| |
Free Radical Research
Group - Our People
Margreet Vissers
 My
research interests are centred on cellular responses to stress, and in
particular stress resulting from exposure to oxidants. Inflammatory cells,
particularly neutrophils, are an abundant source of highly reactive oxidants
that are able to react with many biological targets. On stimulation,
neutrophils generate a variety of oxidants through the action of the
haem enzyme myeloperoxidase that can oxidise either Cl– or
Br– to generate hypohalous acids or can produce hypothiocyanous
acid by reaction with the pseudohalide thiocyanate. E.g.
H2O2 + Cl– + H+  HOCl
+ H2O
HOCl is the reactive component of household bleach, and is famous for
its anti-microbial activity. It is, however, indiscriminate in its action,
can react with most cells and tissues, and is thought to be responsible
for many deleterious effects of chronic and acute inflammation. Both
HOCl and HOBr react readily with amino compounds to generate chloramines
or bromamines, which are themselves potent oxidants.
HOCl + RNH2 RNHCl
+ H2O
Together with hypothiocyanous acid, these oxidants form can intiate
a diverse range of effects on cells and tissues surrounding the stimulated
neutrophil.
My interest in these effects has given rise to the following research
projects, based on cell and tissue responses to myeloperoxidase-derived
oxidants and the ability of natural antioxidants to provide protection.
These processes have broad implications for understanding many disease
processes, including cancer cell biology, the functioning of the immune
system, atherosclerosis and inflammatory diseases.
- The toxicity of myeloperoxidase-derived oxidants to mammalian cells.
This
 project
aims to determine the relative reactivity of hypohalous acids and haloamines
with cell targets. (With Amy Scott-Thomas, Robyn Midwinter, Christine Winterbourn,
Alexander Peskin)
- The ability of myeloperoxidase-derived oxidants to affect cell
signaling responses, particularly in the endothelial cell, with implications
for heart disease. (With Robyn Midwinter, Christine Winterbourn)
- The effect of myeloperoxidase on the apoptosis of myeloid leukaemia
cells in response to chemotherapy agents, and the effect of antioxidants
on this process. (With Amy Scott-Thomas, Mary Morrison, Prachee Gokhalé)
- The contribution of myeloperoxidase to myelodysplasia and the
generation of secondary tumours after chemotherapy, using HL60 cells
as a model. (With Prachee Gokhalé)
- The ability of hypohalous acids, haloamines and HOSCN to modulate
transcription factor activity. Exposure to sub-lethal concentrations
of these oxidants can affect the activity of NFkB
and HIF-1. (With Robyn Midwinter, Christine Winterbourn, Gabi Dachs)
- The effect of neutrophil oxidants on neutrophil apoptosis and
the resolution of inflammation. Neutrophils are themselves the targets
of the oxidants produced during phagocytosis of bacteria. The oxidative
burst is able to modify process of neutrophil apoptosis and the clearance
of these cells by macrophages. (With Mark Hampton, Rachel Wilkie)
- The effect of ascorbate on neutrophil apoptosis and clearance.
Neutrophils contain high concentrations of ascorbate and, using ascorbate-deficient
neutrophils from a knockout mouse, we have found that apoptosis is
severely impaired when ascorbate is absent. This is reflected in a lack of
clearance by macrophages an impaired resolution of inflammation. (With
Rachel Wilkie and Mark Hampton)
- The effect of ascorbate on the hypoxic response and regulation
of hypoxia-inducible factor 1a in tumour
cells and normal human cells. HIF-1a is
an important regulator of tumour cells and controls much of a cell’s
basic metabolism. This transcription factor is controlled by hydroxylases
that require ascorbate for their optimal activity. (With Gabi Dachs, Shoichi Suzuki,
Amy Scott-Thomas, Sarah Gunningham and Margaret Currie)
- The ability of myeloperoxidase-derived oxidants to stabilise
HIF-1a and up-regulate hypoxia-inducible genes under normoxic conditions. This
project will also determine the effect of myeloperoxidase-derived oxidants
on the activity of the prolyl hydroxylases. (With Gabi Dachs, Amy Scott-Thomas)
|
|
