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Asthma and Allergy Group
Asthma and the Immune Response
Asthma is a chronic inflammatory airways disease caused by inappropriate
immune responses to environmental allergens. This persistent inflammation
ultimately triggers structural changes to the airways that underlie the
development of breathlessness and wheezing. The reason why some individuals
develop asthma is often related to genetic and gender predispositions
that allow an allergen-induced immune response to occur more easily. Asthma
susceptibility is also compounded by exposure to irritants such as cigarette
smoke, pollutants and viruses.
Our research is focused on two main themes:
How does exposure to environmental irritants enhance the ability of
allergens to induce asthma?
Glutathione transferase (GST)P1, which is an enzyme found in bronchial
epithelial cells, is known to detoxify irritating chemicals in pollutants
and cigarette smoke. GSTP1 is also known to regulate transcription factors
that are associated with stress responses of cells. Analysis of diverse
population groups suggests a catalytically different form of this enzyme
is more often found in asthmatics. Our studies are the first to directly
demonstrate that GSTP1 suppresses allergic airways disease and that reduced
function of this enzyme is related to a more severe allergic phenotype.
To understand how variants of GSTP1 are linked to asthma susceptibility,
we are studying allergic responses in mice that are genetically modified
to express “humanised” variants of GSTP1 in the lung. We are
also using immune cell based systems to characterise transcription factors
that are regulated by GSTP1.
Why are women more susceptible to asthma?
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Asthma is more common in boys. However coincident with increased
levels of circulating oestrogen, asthma becomes more common
in women, particularly during the early reproductive years and
pregnancy. We have recently described a novel mechanistic pathway
by which a cell membrane-derived lipid mediator, 12-hydroxytetraenoic
acid (HETE), can control asthma-like symptoms. However, the
ability of this bioactive lipid mediator to control allergic
disease is blocked in female mice. As reproductively mature
women are more susceptible to asthma than men, we are studying
whether oestrogen regulates the ability of 12-HETE to inhibit
allergic disease and whether this pathway is related to the
greater incidence of asthma in women. This study will provide
important new information on potential therapeutics for asthma
and will also help in understanding why women are more susceptible
to asthma.
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Collectively, these studies will provide important new information on
the basic mechanisms underlying susceptibility to asthma and new avenues
for therapeutic intervention in asthma.
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