In cardiovascular disease and inflammatory processes the function of the endothelium changes, and these beneficial effects are diminished. We use cultured endothelial cells to research novel ways to prevent adverse changes in the endothelium in order to develop treatments, which will restore normal function and diminish the occurrence of life-threatening events such as myocardial infarction and stroke. We have a particular interest in what triggers untoward changes in the endothelium, and are developing treatments, which inhibit the synthesis of the vasoconstrictor peptide called endothelin, and block pro-coagulatory and pro-inflammatory changes.

By giving financial support to this work you will speed the progress to new treatments for a number of cardiovascular diseases where the endothelium is damaged and cannot be treated by medicines that are currently available. These include chronic heart failure, hypertension, atherosclerosis, pulmonary hypertension, and peripheral vascular disease. This work on endothelial cell function is also likely to yield medicines to control high blood pressure in pregnancy resulting from a common vascular complication called pre-eclampsia.

The MRC BRIGHT Study (British Genetics of Hypertension Study in 6 UK centres to identify genetic loci responsible for hypertension, Ј2.1M over 5 years) is being co-ordinated by Dr Mark Caulfield (Senior Lecturer) in this Department.

Role of nitric oxide in vascular, inflammatory and infectious diseases.

Novel methods for measuring nitric oxide synthesis in man using 15N stable isotope techniques have allowed us to study the importance of this molecule in hypertension and, in the future will enable us to measure alterations in nitric oxide synthesis in a wide range of vascular, infectious and inflammatory conditions.

Human vascular pharmacology.

We have extensive experience of measurement of changes in forearm blood flow with infusion of drugs in the brachial artery and in the dorsal hand vein technique. These methods have provided important information concerning the effects of drugs on human vasculature (Professor Nigel Benjamin and Dr Sharon O’Byrne).

Pharmacokinetic/dynamic modelling

The Department has considerable expertise in measurement of plasma drug concentrations and pharmacokinetic modelling, and provides analytical services for the NHS and many commercial and academic units (Dr Atholl Johnston).

Phase I Unit

This unit is newly built and will be fitted with centralised monitoring equipment for studies in healthy volunteers and ambulant patients (e.g. those with stable renal impairment). The unit has provision for screening services, overnight stay, recreation facilities and on-site blood and urine analysis.

Phase II/III studies

The Department has considerable experience of hypertension treatment trials and has developed a database of hypertensive patients and is setting up a GP framework with local GPs to facilitate the study of this disease, as well as heart failure and ischaemic heart disease.

We are collaborating extensively with Professor Nigel Benjamin (Clinical Pharmacology) on eNOS and nNOS knockouts as part of a collaboration with Dr Paul Huang in Harvard. We are investigating whether the urinary excretion of nitrate is derived from eNOS as part of the study of the role of NOS in cardiovascular disease. In a collaborative study with Professors Mone Zaidi and Malinski in Philadelphia, we are measuring directly with a microsensor the output of nitric oxide from bone cells.

The main aim of the group is to study the role of oxidative stress and free radicals (highly reactive, often toxic, molecules frequently produced as a by-product of respiration) in the function of the lining of blood vessels known as the endothelium. This lining can be viewed as the largest gland in the body and as such is responsible for maintaining blood vessels in good condition by producing a number of important mediators, such as nitric oxide. The impaired functioning of the endothelium is likely to be a key causative agent in the pathogenesis of atherosclerosis and diabetes.

We would therefore like to identify novel targets for therapeutic intervention. Oxidative stress appears to be able to interfere with normal free radical signalling and oxidative stress-response gene activation pathways that the vessel wall uses to protect itself from injury. We use an integrated approach, combining state of the art preclinical and human pharmacology together with biochemistry, molecular and cell biology. Our scientists are currently investigating the following: (i) how free radicals are able to allow cells to communicate with each other, and how they are able to modulate the expression of proteins involved in disease. (ii) the measurement and assessment of endothelial function, and reversal of dysfunction in models of atherosclerosis and diabetes. (iii) the determination of specific and sensitive markers of oxidative injury in human disease and their relationship with endothelial function.

The goal of our research is to design novel therapies which reduce the detrimental consequences of ischaemia-reperfusion injury of e.g. the heart and, hence, to improve outcome. Novel therapies, which are currently under investigation, are e.g. (i) small, cell-membrane permeable radical scavengers, (ii) inhibitors of the activation of certain transcription factors which play a role in local and systemic inflammation (e.g. nuclear factor kappa-B), (iii) inhibitors of poly (ADP-ribose) synthetase (PARS).

To gain a better insight into the above diseases, we use a great variety of scientific techniques from a variety of disciplines including pharmacology, biochemistry and molecular biology.

But while COX-1 produces prostaglandins that promote health and normal bodily functioning, COX-2 produces prostaglandins that drive inflammation and disease processes. So our researchers are trying to understand how cytokines enhance the production of endothelins and prostaglandins, whereabouts in the body these events happen, and how various drugs could be used to redress the balance away from inflammation and back towards normality. To achieve these ends we use a range of tools from cutting edge molecular biology and biochemical techniques to traditional pharmacological preparations.

The glucocorticoids act on cells in several ways, causing changes in the rates of synthesis of key proteins as well as changing other fundamental cellular processes. We have been particularly interested in the activity of one protein called lipocortin (annexin) 1. Glucocorticoids cause changes in the synthesis and sub-cellular distribution of this protein and in doing so enable it to suppress signal transduction systems within cells and to exert anti-inflammatory, anti-proliferative and other effects.

The human recombinant protein has potent anti-inflammatory actions in its own right and, more importantly, these may be mimicked by short peptide sequences taken from the N-terminus of the protein.

Our current work is devoted to elucidating which actions of glucocorticosteroids are mediated through lipocortin 1, how this protein produces its striking biological actions and how we can build upon this knowledge to develop superior steroid-like anti-inflammatory drugs, but without the burden of side effects seen with these hormones.

Our work is supported largely by grants obtained from medical charities such as the Wellcome Trust, the Arthritis and Rheumatism Campaign and the British Heart Foundation.

Angiogenesis. Angiogenesis, the growth of new blood vessels, is essential to the development of chronic inflammation and consequent tissue destruction. Inhibition of angiogenesis represents a novel strategy for treating chronic inflammation.

Apoptosis. Inflammatory cells can breakdown and release mediators that perpetuate the inflammatory response or they can undergo programmed cell death (apoptosis) during which cellular components are packaged into inert apoptotic bodies for removal by phagocytic cells. Induction of apoptosis in inflammatory cells may be a way of controlling excessive tissue damage during inflammation.

Inducible enzymes. Enzymes that give rise to inflammatory mediators, and are induced specifically at inflammatory sites, are attractive targets for antiinflammatory therapy as selective inhibitors should be relatively free of side effects.

PPARs. When activated, peroxisome proliferating activator receptors (PPARs) have the capability of inducing systems for metabolising, and therefore removing, lipid mediators of inflammation. Drugs designed to stimulate these receptors may represent a novel form of antiinflammatory therapy.

Stress proteins. These are induced when cells face stressful conditions and protect, for example, enzymes from becoming denatured and losing activity. Our data suggests that at least one of these proteins, heme oxygenase-1, may have a role in switching off the inflammatory response.

Tolerance induction: Many chronic inflammatory diseases are autoimmune in nature i.e. the mechanisms that normally lead to recognition and removal of infective agents turn against host tissues. The aim of this project is to switch off autoimmune processes by inducing a state of immunological tolerance to proteins endogenous to host tissues.

Many of these projects overlap and are encompassed by an overall philosophy of investigating how the body adapts to inflammatory stresses. In addition, many of these processes impact on other diseases for example tumour growth.