Division of Physiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21205
TWO NEURAL CONTROL MECHANISMS constrict
the airways, cholinergic and noncholinergic. The cholinergic fibers
arise in ganglia within the airway wall. These constrict the
airways by releasing acetylcholine onto muscarinic receptors.
Noncholinergic fibers arise in vagal ganglia at the base of the skull.
These nerves constrict the airways by releasing tachykinins onto
neurokinin receptors. The anatomically distinct origins of these two
systems has allowed their isolation for study.
It has long been known that the functions of the two systems are
changeable and that they respond to inflammatory stimuli that may be
relevant to airway disease. As the function and/or expression of
inhibitory M2 muscarinic receptors on cholinergic fibers is
decreased, release of acetylcholine in the airways is increased after
viral infections, inhalation of allergens, and exposure to ozone
(10). This predictably increases bronchoconstriction and
may also participate in the increased airway secretions characteristic of asthma and chronic obstructive pulmonary disease.
Likewise, the influence of tachykinergic nerves on bronchoconstriction
may also be increased by inflammation. Tachykinin-mediated bronchoconstriction can be potentiated by both increased release and
impaired degradation of these mediators. Such changes have been
described in the same models that increase acetylcholine release.
Changes in the expression of tachykinins in sensory neurons have also
been recognized, both in the airways and elsewhere. Neural plasticity
is likely to be of central importance in the pathogenesis of chronic
pain. Several forms of neural plasticity contribute to this process
(14). One of these, the induced expression of tachykinins
in sensory neurons of the A In recent years, it has become evident that expression of tachykinins
by sensory neurons supplying the lungs can also be changed. Allergen
challenge (13) and viral infection of the lungs
(2) both increase expression of tachykinins in vagal
ganglia. Functional and histological analysis reveals that in these
settings tachykinins are expressed not only by the usual C-fiber
neurons (with cell bodies in the jugular ganglion) but also by neurons
of the A Although a broad range of mediators may contribute to changes in
tachykinin gene expression, work in several systems suggests that
neurotrophins may be particularly important (3). This family of growth factors includes nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4. By signaling through a family of receptor tyrosine kinases, neurotrophins have the
capacity to mediate the sort of neural plasticity observed in the
somatosensory system and airway sensory neurons. In addition to
increasing tachykinin gene expression, neurotrophins increase expression of calcitonin gene-related peptide, the bradykinin B2 receptor, and the VR-1 vanilloid receptor, and may have
important effects on ion channels, all of which may affect neural
function. In the context of the airways, it may be significant that
nerve growth factor levels are increased in asthma and in allergic
rhinitis (1). Exogenous nerve growth factor causes airway
hyperresponsiveness in guinea pigs (4), an effect that is
blocked by blocking the neurokinin (NK)-1 receptor (the substance P
receptor), strongly suggesting the involvement of tachykinins.
In the study by Wu and colleagues, one of the current articles in focus
(Ref. 15, see p. L909 in this issue), the authors report the effects of interleukin-1 This new finding of inducible expression of tachykinins by ganglion
cells within the airway wall is consistent with the findings of de
Vries and colleagues (5), who showed that not only does exogenously applied nerve growth factor induce a tachykinin-mediated airway hyperresponsiveness but that it also does so in isolated tracheal tissues. As these tissues are physically separated from the
vagal sensory neuron cell bodies, induction of tachykinin expression in
the sensory nerves could not be responsible. However, the current
finding that intrinsic airway neurons can be induced to express
tachykinins may explain the ability of nerve growth factor to induce
tachykinin-mediated hyperresponsiveness in the absence of vagal sensory
ganglion cells.
How does interleukin-1 There are other possible mechanisms for the effects of interleukin-1 The provocative studies of Wu and colleagues (15) in this
issue suggest new mechanisms of airway hyperresponsiveness involving plasticity of the intrinsic parasympathetic neurons of the airways. Many important questions remain in understanding neural plasticity in
the airways. What are the molecular mechanisms of the changes in gene
expression? What other neurotransmitters are induced? What other
stimuli can change airway neural gene expression? Are changes in gene
expression in existing neurons or differentiation of neural stem cells
responsible for the observed changes? What other forms might neural
plasticity take in the airways (changes in receptors or structural
changes in addition to changes in transmitter expression)? What is the
role of neural plasticity in airway disease? and is it a potential
therapeutic target? Understanding plasticity of the intrinsic neurons
of the airways is one aspect of understanding airway neural plasticity
in general, which in turn will contribute greatly to our understanding
of the role of altered neural function in the pathogenesis of airway disease.
ARTICLE
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REFERENCES
type, which normally do not express
tachykinins, is likely to be important in the response to inflammation.
type, with cell bodies in the nodose ganglion. Thus
inflammatory stimuli not only alter the function of existing
tachykinergic neurons but also cause a phenotypic change in sensory
neurons that did not previously express these neurotransmitters. Thus a
process similar to that recognized in the somatosensory system is also
present in the airway sensory fibers. This provides an attractive
mechanism whereby bronchoconstriction, hypersecretion, neurogenic
inflammation, and increased vascular permeability (all functions of
tachykinins) might all be upregulated together.
on the responsiveness of ferret
airways. Treatment with interleukin-1
, either in vivo or in isolated
airway segments in vitro, increased contractile responses to
cholinergic stimulation. This could be blocked by depleting tachykinins
or by the NK-1 receptor antagonist CP-99994. Careful immunohistological
studies show expression of tachykinins by parasympathetic ganglia in
the airway wall after treatment with interleukin-1
. The conclusion
is that increased synthesis and release of tachykinins by neurons
intrinsic to the airways, which normally do not synthesize tachykinins,
mediate increased airway responsiveness.
induce this form of neural plasticity? An
attractive possibility might be the observation that interleukin-1
, acting synergistically with tumor necrosis factor-
, stimulates the
expression of nerve growth factor (8) in lung fibroblasts (11) and epithelial cells (6). Thus
interleukin-1
, widely produced in inflammatory conditions of the
airways, might be an important mediator of airway neural plasticity via
its ability to induce nerve growth factor. Similar mechanisms appear to
be important in the effects of interleukin-1
on somatic sensory nerves. Injection of complete Freund's adjuvant into rat footpads causes hyperalgesia that is accompanied by increased interleukin-1
, increased nerve growth factor, and increased substance P expression in
the dorsal root ganglia. Injection of interleukin-1
reproduced these
findings, whereas the hyperalgesia was prevented by neutralizing nerve
growth factor with antiserum (12).
in this study. The effects of lipopolysaccharide on tracheal calcitonin
gene-related peptide are mediated via the production of
interleukin-1
and depend on production of prostanoids (9), suggesting that effects of interleukin-1
on
cyclooxygenase-2 may be important. In visceral afferents in the cat,
interleukin-1
increases the activity of C fibers and sensitizes them
to histamine (7). Thus in addition to effects on
tachykinin expression, interleukin-1
may have other effects on
nerves that contribute to hyperresponsiveness.
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FOOTNOTES |
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Address for reprint requests and other correspondence: A. D. Fryer, Div. of Physiology, Johns Hopkins Univ. Bloomberg School of Public Health, Baltimore, MD 21205 (E-mail: afryer{at}jhsph.edu).
10.1152/ajplung.00128.2002
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