Pharmacological Strategy For Blocking Lung Cell Damage By Toxic Smoke Constituents.
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
People retrieved from burning buildings or other hazardous situations involving fires are often at risk of death due to the effects of inhaled smoke. This reflects the presence of some very toxic substances in smoke that are products of the combustion of wood, vegetation and synthetic building materials. The most toxic substance present within smoke is acrolein, a very reactive chemical that attacks cells in the lining of the lung. This can result in a life-threatening condition known as oedema, ....People retrieved from burning buildings or other hazardous situations involving fires are often at risk of death due to the effects of inhaled smoke. This reflects the presence of some very toxic substances in smoke that are products of the combustion of wood, vegetation and synthetic building materials. The most toxic substance present within smoke is acrolein, a very reactive chemical that attacks cells in the lining of the lung. This can result in a life-threatening condition known as oedema, where the lung is flooded with fluids and is unable to perform its respiratory function. At present, the clinical approaches used to treat smoke inhalation victims are mostly directed against offsetting the symptoms of lung injury and do not take into account the role of lung cell injury by toxic substances in smoke such as acrolein. This project will provide a better understanding of the chemical events underlying the injury caused by smoke to lung cells, and also into possible drug strategies for treating victims of smoke inhalation. The work will explore the ability of a range of compounds that are chemically related to a blood pressure-lowering medicine (hydralazine) to protect lung cells against such smoke-induced damage. The work will employ a range of modern research techniques to understand the events occurring in lung cells exposed to smoke. Once this is understood, these approaches will be used to test the various drug compounds for their abilities to prevent the death of cells exposed to smoke or its toxic constutuent acrolein. This work will yield new information on a series of compounds concerning their ability to block the toxicity of smoke to lung cells. The goal is to identify one or two molecules that can be carried forward to testing in smoke-exposed animals.Read moreRead less
Cytokine And Macrophage Determinants Of Pulmonary Inflammation During Tuberculosis
Funder
National Health and Medical Research Council
Funding Amount
$455,899.00
Summary
Tuberculosis (TB) infects 33% of the world, causing over 2 million deaths per year. TB disease causes damaging lung pathology and new therapies to treat the infection and moderate inflammation are urgently required. TNF is essential for immunity to TB, acting to modulate inflammation. This grant will determine how soluble and membrane- bound TNF regulate the cellular and cytokine control of TB pathology and may lead to new therapies to limit inflammation in TB and other inflammatory diseases.
Pathophysiology Of Malaria-associated Lung Disease
Funder
National Health and Medical Research Council
Funding Amount
$422,517.00
Summary
About 2 million people die each year from complications of malaria infection. A frequent, life-threatening complication of severe malaria is lung oedema. There is no specific treatment for the lung complications, which are poorly understood. There has been until now no good model system to study malaria lung complications. We have developed in mice an experimental model of malaria specifically to determine the mechanisms that cause lung pathology, which has never been done before. Such experimen ....About 2 million people die each year from complications of malaria infection. A frequent, life-threatening complication of severe malaria is lung oedema. There is no specific treatment for the lung complications, which are poorly understood. There has been until now no good model system to study malaria lung complications. We have developed in mice an experimental model of malaria specifically to determine the mechanisms that cause lung pathology, which has never been done before. Such experiments cannot be performed in humans for ethical and logistical reasons. We believe that pulmonary oedema is caused by products of the immune system and we will rigorously test this idea in our study. The aim is to learn more about the processes occurring in this disease so as to devise new treatment strategies.Read moreRead less
Regulation Of The Epithelial Sodium Channel By Cytosolic Chloride And Pro-inflammatory Cytokines
Funder
National Health and Medical Research Council
Funding Amount
$219,750.00
Summary
The regulation of sodium transport by the epithelial sodium channel is essential for the maintenance of blood pressure and the correct amount of fluid in the respiratory tract and gut. Hyperactivity of the sodium channels leads to increased blood pressure and clogging of the gut and bronchi due to dehydration of the surface fluid. Reductions in the activity of the sodium channels lead to abnormally low blood pressure and the accumulation of fluid in the lungs such as occurs in influenza, high al ....The regulation of sodium transport by the epithelial sodium channel is essential for the maintenance of blood pressure and the correct amount of fluid in the respiratory tract and gut. Hyperactivity of the sodium channels leads to increased blood pressure and clogging of the gut and bronchi due to dehydration of the surface fluid. Reductions in the activity of the sodium channels lead to abnormally low blood pressure and the accumulation of fluid in the lungs such as occurs in influenza, high altitude pulmonary oedema and in cardiogenic pulmonary oedema. The present project will examine the mechanisms by which sodium channels are regulated. It will focus on the mechanisms by which cytosolic chloride and inflammatory mediators regulate the activity of the channels.Read moreRead less
An Open-label Extension Of A Randomised Clinical Trail Of Intravitreal Triamcinolone For Diabetic Macular Oedema
Funder
National Health and Medical Research Council
Funding Amount
$167,733.00
Summary
A 25 fold increase in the risk of going blind on diagnosis of diabetes is one of the most daunting threats that patients face. Most cases of vision impairment in diabetes are due to macular oedema that persists or recurs after laser treatment. There are now a number of uncontrolled, anecdotal reports that intravitreal triamcinolone (IVTA) is highly effective for the treatment of diabetic macular edema which is refractory to conventional laser treatment. We commenced the first placebo-controlled, ....A 25 fold increase in the risk of going blind on diagnosis of diabetes is one of the most daunting threats that patients face. Most cases of vision impairment in diabetes are due to macular oedema that persists or recurs after laser treatment. There are now a number of uncontrolled, anecdotal reports that intravitreal triamcinolone (IVTA) is highly effective for the treatment of diabetic macular edema which is refractory to conventional laser treatment. We commenced the first placebo-controlled, double masked clinical trial of intravitreal triamcinolone for refractory macular oedema in 2002. The 3 month results from this study provide the first scientific proof of principle that intravitreal triamcinolone reduces macular thickness and improves vision. The two year results will be available in March 2005, but confidential interim analysis of efficacy data in September 2004 suggested that the beneficial effect of triamcinolone treatment persisted. Thus it appears that treatment with intravitreal triamcinolone may be the most significant development for the prevention of blindness in people with diabetes since the introduction of laser treatment. It would also be a highly cost-effective intervention that could be administered by general ophthalmologists. The treatment cannot be recommended for routine use, however, until its long term efficacy and safety have been established. Since we already have a well studied group of patients who have received treatment for 2 years, we are in a unique position to extend the study in order to provide the long-term (5-year) safety and efficacy data that does not appear to be forthcoming from any other source. The results of this study will significantly improve knowledge of long-term outcomes of local high dose steroids for diabetic macular oedema, allowing the treatment to be used more rationally. Thus the study is very likely to directly reduce the risk of blindness in people with diabetes.Read moreRead less
Modulation Of Endothelial Junctions As Selective Immunotherapy
Funder
National Health and Medical Research Council
Funding Amount
$911,387.00
Summary
We have developed a new drug (CD5-2) that targets the junctions of endothelial cells, the cell that lines all vessels. CD5-2 reduces oedema in diseases such as diabetic retinopathy and tumours. Thus it has potential as a new therapeutic in chronic inflammatory diseases where leaky blood vessels are central to the pathology. This grant will provide fundamental understanding of how CD5-2 induces such profound effects to alter the levels of oedema and alter inflammatory cell infiltrates in tissues.
Invasive Cardiopulmonary Exercise Testing For The Evaluation Of Unexplained And Complex Multifactorial BREATHlessnEss (i-BREATHE)
Funder
National Health and Medical Research Council
Funding Amount
$132,743.00
Summary
Breathlessness is a common symptom that can be caused by diseases of the heart, lungs or muscles. It is not uncommon that the cause is undiagnosed either because conventional tests do not yield a diagnosis, or because an individual suffers from multiple diseases. This research aims to use invasive cardiopulmonary exercise testing, a highly specialised test which simultaneously measures breathing, heart and muscle function, to improve the diagnosis and treatment of patients with breathlessness.