish to investigate the mechanisms through which SB217242 and drugs which stimulate novel protease-activated receptors inhibits the increase in eosinophil numbers in the airways. We will investigate the possibility that these drugs inhibit the migration of eosinophils from the blood into the airways, using a unique microscope that allows us to visualize the movement of eosinophils into tissues such as the airways. These studies are likely to be of considerable strategic value in determining the potential usefulness of these drugs in the treatment of asthma.Read moreRead less