Department of Neurobiology and Anatomy, West Virginia University, Morgantown, West Virginia 26506
AIRWAY SMOOTH MUSCLE TONE, mucus gland
secretion, and blood flow are controlled predominantly by
neurotransmitters released from sensory, sympathetic, and
parasympathetic neurons with axons that supply the airways
(1). The release of neurotransmitters from nerve endings
depends on action potentials arriving at the nerve terminals, allowing
the influx of calcium through voltage-gated channels (14).
Thus the electrical properties of neurons that influence depolarization
and subsequent action potential generation are important in determining
the release of neurotransmitters from nerve terminals and,
consequently, airway reactivity, mucous secretion, and vascular
dynamics. Neurotransmitters are released during basal conditions to
maintain normal airway function. The parasympathetic neurons of airway
ganglia receive presynaptic input originating from preganglionic
neurons located in the vagal nuclei of the brain stem (9).
Previous studies have shown that <50% of preganglionic impulses
reaching the airway ganglia result in the generation of an action
potential in the postganglionic neurons (13). Thus
neurotransmission through airway ganglia is an important mechanism for
controlling neural activity and airway function. Transmission of neural
activity through airway ganglia is partially controlled by the
intrinsic properties of the airway neurons, notably the excitability of
the postganglionic airway neuron. During airway irritation and injury,
such as antigen challenge or irritant exposure, newly generated
inflammatory mediators are released and may modulate neural activity at
synapses in airway ganglia as well as neurotransmitter expression,
resulting in altered airway responses having beneficial or detrimental
effects on airway function.
Neuronal plasticity is the term used to describe changes in functional
and phenotypic properties of neurons. Neuronal plasticity occurring in
the airways is a relatively recent discovery but is likely to be an
important component of adaptation and defense by the airways and may
contribute to airway diseases and conditions such as asthma,
bronchitis, chronic obstructive pulmonary disease, and chronic cough.
Several mechanisms of plasticity have been identified in airway
neurons. In sensory nerves, tachykinin levels are increased by
controlling mRNA levels and translation of message to neuropeptide in
the nerve cell body. This process provides greater amounts of
neuropeptide destined for delivery to and release from the nerve
terminal at the airway target and possibly in the central nervous
system. The upregulation of mRNA levels is initiated through
neurotrophic molecules like nerve growth factor produced by
inflammatory or airway mucosal cells and then transported in axons to
the nerve cell body to initiate signaling cascades. There are now
several studies describing elevated neurotransmitter levels in sensory
neurons of the airways (5, 7, 8). Another example of
plasticity in sensory neurons relates to changes in the excitability.
Kwong and Lee (10) have recently demonstrated that
prostaglandins alter the sensitivity of pulmonary C fibers to mediators
like bradykinin and histamine, suggesting that inflammatory mediators
may influence electrical activity. Plasticity in postganglionic, parasympathetic-like neurons of airway ganglia has not been studied as
extensively as sensory airway neurons, but a few studies suggest that
plasticity in these neurons occurs. IL-1 treatment induced substance P
(SP) expression in ferret tracheal neurons that normally do not
express this neuropeptide (16). These findings support the
concept that inflammatory mediators in the airways may alter nerve
neurotransmitter expression of intrinsic airway neurons. Another
example of plasticity in airway parasympathetic neurons is
altered neuronal excitability. Neurophysiological studies have demonstrated that antigen challenge increases the excitability of
airway neurons and the efficacy of synaptic transmission in airway
ganglia (15). The increased firing rate by these neurons enhances neurotransmitter release, predominantly cholinergic, which
presumably increases smooth muscle tone, mucous secretion, and general
vagal tone in the airways.
The article in focus by Kajekar and coworkers (Ref. 8a,
see p. L581 in this issue) confirms and extends previous
reports of the excitatory influence of antigen on airway neurons and
identifies cyclooxygenase (COX) products as mediators of altered
neuronal excitability. Their study shows that airways isolated from
guinea pigs passively sensitized and challenged with ovalbumin (OVA) produced large quantities of COX-derived prostanoids, especially PGD2 and thromboxanes. More importantly, they showed
that indomethacin or piroxycam, two different COX inhibitors, inhibited
accommodation, the ability of some airway neurons to filter
preganglionic signals. These findings were confirmed by demonstrating
that treatment of airway neurons with PGD2 caused a
substantial attenuation of accommodation, and both PGD2 and
PGE2 decreased the afterhyperpolarization. The attenuation
of accommodation and the decrease in afterhyperpolarization duration
represent electrophysiological changes in active membrane properties that favor increased action potential propagation in the
airway neurons. Thus the released prostaglandins promote less accommodation by neurons in airway ganglia, which may lead to enhanced
airway vagal tone. Interestingly, the OVA-induced,
COX-inhibitable increase in the amplitude of fast excitatory
postsynaptic potential (fEPSP) was enhanced by a different prostanoid,
PGF2 The significance of these studies is that filtering of synaptic signals
at the level of postganglionic airway neurons occurs not only during
basal conditions but that it is regulated, in this case, attenuated,
during immunological challenges through the actions of specific
inflammation mediators. One of the important unanswered questions in
understanding neural control in airway ganglia relates to how these
changes in membrane properties are produced. The active
electrophysiological properties of nerve cell membranes that control
accommodation, afterhyperpolarization, and fEPSP, are determined
predominantly by voltage or ion-coupled sodium and potassium
channels. The findings of the current study suggest that ion
channels are regulated by mediators generated during inflammation, but
identifying the channels involved and determining the influence of
inflammatory mediators will require further studies. Another aspect of
airway neural control that is not well understood relates to the
complex organization of the airway plexus. Although it is tempting to
draw a direct correlation between reduced filtering and increased
cholinergic tone in airway smooth muscle, the precise phenotypes
affected by altered neuronal excitability are not established. For
instance, airway neurons are heterogeneous with respect to
neurotransmitter phenotype, including the expression of ACh, vasoactive
intestinal peptide (VIP), SP, and nitric oxide (NO) (2).
Although the neurochemical phenotype of phasic airway neurons (the ones
that demonstrate accommodation) in guinea pig airways is cholinergic,
the possibility that phasic neurons may also include other
neurotransmitter phenotypes warrants additional studies, especially
where other phenotypes have been identified, such as in ferrets
(2) and in human airways (3). In
addition to the cholinergic system, the inhibitory nonadrenergic,
noncholinergic (iNANC) system is also represented in neurons of
airway ganglia. It is reasonably well established that mediators
released from iNANC neurons control smooth muscle relaxation. NO and
VIP, both potent relaxant mediators released from airway nerve
terminals, are putative transmitters of the iNANC system (4,
6). During airway inflammation, enhanced release of VIP or NO
would presumably promote relaxation and might serve to balance
increased vagal cholinergic tone. On the other hand, failure of iNANC
neurons to respond to inflammatory mediators could mean that only
cholinergic neurons are activated, leading to a selective increase in
cholinergic influence on airway smooth muscle. Thus it will be
important to determine whether all airway neurons are equally
responsive to inflammatory mediators or whether subtypes of
parasympathetic airway neurons respond differently or are without
response. Another consideration that might influence the effect
of altered neuronal excitability is connectivity. Complex communications between individual airway neurons are well documented (12, 17), and different circuits may be involved in
generating separate local airway reflexes (11). Thus
altered neuronal excitability may affect overall activation of the
local circuits within the pulmonary plexus.
A role of the airway parasympathetic nervous system in airway
dysfunction is slowly emerging. A finding from the current article in
focus by Kajekar and coworkers (8a) highlights the importance of airway
inflammation and inflammatory mediators in regulating neural activity
in the airways and illustrates the range of adaptive mechanisms that
may contribute to airway function in health and disease.
ARTICLE
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REFERENCES
, although this prostanoid was not elevated after
OVA exposure. Other prostaglandins tested were without effect on
accommodation, afterhyperpolarization duration, or fEPSP.
Prostaglandins have been associated with enhancing sensitivity
and excitability of pulmonary sensory C fibers (10).
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FOOTNOTES |
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Address for reprint requests and other correspondence: R. D. Dey, Dept. of Neurobiology and Anatomy, West Virginia Univ., Morgantown, WV 26506 (E-mail: rdey{at}hsc.wvu.edu).
10.1152/ajplung.00015.2003
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