Inflammation.

Our focus is to understand how reactive chemicals called oxidants, produced by the body during inflammation, can affect the function of blood vessels,

to better understand the changes that occur in the arteries during the early stages of atherosclerosis.

What impact will this research have?

Understanding changes that occur in the arteries during the early stages of atherosclerosis is vital to the rational development of new drugs and therapies to prevent this disease.

Current projects and goals

We are particularly interested in oxidants produced by an enzyme called myeloperoxidase, which is produced in the arteries by infiltrating immune cells during the inflammation. Myeloperoxidase is both a risk factor for coronary artery disease and a prognostic agent for patient outcome following cardiac complications, and is strongly associated with the development of atherosclerosis.

Myeloperoxidase (MPO) is released from phagocytes under inflammatory conditions, where it catalyses the production of potent chemical oxidants, including hypochlorous acid (HOCl, bleach) and hypothiocyanous acid (HOSCN). These MPO-derived oxidants are a critical component of the human immune system, but they have also been implicated as playing a causal role in the development of many inflammatory pathologies. Evidence linking MPO and atherosclerosis is particularly compelling. In addition to studies showing elevated MPO and oxidative damage in atherosclerotic lesions, MPO is recognised as both an independent risk factor for the development of disease, and a powerful prognostic agent for patient outcome. Understanding the key mechanistic elements involved in MPO-derived oxidant mediated biological damage, and how this drives atherosclerotic lesion development, is a major focus of the Inflammation Group.

Role of modified bad cholesterol in atherosclerosis

A key event in the initiation of atherosclerosis is the oxidative modification of low-density lipoprotein (LDL or ‘bad’ cholesterol), which causes the uncontrolled cellular uptake of lipid and triggers a cascade of inflammatory events. The uptake of modified LDL by cells in the arterial wall induces cellular dysfunction and propagates the development of atherosclerosis. We are examining the role of different types of modified LDL on vascular cell function to investigate novel strategies to modulate these damaging reactions.

Cellular mechanisms linking smoking and cardiovascular disease

Atherosclerosis is four times more prevalent in people who smoke, resulting in far more deaths from coronary heart disease in smokers than non-smokers. Although it is well established that smoking independently increases the risk of dying from cardiovascular disease, the mechanisms responsible for this elevated risk are not well understood. Smokers have elevated plasma levels of thiocyanate and hence produce greater amounts of the myeloperoxidase-derived oxidant hypothiocyanous acid (HOSCN). The selectivity and reactivity of this oxidant is markedly different to the chlorinating myeloperoxidase oxidant hypochlorous acid (HOCl). We are examining the role of HOSCN to modulate vascular cell function and investigating novel, targeted, antioxidant therapies to prevent or modulate this process.

Exploring the novel cellular interactions of chlorinated nucelosides

Chlorine is a potent disinfectant, which is mainly present in aqueous solution as hypochlorous acid (HOCl), and molecular chlorine (Cl 2). Hypochlorous acid is used widely to kill harmful bacteria in both drinking water and swimming pools. This disinfectant is also produced in the body by activated leukocytes (white blood cells) via the myeloperoxidase-catalysed reaction of hydrogen peroxide with chloride ions. HOCl chlorinates the nucleoside building blocks of RNA and DNA, and these products are seen in diseased tissue, including atherosclerotic lesions. We are investigating the reactivity of chlorinated nucleosides with different cell types, and the contribution of these reactions to inflammatory disease and the development of atherosclerosis.

Extracellular Traps and DNA Damage – key players in atherosclerosis?

Neutrophils (a type of white blood cell) release extracellular traps, termed “NETs”, following a novel mode of cell death called NETosis. These structures trap and kill bacteria, and consist of a mesh of DNA and histones decorated with neutrophil proteins including myeloperoxidase (MPO) and elastase. In addition to the well-defined role of NETs in innate immunity, there is growing evidence for a key role of NETs and extracellular traps (ETs) from other immune cells in disease, particularly where inflammation is involved in pathogenesis. We are studying the role of ETs from immune cells in the development of lesions in atherosclerosis.

Investigating the molecular mechanisms involved in vascular cell damage and death, within the setting of atherosclerosis

There is epidemiological, clinical, and experimental evidence that cellular stress and excessive inflammation are causally linked to various pathological conditions including atherosclerosis. One of the hallmarks of atherosclerosis is the infiltration of macrophages within the vascular wall at sites of inflammation, contributing to atherosclerotic lesion formation. Excessive oxidant formation within this environment, generated as part of the inflammatory response to injury, results in oxidative stress, damage and ultimately death to all cells of the vasculature. We are investigating how inflammatory oxidants modulate the cellular redox environment and cause changes in gene expression, which may contribute to the development of disease.

Professor Clare Hawkins
Research group led by:
Research covers areas of:
Latest news

Easy School Lunch ideas for kids (..and big kids!)

Making kid's school lunches takes a good 20-minute chunk out of your morning routine. And some days it’s hard work. Dealing with fussiness. Ensuring that it’s healthy. Making sure you are giving them the right amount of food. Making sure that it stays fresh because it can’t be re-heated and it’s not stored in a fridge. Phew! Coming up with ideas to keep your kids interested and well-nourished is a huge challenge! Here are some tips for creating a nourishing, yet uncomplicated school lunch box.

Achievements

In the last 5 years, the Inflammation Group has published over 30 papers and has contributed to the training of numerous PhD and Honours students. Our students and Early Career Researchers have gained international recognition through the receipt of Young Investigator Awards at conferences and Travel Grants to facilitate conference attendance.

Help fund vital research into heart disease

Select your donation details
You can choose between donating once or monthly.
Please enter or select your donation amount.
Invest in a future free from cardiovascular disease.
Your donation will allow great science to flourish.
All donations are tax deductible.