1 Department of Neurobiology and Anatomy, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown 26506; and 2 Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505
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ABSTRACT |
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Interleukin (IL)-1 causes airway
inflammation, enhances airway smooth muscle responsiveness, and alters
neurotransmitter expression in sensory, sympathetic, and myenteric
neurons. This study examines the role of intrinsic airway neurons in
airway hyperresponsiveness (AHR) induced by IL-1
. Ferrets were
instilled intratracheally with IL-1
(0.3 µg/0.3 ml) or saline (0.3 ml) once daily for 5 days. Tracheal smooth muscle contractility in vitro and substance P (SP) expression in tracheal neurons were assessed. Tracheal smooth muscle reactivity to acetylcholine (ACh) and
methacholine (MCh) and smooth muscle contractions to electric field
stimulation (EFS) both increased after IL-1
. The IL-1
-induced AHR
was maintained in tracheal segments cultured for 24 h, a procedure that depletes SP from sensory nerves while maintaining viability of
intrinsic airway neurons. Pretreatment with CP-99994, an antagonist of
neurokinin 1 receptor, attenuated the IL-1
-induced hyperreactivity to ACh and MCh and to EFS in cultured tracheal segments. SP-containing neurons in longitudinal trunk, SP innervation of superficial muscular plexus neurons, and SP nerve fiber density in tracheal smooth muscle
all increased after treatment with IL-1
. These results show that
IL-1
-enhanced cholinergic airway smooth muscle contractile responses
are mediated by the actions of SP released from intrinsic airway neurons.
airway inflammation; airway smooth muscle contraction; muscarinic agonists; neurokinin receptor; airway innervation
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INTRODUCTION |
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INTERLEUKIN-1
(IL-1), an inflammatory cytokine, has been reported to increase
substance P (SP) release and gene expression in neurons of sensory and
sympathetic ganglia (27, 31, 45). The IL-1 level in
bronchoalveolar lavage fluid is increased in asthmatic patients
(6, 7), and IL-1
induces airway hyperresponsiveness (AHR) in rats (50) and isolated human bronchi (4,
23). However, the mechanism of IL-1
-induced AHR is still not
clear. Recent studies show that IL-1
can stimulate sensory afferent fibers (20, 27) and elicit the local release of SP. In
enteric neurons of the gastrointestinal tract, IL-1
causes SP
release in a time- and concentration-dependent manner
(26). Therefore, we hypothesized that the actions of
IL-1
in the airway may be mediated by altering SP expression of
intrinsic airway neurons.
Neurons that comprise intrinsic airway ganglia are heterogeneous with regard to both function and neurotransmitter expression. Some intrinsic neurons represent classical postganglionic, cholinergic parasympathetic pathways, receiving input from vagal preganglionic neurons (46) and regulating smooth muscle, secretory glands, and blood vessels in the airway walls by releasing acetylcholine (ACh) (42). However, other neurons in the plexus contribute to inhibitory nonadrenergic noncholinergic innervation present in the airways (11, 56). Airway ganglia act as signal filters limiting electrical transmission of signals between presynaptic and postsynaptic neurons (8, 38, 39) and may be involved in the integration and control of airway function (2, 3, 10, 14, 17). Nerve cell bodies are located in large ganglia of the longitudinal trunk and in smaller ganglia of the superficial muscular plexus. Essentially all nerve cell bodies in the longitudinal trunk ganglia are cholinergic and do not normally contain detectable levels of nitric oxide (NO) synthase, SP, or vasoactive intestinal peptide (VIP) (14). Cell bodies in the superficial muscular plexus contain predominantly VIP and NO with a small population containing SP. Recently, the enzyme heme oxygenase-2, an enzyme that synthesizes carbon dioxide from heme, was identified in neurons of human and guinea pig airway ganglia (9). Neurons in both longitudinal trunk and superficial muscular plexus ganglia project to structures in the airway wall, including airway smooth muscle, and communications exist between airway neurons as well (57). Airway neurons may be capable of modulating neural activity within the airways and could provide local neural reflexes through their connections with the epithelium (18).
SP is a member of the tachykinin family and has potent effects on
airway smooth muscle tone, vascular permeability to protein, and mucus
secretion (5, 33, 35). Immunocytochemical studies have
demonstrated that SP localized in the peripheral endings of nerves
innervating the lung and airways originates in nerve cell bodies
located both in sensory (15, 25) and intrinsic airway
(13, 14, 16, 18, 33) ganglia. Furthermore, peptidergic innervation of airway smooth muscle, glands, and blood vessels originates from neurons with cell bodies located in intrinsic airway
ganglia (13, 16). Inflammation and smooth muscle
hyperresponsiveness are closely associated with increased SP release in
the airway (34, 54). Although there is evidence suggesting
that IL-1 releases SP from sensory nerves, IL-1
may also induce
SP release from intrinsic airway neurons and result in airway
inflammation or AHR. Therefore, the purpose of this study was to
evaluate the effect of IL-1
on airway responsiveness and to
determine whether these effects are mediated through enhanced synthesis
and release of SP from the intrinsic neurons of airway ganglia.
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METHODS |
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Female nonalbino ferrets (Marshall Farms, North Rose, NY) weighing 250-500 g were housed two to four per cage with access to food and water ad libitum in an American Association for Accreditation of Laboratory Animal Care-accredited facility. All procedures were performed in accordance with the recommendations of the Guide for the Care and Use of Laboratory Animals, published by the National Institutes of Health, and were also approved by the West Virginia University Animal Care and Use Committee.
In vivo IL-1 treatment.
Ferrets were anesthetized with ketamine (25 mg/kg) and xylazine (2 mg/kg) in a single intraperitoneal injection. An 18-gauge steel tube 15 cm in length, marked to indicate when the tip reached the carina, was
connected to a 1-ml tuberculin syringe filled with IL-1
(1 µg/ml)
or saline and inserted through the oral cavity and pharynx into the
trachea. Once per day for 5 days 0.3 ml of IL-1
or saline was
instilled into the trachea and deposited at four equal intervals along
the trachea from immediately superior to the carina to immediately
inferior to the larynx. One hour after the last IL-1 or saline
treatment, ferrets were killed and tracheas were removed and cut into
several segments to measure smooth muscle contractions and for immunocytochemistry.
In vitro tracheal segments cultured for 24 h.
Organotypic cultures of tracheas from normal ferrets were used
following a modification of our previously described technique (18). Under sterile conditions, tracheas were removed and
washed with cold culture medium (described below). The tissue was then placed in a petri dish with culture medium and cut into 10-mm-long segments beginning at the carina. After a second wash, the segments were placed directly on the bottom of petri dishes containing fresh
culture medium with IL-1 (final concentration 10 ng/ml) or saline.
In some experiments, CP-99994 (3 × 10
6 M) was added
to the culture media 30 min before IL-1
and maintained throughout
the experiment to determine the role of SP in intrinsic airway neurons.
The antagonist concentration was based on previous studies (28,
51, 55). The petri dishes were then placed in a controlled
atmosphere culture chamber and gassed with a mixture of 95%
O2 and 5% CO2. The chamber was placed on a
rocker and incubated at 37°C for 24 h. After culture, smooth
muscle responses were measured in the segments. The culture
medium consisted of CMRL 1066 containing 0.1 µg/ml
hydrocortisone hemisuccinate, 1 µg/ml recrystallized bovine insulin,
60 µg/ml penicillin G (100 units/ml), 10 µg/ml amphotericin B,
100 µg/ml streptomycin, and 5% heat-inactivated fetal calf serum.
Verification of SP depletion during 24-h culture.
Previous studies using fluorescence microscopy suggest that sensory
fibers are depleted from the ferret trachea during culture periods of 3 days or longer (18). However, functional evidence supporting selective SP depletion in sensory nerves during culture is
not available. Therefore, to verify for this study that sensory nerves
were nonfunctional after 24 h in culture, tracheal smooth muscle
contractility to electric field stimulation (EFS) was determined before
and 20 min after application of capsaicin (107 M) in
three separate experimental groups: 1) fresh, noncultured tracheal segments, 2) segments cultured for 24 h in
capsaicin (10
5 M), and 3) segments cultured
for 24 h in vehicle. The capsaicin doses were based on previous
reports that 10
7 M capsaicin enhances smooth muscle
contractility by releasing SP (47, 48) and that
10
5 M capsaicin is effective in depleting SP from sensory
nerve terminals (21, 36, 53). Prior studies have shown
that capsaicin depletes SP selectively from sensory nerves without
affecting SP content in nonsensory nerves (29). The
hypothesis that the 24-h culture functionally depletes SP from sensory
nerves would be supported if smooth muscle responses to EFS in both
cultured groups were not different before and after capsaicin
application. The capsaicin response in the fresh trachea is included
only to demonstrate the effectiveness of 10
7 M capsaicin
on smooth muscle contractility.
Measurement of tracheal smooth muscle contraction in vitro.
Tracheal smooth muscle reactivity was evaluated by measuring
contractile responses to ACh, methacholine (MCh), or EFS. ACh and MCh
responses measure smooth muscle responses to the applied agonist,
whereas EFS evaluates cholinergic responses resulting from the release
of ACh from airway nerves. Tracheal segments from ferrets 1 h
after the last treatment with IL-1 or saline, from the 24-h cultures
and capsaicin study were cut into 3-mm-wide strips, mounted in holders,
and maintained in gassed (95% O2-5% CO2)
modified Krebs-Henseleit (MKH) solution at 37°C with a composition (in mM) of 113 NaCl, 4.8 KCl, 2.5 CaCl, 1.2 MgSO4, 24 NaHCO3, 1.2 KH2PO4, and 5.7 glucose, pH 7.4. The strips were tied at each end with 4-0 silk and
positioned between the rings of platinum electrodes attached to tissue
holders. Each holder was anchored in a 10-ml water-jacketed organ bath,
and the top string was attached to a force-displacement transducer
connected to a recorder (Gould Instruments, Valley View, OH). Strips
were equilibrated for 60 min at a resting tension of 1.0 g,
determined in preliminary studies to be optimal for contraction, during
which time the MKH solution in the baths was changed every 15 min.
After equilibration, we constructed cumulative concentration-response
curves for ACh and MCh for separate strips by adding a series of
concentrations of ACh or MCh to the bath in half-log increment
concentrations ranging from 109 to 10
3 M. The next concentration was not added until the previous response reached a plateau. After concentration response curves were completed, EFS-induced responses were obtained with a Grass S48 stimulator (Grass
Instruments, West Warwick, RI). We constructed frequency-response curves by increasing the frequency from 0.3 to 30 Hz using a submaximum voltage of 120 V, 0.2-ms pulse duration, and 10-s train duration. Between each stimulation period, 10 min were allowed for
the previous response to return to baseline. EFS-induced contractions
were normalized as a percentage of the response to 10
3 M
ACh (%ACh response). In some experiments, atropine (10
6
M) was added to the Krebs solution to verify that the responses elicited by EFS were mediated by the release of ACh from cholinergic neurons.
Immunocytochemistry.
Tracheal segments from IL-1- or saline-treated ferrets were fixed in
picric acid-formaldehyde fixative for 3 h and rinsed three times
with a 0.1 M phosphate-buffered saline containing 0.3% Triton X-100
(PBS-Tx). The airways were frozen in isopentane, cooled with liquid
nitrogen, and stored in airtight bags at
80°C. The tracheas were
frozen on cock supports and oriented with the dorsal surface uppermost
so the tracheal muscle would be sectioned in a coronal plane.
Data analysis. Unless otherwise stated, results are expressed as means ± SE. Contractions elicited by EFS were expressed as a percentage of the maximal contraction elicited by ACh. Contractions to ACh and MCh were normalized as a percentage of the respective maximal responses for each agonist. The half-maximal concentrations (EC50) for ACh and MCh were calculated using a four-parameter logistic curve fit (Sigmoidal, SigmaPlot 2000) and are presented with a 95% confidence interval in parentheses. Force development was expressed by normalizing force (g) divided by the wet weight of the tissue. Longitudinal trunk neurons were expressed as percent SP-positive cell bodies, and superficial muscular plexus neurons were expressed as percent SP-innervated cell bodies. Nerve fiber density was expressed as percent area of SP-immunoreactive nerve fibers in the total area of the smooth muscle. Statistical analyses of immunocytochemistry, EC50, and EFS were performed using Student's t-test or two-way repeated-measures analysis of variance. A P value <0.05 was considered significant, and n represents the number of animals studied.
Materials.
ACh chloride, MCh chloride, atropine sulfate, IL-1 human
recombinant, hydrocortisone hemisuccinate, amphotericin B, and
recrystallized bovine insulin were obtained from Sigma (St. Louis, MO).
Penicillin G, streptomycin, fetal calf serum, and CMRL 1066 were
obtained from GIBCO (Grand Island, NY). CP-99994 was obtained from
Pfizer (Groton, CT). SP antibody was obtained from Peninsula (Belmont, CA). VIP was a gift from John Pocter (University of Texas, Health Science Center, Dallas, TX). Fluorescein isothiocyanate-labeled goat
anti-rabbit antibody was obtained from ICN Immunobiologicals (Costa
Mesa, CA).
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RESULTS |
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Effect of IL-1 on airway responsiveness in noncultured and
cultured tracheas.
The initial experiments examined the effect of IL-1
on tracheal
smooth muscle sensitivity in noncultured tracheas. Cumulative concentration-response curves for ACh and MCh were markedly shifted to
the left (Fig. 1, A and
B), and the EC50 values (Table
1) were decreased by 59 and 61%,
respectively, in the IL-1
treatment group (P
0.001).
IL-1
also increased contractile responses to EFS. A leftward shift
in the frequency-response curve was observed in IL-1
-treated animals
(Fig. 1C), and contractions produced by EFS at 10 and 30 Hz
were significantly increased by 19 and 16%, respectively, after
treatment with IL-1
(P
0.05).
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Role of SP in IL-1-induced AHR in cultured tracheas.
The next experiments examined the involvement of SP in IL-1
-enhanced
airway responsiveness by blocking the neurokinin (NK)-1 receptor. Cumulative concentration-response curves
for ACh and MCh (Fig. 4, A and
C; Table 3) and the
EFS-stimulated contractions at 10 and 30 Hz (Fig. 4E)
demonstrated expected changes in organotypic cultured tracheal segments
after IL-1
treatment. EC50 values (Table 3) for ACh and
MCh were decreased by 67 and 64% respectively, and contractions
produced by EFS at 10 and 30 Hz were significantly increased in
tracheal strips cultured with IL-1
. However, administration of the
NK-1 antagonist CP-99994 attenuated the IL-1
-enhanced contractile
responses to ACh, MCh (Fig. 4, B and D; Table 3), and EFS (Fig. 4F). EC50 values for ACh and MCh
decreased by only 32 and 36%, respectively, after pretreatment with
CP-99994 in tracheal strips cultured with IL-1
. There was no
significant difference in responses to the same frequency of EFS
between tracheal strips cultured with IL-1
and strips cultured with
saline after treatment with CP-99994.
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Changes in immunoreactive SP-containing intrinsic airway neurons.
SP-containing cell bodies were present within longitudinal trunk and
superficial muscular plexus in control animals and after repeated
IL-1 treatment for 5 days (Fig. 5).
About 70% of the longitudinal trunk cell bodies labeled for SP (Figs.
5A and 6 A) and
~66% of the superficial muscular plexus neurons were innervated by
SP-containing nerve fibers in control ferrets (Figs. 5C and 6B). After repeated treatment with IL-1
, >92% of the
cell bodies in the longitudinal trunk contained SP (Figs. 5B
and 6A), and nearly 84% of the cell bodies in the
superficial muscular plexus were innervated by SP-containing nerve
fibers (Figs. 5D and 6B). Also, SP nerve fiber
density from in the tracheal smooth muscle was significantly increased
by 38% from 0.39 (control) to 0.54 after repeated IL-1
treatment
(Figs. 5, E and F, and 6C;
P
0.05).
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DISCUSSION |
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This study shows that IL-1 enhances cholinergic responsiveness
in ferret airway smooth muscle, as shown by elevated atropine-sensitive contractility to ACh, MCh, and EFS in ferrets. The elevation of airway
smooth muscle responses by IL-1
was attenuated by treatment with a
NK-1 receptor antagonist, indicating that endogenously released SP was
involved. NK-1-dependent AHR induced by IL-1
was elicited in
tracheal segments cultured for 24 h, a procedure both shown in
previous study (18, 53) and verified in the present
experiment to cause a significant anatomical and functional loss of SP
from airway projections of sensory nerves. Because the IL-1
effect
was maintained in sensory-denervated tracheal segments, the findings
suggest that neurons in airway ganglia may be the main source for SP in
these airways. The observations that IL-1
treatment increased the
level of SP in longitudinal trunk neurons, SP innervation of
superficial muscular plexus neurons, and SP innervation of tracheal
smooth muscle all support the conclusion that IL-1
elevates
endogenous SP levels in intrinsic airway neurons.
IL-1 is produced by alveolar macrophages and tracheal epithelial
cells, and levels are elevated in bronchoalveolar lavage fluid during
airway injury (12, 19, 37). Furthermore, IL-1
is
elevated in the bronchoalveolar lavage fluid from asthmatic patients
(6, 7). IL-1
has been implicated in the development of
AHR in animal models and isolated human bronchi (4, 23, 50). Recent studies further found that IL-1
plays an
important role not only in up- and downregulation of acute and chronic
inflammation (1, 32), but also in regulation of neuronal
development and plasticity (20, 27, 30). SP is generally
considered a sensory neuropeptide in the airways and has been
associated with inflammation mediated through sensory pathways, but we
have demonstrated previously that SP is also synthesized in the airway
neurons (16, 18). Furthermore, inhalation of irritants or
antigens enhances neuronal levels of SP and preprotachykinin mRNA in
both sensory neurons and airway neurons (22, 34, 54, 55).
One of the significant findings in this study is that IL-1
enhances
SP expression in airway neurons. The present study provides evidence
that airway neurons, like sensory neurons, are able to respond to
inflammatory cytokines. IL-1
is known to cause the release and
synthesis of SP from myenteric neurons of the gastrointestinal tract
(26, 27, 31), which are embryologically and functionally
analogous to intrinsic airway neurons. In the present study, we
hypothesized that IL-1
in the airways may mediate SP expression in
intrinsic airway neurons as well. The immunocytochemical data
demonstrating that SP in longitudinal trunk neurons and SP innervation
of superficial muscular plexus neurons in trachea were both increased
after repeated IL-1
treatment provide evidence that IL-1
treatment enhances SP levels in intrinsic airway neurons. In separate
studies of airways from severe asthmatics, SP nerve fiber density in
airway smooth muscle (43) and IL-1
in bronchoalveolar
lavage fluid were increased (6, 7). Thus IL-1
released
during airway inflammation may influence SP expression in airway neurons.
The finding that the NK-1 antagonist CP-99994 significantly attenuates
the effect of IL-1 on cholinergic and EFS-stimulated contractile
responses implicates the involvement of SP as the mediator of IL-1
action on airway smooth muscle. Although SP is a known
bronchoconstrictor (5, 35), direct action of SP on smooth
muscle does not appear to be an important effect in this study, because
all of the smooth muscle contractile effects of IL-1
were atropine
sensitive. Thus the logical explanation of the IL-1
effect is that
SP alters cholinergic responsiveness. Previous studies have shown that
SP enhances cholinergic responsiveness either through a direct effect
on airway smooth muscle (49) or by enhancing ACh release
from parasympathetic nerve terminals (40, 44, 52). The
data in the present study do not discriminate between these two
mechanisms because cholinergic responsiveness was enhanced both by
cholinergic agonists and by EFS. This would suggest that enhanced
smooth muscle responsiveness accounts for at least part of the enhanced
cholinergic sensitivity but that enhanced ACh release from
prejunctional terminals is not ruled out.
Another possible mechanism of SP action may be related to the complex
circuitry of the ferret tracheal plexus. Nerve cell bodies are located
in large ganglia of the longitudinal trunk and in ganglia of the
superficial muscular plexus. Longitudinal trunk neurons are
predominantly cholinergic, and cell bodies in the superficial muscular
plexus contain predominantly VIP and NO with a small population
containing SP (16, 18). Both longitudinal trunks and
superficial muscular plexus project to airway smooth muscle and
communicate freely between neurons in the plexus (57). The
present study suggests that SP release may be enhanced at VIP/NO
neurons in the superficial muscular plexus ganglia. We demonstrated
recently that ozone inhalation causes enhanced SP content in
longitudinal trunks neurons, increased SP innervation of superficial
muscular plexus neurons, and increased SP innervation of airway smooth
muscle (55). These findings suggest that SP innervation of
VIP/NO neurons may be involved in modulating SP-mediated responses in
the ferret tracheal plexus. Unfortunately, the effects of SP on these
neurons are not known, and the presence of NK receptors has not been
determined in these specific neurons. There is evidence that NK-3
receptors on presumably cholinergic neurons of guinea pig airway
mediate membrane hyperpolarization in response to topical SP
application (41). Thus it is likely that enhanced SP
production in airway ganglia induced by IL-1 increases neural
activity within the airways through local neural reflexes that could
involve modulation of cholinergic or VIP/NO pathways.
Although IL-1 caused enhanced SP expression in airway neurons, the
precise signaling pathways involved are still not clear. Treatment of
pure neuronal cultures with IL-1
fails to induce expression of
preprotachykinins in sympathetic neurons (31), suggesting
either that IL-1
acts on nonneuronal cells, which, in turn, release
another factor or that a nonneuronal cell cofactor is necessary for
IL-1
actions on neurons. A recent study has found that IL-1
may
regulate leukemia inhibitory factor (LIF) release from ganglion
nonneuronal cells, that treatment of pure neuronal cultures with LIF
induces SP expression, and that cocultures with LIF antibody prevent
the SP increase caused by nonneuronal cells (31, 45).
These studies provide further support for LIF as a signaling molecule
regulating SP expression in airway ganglia. Another mechanism of
IL-1-induced SP release may involve a prostaglandin intermediate
pathway. Pretreatment with cyclooxygenase inhibitors attenuates the
stimulation of sensory neurons by IL-1
(20).
Furthermore, cyclooxygenase inhibitors completely abolish SP release
induced by IL-1
in dorsal root ganglia. Also, IL-1
increases
cyclooxygenase-2 mRNA expression in the same ganglia (27).
Prostaglandins directly evoke SP release from sensory neurons
(24), but their effect on intrinsic airway neurons is not known.
In conclusion, our results show that repeated intratracheal treatment
with IL-1 increases SP levels in and around airway neurons and
tracheal smooth muscle. At the same time, sensitivity of airway smooth
muscle is increased. This effect is maintained in tracheal segments
cultured for 24 h. Administration of CP-99994, an antagonist of
the NK-1 receptor, attenuates the IL-1
-induced airway responses in
cultured tracheal segments. The findings indicate that IL-1
induces
AHR by enhancing SP expression in airway neurons.
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ACKNOWLEDGEMENTS |
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The authors are grateful to Dr. G. Hobbs (Department of Statistics, West Virginia University) for statistical analysis. The authors also thank Pfizer for the supply of CP-99994.
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FOOTNOTES |
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This study was supported by National Heart, Lung, and Blood Institute Grant RO1-HL-35812.
Address for reprint requests and other correspondence: R. D. Dey, Dept. of Neurobiology and Anatomy, PO Box 9128, West Virginia Univ., Morgantown, WV 26506 (E-mail: rdey{at}hsc.wvu.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
April 12, 2002;10.1152/ajplung.00363.2001
Received 12 September 2001; accepted in final form 4 April 2002.
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