doi:10.1594/eaacinet2007/EO/4-300307
http://www.eaaci.net
HAVE WE FORGOTTEN ABOUT THE ROLE OF
NERVES IN ASTHMA?
Ulrike Raap MD
Dept. of Dermatology and Allergology, Hannover Medical University,
Germany
Correspondence: mail@ulrike-raap.de
doi:10.1594/eaacinet2007/EO/4-300307
http://www.eaaci.net
ABSTRACT
Bronchial asthma is well defined by the clinical characteristics including chronic
airway inflammation, recurrent reversible airway obstruction and development of
airway hyperresponsiveness as pathogenic components. Several studies have
shown that genetic, environmental, immunologic, and pharmacologic factors
contribute to the development of this complex disease. However, there is one
important component which had long been forgotten but now steps out of the
shadow into the spotlight of bronchial asthma: the neuronal network. Our
approach to understanding bronchial asthma needs to be broadened to include
alterations in the function of this neuronal network with afferent nerves that
supply airways and modulate neuroimmune interactions. Changes in the activity
of these nerves offer a possible mechanism by which asthmatic subjects are
uniquely responsive to a wide range of physiological and chemical stimuli- which
may offer novel therapeutic strategies.
Key words: Bronchial asthma, eosinophils, neuronal network, neuropeptides,
neurotrophins
doi:10.1594/eaacinet2007/EO/4-300307
http://www.eaaci.net
INTRODUCTION
Inflammatory cells such as T-helper 2 cells, eosinophils, and cytokines play a
critical role in orchestrating and perpetuating inflammation in bronchial asthma. It
is now widely accepted that airway inflammation is one of the key factors
underlying the pathogenesis of asthma (1). Even though many promising single
agents antagonising specific cytokines or key effector cells in asthma have been
investigated for the treatment of asthma, no single drug is able to cure asthma.
Therefore, it is tempting to argue that besides cytokines and key effector cells
one important compartment deserves more attention within the airways: the
neuronal network. Airway nerves not only present the backbone for neuronal
interactions but most importantly they represent the hotline for neuroimmune
interactions between key target effector cells and nerves in asthma.
The
airways
are
supplied
with
a
network
of
nerves
that
can
cause
bronchoconstriction or relaxation. Constriction of airway smooth muscle is
controlled by sensory and motor neurons innervating the airways and the lung. In
addition to effects on airway smooth muscle tone, the nerves regulate many
aspects of airway function including mucus secretion, bronchial microcirculation,
vascular permeability and most importantly have a bidirectional interaction with
immune cells. The autonomic nerves that regulate many aspects of airway
function can be functionally subdivided into cholinergic, adrenergic and nonadrenergic non-cholinergic (NANC) pathways.
PARASYMPATHETIC NERVE SYSTEM
The parasympathetic nerve system is the dominant neuronal pathway in the
control of airway smooth muscle tone. Stimulation of cholinergic nerves causes
bronchoconstriction and mucus secretion. Three types of muscarinic receptors
(M1-3) have been investigated thus far. Dysfunction of the M2 receptor has been
proposed as a mechanism leading to excessive bronchoconstriction and mucus
secretion in asthma (2). Indeed, some asthmatics represent a dysfunctional M2
receptor (3). Although some studies have concluded that the cholinergic nerves
are not important in allergic asthma (4), others have shown that anticholinergics
given intravenously are effective bronchodilators demonstrating vagal nerve
blockade (5). In this regard, viral infection has been shown to be clearly
doi:10.1594/eaacinet2007/EO/4-300307
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associated with airway hyperresponsiveness that is vagally mediated (6). M2
receptor dysfunction and vagally mediated hyperresponsiveness are absolutely
dependent on an inflammatory response. The eosinophil granulocyte has been
questioned to contribute to airway hyperreactivity. However, eosinophils have
been found in high concentrations in the vicinity of airway nerves (7) and were
found to be responsible for the loss of M2 receptor function by the release of
major
basic
protein
(MBP)
leading
to
excessive
bronchoconstriction
(8),
underlining their importance for neuroimmune interactions in asthma.
THE NON-ADRENERGIC NON-CHOLINERGIC NERVE SYSTEM
The only bronchodilator pathways in human airways are presented by the
inhibitory non-adrenergic non-cholinergic (i-NANC) nerves containing vasoactive
intestinal peptide (VIP) and nitric oxide (NO). Although a dysfunction of i-NANC
nerves has been proposed in asthma, thus far, no difference in the i-NANC
responses have been found between asthmatics and healthy subjects (4).
This is in contrast to the excitatory-NANC (e-NANC) nerves containing tachykinins
including
substance p
(SP)
and
neurokinin-A (NKA)
which
contribute
to
bronchoconstriction, mucus secretion, vascular hyperpermeability, cough and
vasodilatation (9,10). In guinea pigs SP induces airway hyperreactivity (11).
Whereas in a mice model for allergic airway inflammation it has been clearly
shown that NK1 receptor- to which SP binds with high affinity- knock-out animals
promote feature of remodelling such as goblet cell hyperplasia (12). In addition,
tachykinins stimulate the proliferation of fibroblasts, epithelial, endothelial and
airway smooth muscle cells.
Further,
SP
stimulates the chemotaxis of
lymphocytes, monocytes, neutrophils, eosinophils and is able to induce the
release of eosinophilic cationic protein (ECP) and reactive oxygen species in
human eosinophils (13,14). Most strikingly, eosinophils are a source of SP itself,
underlining their participation in neuronal reflex circuits being able to stimulate
nerves (15). Interestingly, increased baseline levels of SP have been found in
upper and lower airways of asthmatics compared with healthy subjects which
further increased after allergen challenge (16), suggesting that SP may also
account for nasobronchial interaction mechanisms, which represents an important
feature for bronchial asthma (17).
doi:10.1594/eaacinet2007/EO/4-300307
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NEUROMEDIATORS IN BRONCHIAL ASTHMA
In addition to tachykinins, neurotrophins originally defined as neuronal growth
factors, have been identified as important modulators for the functional plasticity
of sensory and motor neurons and inflammatory signals regarding the bronchial
nervous system. Animal data demonstrate that a number of pathomechanisms
controlling allergic diseases are directly related to neurotrophin function, including
the development of airway hyperresponsiveness (18,19). Increased levels of
neurotrophins such as nerve growth factor (NGF) but also brain-derived
neurotrophic factor (BDNF) have been found in the peripheral blood, bronchoalveolar lavage and nasal lavage fluid (NGF) of patients with allergic airway
inflammation
(20,21).
However,
it
still
remains
unclear
whether
or
not
neurotrophins also contribute to nasobronchial interactions which represent an
important feature for neuronal reflex circuits in bronchial asthma. Interestingly,
neurotrophins not only directly modulate the functional activity of nerves- termed
neuronal plasticity, but also have a direct functional effect on peripheral immune
cells- counting for immunological plasticity. Again, this has been best investigated
for the eosinophil granulocyte, which is not only a source of NGF and BDNF
(23,24) but also target of BDNF and NGF as shown in functional studies of human
eosinophils in vitro (23,25).
CONCLUSION
Patients
with
asthma
feature
both
airway
inflammation
and
airway
hyperresponsiveness to non-specific stimuli which is partly neuronally controlled.
Neurotrophins have been shown to be exceptional in supporting survival of
neurons in the central and peripheral nervous system. In addition, tachykinins
and neurotrophins modulate the functional activity of key effector cells of the
inflammatory
infiltrate,
supporting
the
immunological
plasticity.
Further,
inflammatory key effector cells such as eosinophil granulocytes, which are in
close
vicinity
of
airway
nerves
produce
tachykinins
and
neurotrophins
orchestrating neuronal feedback mechanisms. This bidirectional interaction of
neuromediators between nerves and key effector cells bridges the gap between
neuronal and immunological plasticity (Fig. 1). Therefore, bronchial asthma
presents a complex disease in which nerves and their mediators are of major
doi:10.1594/eaacinet2007/EO/4-300307
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importance closing the loop for neuroimmune interactions, presenting promising
therapeutic targets for the future.
Figure 1
Concept for the role of neuromediators including tachykinins and neurotrophins bridging the gap
between neuronal and immunological plasticity in bronchial asthma. NANC= Non-adrenergic noncholingeric, SP= Substance P; NKA= Neurokinin-A; BDNF= Brain-derived neurotrophic factor, NGF=
Nerve growth factor, NT-3= Neurotrophin-3.
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