The role of arachidonic acid metabolism in the pathogenesis of atherosclerosis

Cardiovascular disease, and in particular, the atherosclerotic disorders, are the chief cause of illness, disability and death in many regions of the developed world, where they inflict very high personal, community and health care costs on society. Atherosclerosis, commonly referred to as hardening of the arteries, is an inflammatory disease and is the primary cause of heart attacks, strokes, lower limb loss in diabetics, aneurysms and chronic transplant rejection. Atherosclerosis results in the narrowing of arteries which leads to reduced blood supply, oxygen and nutrients to the affected tissues. Occasionally these plaques can rupture causing a complete blockage of blood supply which can be fatal if it occurs in the heart (eg. heart attack) or brain (eg. stroke). Damage to the inner lining of the blood vessel wall is believed to be the initiating event of this disorder but the mechanism(s) responsible for this injury remain unclear. In the current project, we are interested in how long term use of certain pain relief medications, referred to as anti-inflammatories, contributes to the generation of deleterious oxidative stress which can trigger the onset and progression of atherosclerosis. In recent years there has been much attention given towards this topic as certain pain remedies such as VioxxTM have been pulled off the shelves due to their association with increased cardiovascular events that occur with their chronic use. Based on our previous research, we believe we have identified an oxidative stress pathway that may be induced indirectly as a consequence of the chronic administration of these drugs. We have previously shown that a group of enzymes (CYP2C) can produce reactive oxygen during heart attacks which leads to the abnormal functioning of blood vessels. This dysfunctioning of blood vessels, which is also an early event in atherosclerosis, can be blocked with inhibitors, but it is not known whether CYP2C inhibition prevents atherosclerosis. The current proposal will investigate whether we can prevent atherosclerosis if we inhibit the activation of the CYP2C enzyme. We will also examine whether the administration of certain anti-inflammatories, known to increase cardiovascular events, increase the activity of CYP and reactive oxygen production. Finally, as many people depend on chronic administration of pain relievers such as these, we will investigate the effects of combined administration of CYP2C inhibitors and anti-inflammatory agents towards atherosclerosis pathogenesis. Results from these studies will help us to establish the role CYP2C in atherosclerosis and whether CYP2C inhibitors could be used as pre-emptive treatment for patients identified to be at a high risk for atherosclerotic disease

Genetic and epigenetic studies of innate immunity related genes in the development of asthma in childhood: the role of airway epithelial cells

Asthma is the most common chronic disease in children. It affects eight to 10 per cent of the population in developed countries, and rates are increasing. Susceptibility to asthma and other allergic diseases runs in families, which indicates that genes influence its development. However, numerous studies examining the influence of changes in the genetic code have led to inconsistent results. A possible explanation for the inconsistency is a failure to account for epigenetics. This emerging field of study involves investigating the basis of inherited traits that affect how genes function without affecting the sequence of the underlying genetic code. The airway lining cells, or epithelium, are a promising cell type in which to identify novel mechanisms of asthma. Jian-Qing He is studying cultured airway epithelial cells from 150 asthmatic and non-asthmatic children to explore whether a combination of genetic and epigenetic changes in immunity-related genes are central to the development of childhood asthma. Results from this study will allow for a better understanding of how genetic and epigenetic differences in epithelial cells are related to the development of asthma. Potentially, such knowledge could contribute to the development of more effective methods of screening for susceptibility to asthma and better preventive strategies.

Acute lung injury: FasL, apoptosis and protection by erythropoietin

Acute Respiratory Distress Syndrome (ARDS) is a common catastrophic lung condition that complicates critical illnesses of many types, most commonly severe infections. In ARDS, the cells that line the airspaces of the lung are injured and die. As a result, the lungs flood with fluid, becoming stiff, scarred and unable to transport oxygen into the bloodstream. Half of all patients with ARDS die, and there are currently no specific therapies to treat the condition, other than to provide supportive care. Erthropoieten (EPO) is a natural hormone that regulates the production of red blood cells in bone marrow. Injecting EPO is an established and safe therapy for anemia in patients with kidney failure, and it has been shown to protect against cell death in experimental models of stroke and heart attack. Patients with critical illness in the intensive care unit have abnormally low levels of EPO in their blood, leading to the hypothesis that low levels of EPO in the lung might contribute to cell injury and death in ARDS. Dr. Ruth MacRedmond’s research is the first to study the presence and activity of EPO in the lung. She is examining the ability of EPO treatment to prevent cell death caused by infection and the protective properties of EPO treatment in preventing ARDS. This project will expand our understanding of the mechanisms of cellular injury and death in ARDS, and explore the potential of EPO to act as a novel and important therapy for this devastating disease.

Clinical outcomes of acute lung injury: role of cytokine gene polymorphisms as predictors

Acute lung injury is a very common cause of respiratory dysfunction among critically ill patients in intensive care units. It is caused by excessive inflammation in response to infection or major injuries. The widespread inflammation interferes with oxygen transfer such that patients with the condition often require the support of a mechanical ventilator. Despite advances in understanding how acute lung injury develops, the mortality rate from the condition has remained at 30 to 40 per cent. Dr. Sanjay Manocha is investigating whether genetic variations predispose some patients to excessive inflammation. Understanding which genes influence the development of acute lung injury could help identify those at high risk, and lead to more targeted therapies to treat this debilitating condition.

Contribution of genes other than the CFTR gene to disease severity in Cystic Fibrosis

Cystic fibrosis (CF) is a severe genetic disorder caused by one gene: the cystic fibrosis transmembrane regulator gene (CFTR). Inheriting the gene from both parents leads to CF. People with CF experience chronic respiratory infections that cause lung damage and ultimately lead to lung failure and death. Lung damage in CF is not fully understood and cannot be completely explained by the CFTR gene defect. There are considerable differences in the severity and progression of lung disease, for example, among patients with the same mutation in the CF gene. Some may require lung transplantation by their teenage years, while others may not experience severe lung disease until adulthood. Daisy Frangolias is looking specifically at two types of genes: ones that are involved in fighting lung infections, and those that are involved in initiating and controlling the inflammatory response to the bacteria that cause lung infections. Her findings will increase the understanding of the relationship between the CF gene disorder and other genes in defining the long-term progression of CF, and may provide therapeutic targets for reducing lung damage.