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
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 Efficacy And Safety Of Acupuncture For Seasonal Allergic Rhinitis: A Prospective, Randomised Controlled Trial
Funder
National Health and Medical Research Council
Funding Amount
$175,732.00
Summary
Seasonal allergic rhinitis, also known as hay fever, is a common condition with high prevalence in Australia, being most pronounced during spring and early summer when pollen counts are highest. There is no proven cure for hay fever. Many hay fever sufferers seek alternative therapies such as acupuncture. We propose to undertake a rigorous study, using well-established clinical trial methodology, to evaluate the efficacy and safety of acupuncture in the treatment of hay fever.
ORIGIN AND REGULATION OF VAGAL PREGANGLIONIC NEURON SUBTYPES CONTROLLING AIRWAY SMOOTH MUSCLE TONE
Funder
National Health and Medical Research Council
Funding Amount
$438,700.00
Summary
The primary role of the airways is to allow the exchange of oxygen and carbon dioxide between the environment and the lungs. However, the airways are not merely a series of static tubes, but rather their size (or caliber) is subject to breath-by-breath alterations, thereby regulating gas exchange to match the body's demands. Regulation of airway caliber is achieved largely by subconscious changes in the tone of the muscle lining the airway wall. Airway muscle tone is primarily under the control ....The primary role of the airways is to allow the exchange of oxygen and carbon dioxide between the environment and the lungs. However, the airways are not merely a series of static tubes, but rather their size (or caliber) is subject to breath-by-breath alterations, thereby regulating gas exchange to match the body's demands. Regulation of airway caliber is achieved largely by subconscious changes in the tone of the muscle lining the airway wall. Airway muscle tone is primarily under the control of the parasympathetic division of the autonomic nervous system. Two distinct types of parasympathetic nerves innervate the airways: One type employs the neurotransmitter acetylcholine which causes airway muscle to contract and the airways to constrict, while the other type employs nitric oxide which evokes airway dilatation. The normal regulation of airway caliber is altered in a variety of inflammatory airways diseases. In asthma and chronic obstructive pulmonary disease (COPD) there is an increase in airway muscle tone (airway constriction) which compromises the normal movement of gasses and contributes to the morbidity and mortality of the diseases. There is a growing body of evidence to suggest that exaggerated airway muscle tone may in part result from dysfunction of either the contractile or relaxant parasympathetic nerves innervating the airways. However, at present very little is known about the parasympathetic pathways regulating airway caliber. A complete understanding of the mechanisms controlling airway smooth muscle tone is therefore essential to fully understanding possible role of autonomic dysfunction in the pathogenesis of obstructive airways diseases. The aim of this grant is to better define the physiological and anatomical properties of airway parasympathetic nerves in the brain stem.Read moreRead less
Airway Epithelial Barrier Function, Asthma And Aero-allergen Sensitization.
Funder
National Health and Medical Research Council
Funding Amount
$527,886.00
Summary
There is a strong association between allergy and asthma. This association been almost universally assumed to be causative. However, recent evidence suggests an alternative explanation ie., that the abnormal epithelium in asthma allows or facilitates sensitization to airborne allergens. This project will test this alternative hypothesis using human lung tissue and an animal model.