2990 Microsurgery.qxd - O'Brien Institute

Scientific Research
Bernard O’Brien Institute of Microsurgery
AIRWAYS INFLAMMATION AND ASTHMA RESEARCH LABORATORY
Members of the Laboratory:
D Fernandes, E Guida, T Harris, V Kalafatis,
K Knight, A Messina, A Pirdas-Zivcic,
C Ravenhall, A Stewart, P Vadiveloo and
R Vlahos.
... and Major Collaborators:
1
M Ayad, 2 J Bartolo, 3 J Bertram, 1 S Brenton,
1
J Burdon and 2 J Wilson.
1 Department of Respiratory Medicine,
St Vincent’s Hospital Melbourne.
2 Department of Respiratory Medicine,
Alfred Hospital.
3 Department of Anatomy, University
of Melbourne.
The major work of this laboratory is concerned
with airway wall thickening which occurs during
asthma. In this study we have been testing a
number of drugs which modulate the growth
rate (proliferation) of airways smooth muscle
cells during this inflammatory disease. These
drugs may not only be of some use in the
treatment of asthma, but also of other
inflammatory diseases. Many of the lessons
we have learned about airways smooth
muscle cells can apply equally to vascular
smooth muscle cells.
Another aspect of airways inflammation research
is an investigation into the pathogenesis of
emphysema and a particular variant of that
known as alpha-1-antitrypsin deficiency. This
research has continued over the past year in
collaboration with the Department of
Respiratory Medicine, St Vincent’s Hospital.
As the national reference and resource centre
for alpha-1-antitrypsin deficiency and lung
disease, referrals and registrations of patients
with alpha-1-antitrypsin deficiency and requests
for information and guidance continue. It is
thought that, in addition to alpha-1-antitrypsin,
secretory leucocyte protease inhibitor (SLPI)
might play a significant protective role in the
lungs of patients with this disease. A study
of these two proteins in alpha-1-antitrypsin
deficient patients may help to explain why some
patients develop symptoms of emphysema at a
much younger age than others.
Airway wall thickening in asthma
Asthma is characterized by an increase in
bronchial reactivity to a range of
bronchoconstrictor substances. The mechanisms
underlying this increased bronchial reactivity
are not known. Recently, it has been suggested
that structural changes involving airway wall
thickening make a major contribution to the
increase in bronchial reactivity. The airway
wall thickening is mainly the result of an
increase in the number of smooth muscle cells
and fibroblasts. There is a paucity of data on
the factors that regulate the growth of these
cells. In these studies we have set out to identify
and characterize the factors that control the
growth of airway cells by developing in vitro
cultures of human airway smooth muscle cells.
Clinical studies indicate a greater benefit to
asthmatic patients being treated with both
steroids and ß 2 -adrenoceptor stimulants.
We are examining whether these agents give
greater control of smooth muscle growth
when added together.
ß 2 -adrenoceptor stimulants (inhaled drugs
which relax muscle of the airway passages)
reduced cell division irrespective of the
stimulant (bFGF, EGF, thrombin). The
mechanism of the inhibitory effect involves
increased production of an enzyme regulator
called cyclic AMP. We have identified the point
in the replication cycle of the cell at which the
ß 2 -adrenoceptor stimulants act to inhibit the
production of proteins called cyclins and
promote the formation of cyclin-dependent
kinase inhibitors.
A further series of studies are underway
to search for novel inhibitors of division of
smooth muscle cells that bind to distinct
steroid receptors. One such molecule is a
breakdown product of the female sex hormone,
estradiol. The metabolite, 2-methoxyestradiol
reduces all division responses of a number of
different cell types and has potential as a new
treatment for asthma.
A model of airway wall thickening is being
developed in allergic rats. Inflammatory
changes in the airways mimic those of asthma
and are accompanied by increased airway
constriction. We are now using new microscopic
techniques to accurately determine changes in
the number of airway smooth muscle cells in
the inflamed airways.
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