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Role of eosinophils and muscarinic receptors in paradoxical airway hyperreactivity associated with...
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Role of eosinophils and muscarinic receptors in paradoxical airway hyperreactivity associated with antigen challenge
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Rights
http://www.ohsu.edu/xd/education/library/services/theses-dissertations/rights-statement.cfm
Title
Role
of
eosinophils
and
muscarinic
receptors
in
paradoxical
airway
hyperreactivity
associated
with
antigen
challenge
Creator.PersonalName
Verbout
,
Norah
G
.
Thesis.Degree
M.S.
Thesis.DateDegreeAwarded
June
2008
Institution
Oregon Health & Science University
School
School of Medicine
Department
Dept. of Physiology and Pharmacology
Thesis.Advisor/Mentor
Fryer, Allison D.
Thesis.Committee
Farrell, David H.
Lein, Pamela J.
Jacoby, David B.
McCarty, Owen J. T.
Brooks, Virginia L.
Subject.MeSH
Eosinophils
Bronchial Hyperreactivity -- prevention & control
Parasympathetic Nervous System
Receptors, Muscarinic
Call Number
Q171 V479 2008
Description.Abstract
The
novel
results
presented
in this
thesis
demonstrate
that
human
and
guinea
pig
eosinophils
express
muscarinic
receptors
,
which
inhibit
eosinophil
activation
in
vitro
(Chapter
V)
.
Furthermore
,
I
have
demonstrated
that
muscarinic
blockade
during
antigen
challenge
significantly
increases
eosinophil
activation
and
subsequent
vagally
mediated
hyperreactivity
in
guinea
pigs
(Chapter
III
and
IV)
via
a
mechanism
involving
eosinophils
(Chapter
III)
and
nerve
growth
factor
(NGF)
(Chapter
IV)
. These
data
suggest
that the
inhibitory
muscarinic
receptors
I
have
identified
in
vitro
are
functional
in
vivo
.
Previous
work
has
demonstrated
that
antigen-induced
airway
hyperreactivity
in
guinea
pigs
is
mediated
by
eosinophil
major
basic
protein
(MBP)
and
neuronal
M2
receptor
dysfunction
. In this
thesis
,
I
have
identified
an
alternative
mechanism
by
which
eosinophils
mediate
hyperreactivity
in
antigen
challenged
guinea
pigs
that
is
not
mediated
by
loss
of
neuronal
M2
function
. In this
newly
identified
pathway
,
both
eosinophils
and
NGF
play
a
critical
role
since
anti-IL-5
and
anti-NGF
antibodies
prevent
antigen-induced
airway
hyperreactivity
.
NGF
may
be
acting
upstream
of
eosinophil
activation
,
since
anti-NGF
antibodies
prevent
increased
eosinophil
activation
.
One
possible
explanation
is
that
NGF
induces
eosinophils
to
release
a
mediator
that
alters
nerve
function
, and
release
of this
factor
is
inhibited
by
acetylcholine
.
Eosinophils
produce
a
number
of
mediators
that
may
alter
nerve
function
,
including
NGF
.
One
key
effect
of
neurotrophins
is
that they
can
alter
neuronal
neurotransmitter
content
, a
phenomenon
called
neural
plasticity
.
Thus
,
eosinophils
mediate
airway
hyperreactivity
via
multiple
mechanisms
,
one
involving
MBP
blockade
of
neuronal
M2
receptors
and the
other
involving
NGF
and
possibly
neural
plasticity
. The
implications
of these
findings
are
clinically
relevant
,
considering
the
poor
performance
of
anticholinergics
in
management
of
chronic
asthma
.
Anticholinergic
drugs
are
effective
bronchodilators
when
given
during
an
asthma
exacerbation
.
However
, these
drugs
are not as
effective
as
predicted
from
animal
studies
and are not
recommended
for
chronic
treatment
of
asthma
. The
findings
in this
thesis
provide
an
explanation
for this
paradox
, and
suggest
that
timing
of
anticholinergic
administration
is
very
important
.
Anticholinergics
after
antigen
challenge
are
effective
bronchodilators
, but if
administered
prophylactically
, as would be the
case
if
given
chronically
,
may
make
hyperreactivity
worse
. In
summary
,
I
have
discovered
a
novel
interaction
between
the
parasympathetic
nerves
and
eosinophils
.
While
it
has been
known
that
eosinophils
can
affect
parasympathetic
nerve
function
,
I
have
identified
a
potential
mechanism
by
which
nerves
may
inhibit
eosinophil
function
. This
potential
mechanism
may
be a
negative
feedback
loop
in
which
acetylcholine
release
from
nerves
dampens
the
negative
effects
of
eosinophils
on
neuronal
M2
receptor
function
in
allergic
asthma
. These
observations
are
clinically
important
because
they
may
explain
why
anticholinergics
treatments
that should be
effective
in
managing
asthma
are not,
despite
the
current
body
of
knowledge
in this
field
and
may
provide
a
rationale
for
new
approaches
to
pharmacological
control
of the
lungs
. These
findings
are
significant
because
they
contribute
to
our
understanding
of the
complex
interactions
between
the
immune
and
nervous
systems
and
because
they will
influence
future
therapeutics
for
treating
diseases
characterized
by
increased
eosinophil
activation
,
such
as
asthma
.
Language
eng
Type
Text
Format.Use
Needs Adobe Acrobat to view
Format.FileSize
3353828 Bytes
OCLC number
244791416
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