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Department of Physiology, University of Kentucky, Lexington, Kentucky 40536
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Wu, Zhong-Xin, Robert F. Morton, and Lu-Yuan Lee. Role
of tachykinins in ozone-induced airway hyperresponsiveness to cigarette
smoke in guinea pigs. J. Appl.
Physiol. 83(3): 958-965, 1997.
Acute exposure to ozone
(O3) induces airway
hyperresponsiveness to various inhaled bronchoactive substances.
Inhalation of cigarette smoke, a common inhaled irritant in humans, is
known to evoke a transient bronchoconstrictive effect. To examine
whether O3 increases airway
responsiveness to cigarette smoke, effects of smoke inhalation
challenge on total pulmonary resistance
(RL) and dynamic lung
compliance (Cdyn) were compared before and after exposure to
O3 (1.5 ppm, 1 h) in anesthetized
guinea pigs. Before O3 exposure,
inhalation of two breaths of cigarette smoke (7 ml) at a low
concentration (33%) induced a mild and reproducible
bronchoconstriction that slowly developed and reached its peak
(
RL = 67 ± 19%, Cdyn = 
29 ± 6%) after a delay of >1 min. After exposure to
O3 the same cigarette smoke
inhalation challenge evoked an intense bronchoconstriction that
occurred more rapidly, reaching its peak
(RL = 620 ± 224%, Cdyn = 35 ± 7%) within 20 s, and was sustained for >2
min. By contrast, sham exposure to room air did not alter the
bronchomotor response to cigarette smoke challenge. Pretreatment with
CP-99994 and SR-48968, the selective antagonists of neurokinin type 1 and 2 receptors, respectively, completely blocked the enhanced
responses of RL and Cdyn to
cigarette smoke challenge induced by
O3. These results show that
O3 exposure induces airway
hyperresponsiveness to inhaled cigarette smoke and that the enhanced
responses result primarily from the bronchoconstrictive effect of
endogenous tachykinins.
neurokinin receptor antagonists; bronchopulmonary C-fibers; inhaled
irritants; neurokinin A; substance P; bronchoconstriction
INTRODUCTION IT HAS BEEN REPEATEDLY demonstrated that, in several
species, including humans, acute exposure to ozone
(O3), one of the major air
pollutants in urban areas, produces epithelial injury and inflammation
in the airways, accompanied by bronchial hyperresponsiveness to a
variety of bronchoactive substances (4, 10, 15, 17, 26, 30). In guinea
pigs the bronchial hyperreactivity induced by
O3 cannot be totally abolished by
premedication with atropine or by bilateral vagotomy and exists even in
an isolated airway preparation, indicating that a noncholinergic
mechanism is involved (4, 27, 31). Recent studies have provided further
evidence to suggest that endogenously released tachykinins may play a
part in O3-induced airway
hyperresponsiveness (13, 15, 28, 30). Tachykinins such as substance P
(SP) and neurokinin (NK) A (NKA) are colocalized and coreleased from
bronchopulmonary C-fiber afferent endings and can generate potent
bronchoconstrictive effects. Pretreatment of guinea pigs with a high
dose of capsaicin, which is known to deplete SP and NKA in the lung,
reduces the magnitude of
O3-induced airway
hyperresponsiveness to aerosolized histamine (28, 30). However, more
direct evidence showing that tachykinins play an important role in
O3-induced airway
hyperresponsiveness remains to be established. The recent development
of selective NK1- and NK2-receptor antagonists, such as
CP-99994 and SR-48968, has made it feasible to address this question.
Inhalation of cigarette smoke, a common inhaled irritant in human
airways, is known to induce a transient bronchoconstrictive effect. Our
recent studies have shown that inhalation of a small volume (10 ml) of
cigarette smoke induces a biphasic bronchoconstriction in guinea pigs:
the first phase is caused by a combination of cholinergic reflex and
release of tachykinins; the second phase involves the action of
arachidonic acid metabolite(s) of the cyclooxygenase pathway (12).
Furthermore, our results strongly suggest that the first phase is
mediated primarily through the activation of bronchopulmonary C fibers
(12, 19). However, these studies did not determine whether this
smoke-induced bronchoconstriction could be altered by
O3 exposure. The purposes of the
present study were 1) to determine
whether the bronchoconstrictive effect of inhaled cigarette smoke is
enhanced when airway hyperreactivity is induced by acute exposure to
O3 and
2) to characterize the role of
endogenous tachykinins in the development of airway hyperresponsiveness to smoke.
METHODS The procedures were performed in accordance with the recommendations of
the National Institutes of Health (26a) and were approved by the
University of Kentucky Institutional Animal Care and Use Committee.
Male Hartley guinea pigs (320-450 g body wt) were anesthetized
with Transpulmonary pressure was measured as the difference between the
tracheal pressure and the intrapleural pressure with a differential
pressure transducer (model MP 45-28, Validyne) positioned between a
sidearm of the trachea cannula and the intrapleural cannula.
Respiratory flow was measured with a heated pneumotachograph and a
differential pressure transducer (model MP 45-14, Validyne) and was
integrated to give VT. The
pneumotachograph had a linear flow-pressure relationship in the range
of 0-20 ml/s and a flow resistance of 0.046 cmH2O · ml Cigarette Smoke Challenge
-chloralose (100 mg/kg ip) and urethan (500 mg/kg ip) dissolved
in a 2% borax solution. The trachea was cannulated below the larynx
with a short tracheal cannula via a tracheotomy. The animals were
placed in a supine position and were ventilated with a respirator
(model 683, Harvard) at the constant rate of 44 breaths/min. Tidal
volume (VT) was adjusted
according to the body weight of each animal (8 ml/kg). The right
jugular vein and carotid artery were cannulated for intravenous
injections and for arterial blood pressure measurement with a pressure
transducer (model P23AA, Statham). A catheter for measuring
intrapleural pressure was inserted into the right intrapleural cavity
via a surgical incision between the fifth and sixth ribs; this incision
was subsequently sutured and further sealed airtight with silicone
jelly. The pneumothorax was then corrected by briefly opening the
intrapleural catheter to ambient air during a held hyperinflation (3 × VT). The animals were
paralyzed with pancuronium bromide (30 µg/kg iv) during the experiment to prevent spontaneous breathing after the smoke inhalation challenge. Additional doses of pancuronium were given only after the
effect of the original dose had worn off and the depth of anesthesia
had been checked; additional doses of anesthetics were administered,
whenever necessary, to abolish the reflex changes in arterial blood
pressure and heart rate in response to pain induced by toe pinch. A
heating pad was placed under the animal to maintain the body
temperature at 36-37°C during the experiment.
1 · s.
All signals were recorded on a chart recorder (model 7, Grass) and also
on a tape recorder (model 3968A, Hewlett-Packard) for an on-line
breath-by-breath computer analysis of total pulmonary resistance
(RL) and dynamic lung
compliance (Cdyn). Results obtained from the computer were routinely
checked by hand calculation for accuracy.
Acetylcholine Challenge
A dose-response curve of RL to bolus injections (0.2 ml volume) of acetylcholine (ACh) solution (1.00-5.06 µg/kg iv) was obtained in each animal by successive increases of the ACh concentration of the injectate by 50% at 5-min intervals. The baseline and peak responses of RL to each injected dose of ACh were measured by averaging the RL of three consecutive breaths immediately before and within 10 breaths after the injection, respectively. The lungs were hyperinflated (3 × VT) 2 min before each ACh injection.O3 Exposure
O3 was generated by passing a constant flow of filtered dry oxygen into a commercial O3 generator (model 03v1, Orec) and mixed with a diluting flow of filtered dry air in a mixing chamber (4 × 4 × 4 ft). The concentration of O3 (1.5 ppm) in the chamber was continuously monitored with an O3 analyzer (model 1003-AH, Dasibi), and its accuracy was calibrated by a potassium iodine method. The O3-air mixture was drawn by the respirator and delivered directly into the lung; each exposure lasted for 1 h. The concentration of O3 used in this study was higher than that normally existing in the environment. Breathing via the tracheal cannula in these animals may have further increased the concentration of O3 that reached the lung periphery. To avoid decomposition of O3, all the tubings exposed to O3 were made of glass or Teflon. A separate group of animals was subjected to the sham exposure, in which procedures identical to those described above were followed, except O3 was not delivered to the mixing chamber.Experimental Protocol
Study series 1. This series of experiments was carried out to examine the effect of O3 exposure on bronchomotor responses to inhaled cigarette smoke in nine guinea pigs. Responses of RL and Cdyn to cigarette smoke inhalation challenge were obtained twice before exposure to O3 and at 1, 2, and 3 h after exposure. In addition, the bronchomotor responses to ACh challenge were also obtained before and at 1.5 and 2.5 h after O3 exposure to verify whether O3 induced airway hyperresponsiveness in these animals. Study series 2. The effect of sham exposure to room air, instead of O3, on the bronchomotor responses to ACh and to cigarette smoke was determined by following the protocol used in study series 1. Study series 3. To determine the possible involvement of endogenously released tachykinins, the bronchomotor responses to cigarette smoke were tested first at 1 h after O3 exposure, and then again at ~2 h after O3 exposure, i.e., 30 min after pretreatment with CP-99994 (0.3 mg/kg iv), the antagonist of NK1 receptors, and SR-48968 (0.3 mg/kg iv), the antagonist of NK2 receptors. The doses of these antagonists were determined on the basis of our previous findings (12). To determine the relative contribution of NK1- and NK2-receptor activation to the observed responses, we studied the effects of these antagonists separately in two additional groups of guinea pigs. In one group (n = 5), we tested the post-O3 responses to smoke inhalation challenge before and after the administration of SR-48968 alone and again after the combination of CP-99994 and SR-48968. In the second group (n = 5), the sole effect of CP-99994 was studied first following an identical protocol.Statistical Analysis
To pool the data from all the animals for statistical analysis, we chose the six consecutive breaths immediately before the cigarette smoke challenge as the baseline, the six consecutive breaths with peak increase in RL that occurred within 20 breaths after the smoke challenge as the first-phase response, and breaths 75-80 as the second-phase response. A two-way analysis of variance was used for the statistical analysis: one factor was the treatment effect of O3 or pharmacological agents, and the other factor was the effect of smoke inhalation challenge. When the two-way analysis of variance showed a significant interaction, pairwise comparisons were made with a post hoc analysis (Fisher's least significant difference). Values are means ± SE. P < 0.05 was considered significant.Materials
Pancuronium bromide (2 mg/ml; Elkins-Sinn Pharmaceuticals) and ACh chloride (Sigma Chemical) were diluted with saline. CP-99994 and SR-48968 were first dissolved in polyethylene glycol (average mol wt 200; Sigma Chemical) and then diluted in saline at 1:14 and 1:1, respectively, to a final concentration of 0.67 mg/ml for both.RESULTS
Study Series 1: Effect of O3 Exposure on Bronchomotor Responses to Cigarette Smoke
In this study the bronchomotor responses to ACh were compared before and at 1.5 and 2.5 h after exposure to O3. The dose response of RL to ACh was markedly elevated after exposure to O3 (Fig. 1A), verifying the presence of O3-induced bronchial hyperreactivity. Before O3 exposure, cigarette smoke (7 ml, 33%) inhalation challenge induced a mild and reproducible bronchoconstriction that slowly increased and reached its peak (RL = 67 ± 19%, Cdyn = 29 ± 6%) after a delay of >1 min;
there was no detectable first-phase response (Figs.
2 and 3). The
peak RL in the second phase was not significantly different from the baseline, but Cdyn was
significantly reduced (P < 0.05;
Figs. 3 and 4). After exposure to
O3, the baseline RL was not significantly
different from control, but the baseline Cdyn was reduced by 27%
(Figs. 3 and 4). In sharp contrast, the same cigarette smoke inhalation
challenge evoked an intense bronchoconstriction that occurred more
rapidly and reached its peak within 20 s (Fig. 3). This augmented
first-phase response was found at 1 h after O3 exposure and lasted for >3 h;
the hyperresponsiveness to smoke appeared to reach its peak
(RL = 620 ± 224%,
Cdyn = 35 ± 7%) at ~2 h after
O3 exposure (Fig. 4); the
O3-induced increases in the
responses of RL and Cdyn to
cigarette smoke were significantly correlated
(r = 0.73,
P = 0.027). After
O3 exposure, the second-phase response of RL to smoke
inhalation challenge was not significantly different from control (Fig.
4).
; inspiratory flow:
positive), and arterial blood pressure (ABP) to cigarette smoke in an
anesthetized guinea pig (394 g). Cigarette smoke (7 ml, 33%
concentration) was delivered into lung by respirator in 2 consecutive
breaths (horizontal bar). A: before
O3 exposure; B: 2 h after
O3 exposure (1.5 ppm, 1 h).
, Smoke inhalation challenge before
O3 exposure; 
, same challenge at 2 h after O3 exposure (1.5 ppm,
1 h) in same group of animals. Cdyn, dynamic lung compliance. Cigarette
smoke was delivered into lung by respirator during time period
represented by segment between 2 arrows. Values are means ± SE of 9 guinea pigs.
significantly different from corresponding data before
O3 exposure.
Study Series 2: Effect of Sham Exposure on Bronchomotor Responses to Cigarette Smoke
After sham exposure to room air the dose response of RL to ACh was not significantly different from that obtained before sham exposure (P > 0.05; Fig. 1B). Similarly, the bronchomotor responses to cigarette smoke inhalation challenge were not different from those obtained before sham exposure (Figs. 5 and 6), indicating that the O3-induced hyperresponsiveness to smoke was not due to the procedures of exposure. Furthermore, the smoke-induced reduction in Cdyn from baseline (Cdyn = 26 ± 6%)
before the sham exposure was not different
(P = 0.96) from that obtained in
study series 1 (Cdyn = 27 ± 4%)
before the O3 exposure.
, Smoke inhalation challenge before sham exposure; , same challenge at 2 h after sham
exposure in same group of animals. Values are means ± SE of 5 guinea pigs. See legend of Fig. 3 for further explanation.
Study Series 3: Role of Tachykinins
In this group of animals, the cigarette smoke-induced changes in RL and Cdyn were augmented after O3 exposure; the amplitude and the time course of the response were very similar to those observed in study series 1 (Figs. 7 and 8). The first-phase responses to smoke were markedly potentiated at 1 h after O3 exposure (RL = 611 ± 208%, Cdyn =
36 ± 8%) compared with those before exposure (RL = 25 ± 10%,
Cdyn = 9 ± 3%;
Figs. 7 and 8). After pretreatment with CP-99994 and SR-48968, the
baseline of RL and Cdyn were not significantly altered, but the exaggerated first-phase responses to
cigarette smoke after O3 exposure
were abolished (RL = 27 ± 9%, Cdyn = 4 ± 2%; Fig. 8). Furthermore, after
O3 exposure the further decreases
in Cdyn after the smoke inhalation challenge were also abolished by
pretreatment with the NK1- and
NK2-receptor antagonists (Fig. 8).
, Smoke inhalation
challenge before O3 exposure; ,
same challenge at 1 h after O3
exposure; 
, same challenge at 30 min after administration of
CP-99994 and SR-48968 (~2 h after
O3 exposure). Values are means ± SE of 6 guinea pigs. See legend of Fig. 3 for further explanation.
significantly different from corresponding data before
O3 exposure. See legend of Fig. 4
for further explanation.
In five additional animals, administration of SR-48968 alone almost
completely abolished the
O3-induced increases in the
responses to smoke inhalation challenge (before SR-48968:
RL = 676 ± 278%, Cdyn = 35 ± 9%;
after SR-48968: RL = 41 ± 18%, Cdyn = 3 ± 1%). In contrast, in five other
animals, administration of CP-99994 alone did not significantly change
the O3-induced increases in the
responses to smoke inhalation challenge (before CP-99994: RL = 656 ± 247%,
Cdyn = 34 ± 6%;
after CP-99994: RL = 643 ± 261%, Cdyn = 33 ± 6%); the residual responses
were abolished after the addition of SR-48968 in these animals.
DISCUSSION
Previous investigators have reported that acute exposure to O3 induced airway hyperresponsiveness to various inhaled or injected bronchoactive substances (4, 15, 27, 31). Our results obtained in this study are consistent with their findings; the dose response of RL to intravenous injections of ACh was significantly elevated after exposure to O3 in guinea pigs (Fig. 1). Moreover, our results clearly demonstrate that the bronchoconstrictive effect of inhaled cigarette smoke was markedly enhanced after O3 exposure (Figs. 2 and 3); the increased bronchomotor response was abolished by pretreatment with NK1- and NK2-receptor antagonists (Figs. 7 and 8), indicating that endogenously released tachykinins were involved.
The localization of various types of tachykinins in the peripheral endings of the bronchopulmonary C-fiber afferents has been clearly documented by using the immunohistochemical technique in several species, including humans (1, 9, 20, 21). Stimulation of the bronchopulmonary C-fiber afferents is known to trigger the release of tachykinins from these endings and to elicit the "axon reflex," which is particularly prominent in rodents (1, 5, 21, 23). Bronchoconstriction, vasodilatation, and extravasation of macromolecules in the tracheobronchial tree are induced even in vagotomized guinea pigs by inhalation of various chemical irritants (e.g., cigarette smoke) known to activate C-fiber endings or by electrical stimulation of distal ends of cut vagus nerves (1, 21, 22). These responses are resistant to atropine and are absent in guinea pigs in which sensory neuropeptides have been depleted from C-fiber afferents by neonatal capsaicin treatment (21, 22). Among the various types of tachykinins that have been identified in the guinea pig airways, NKA is a more potent agonist of the NK2 receptor, which mediates the airway smooth muscle contraction, whereas SP has a more potent effect on the NK1 receptor, which mediates protein extravasation (1, 21). To determine the relative contribution of the activation of NK1 and NK2 receptors to the O3-induced hyperresponsiveness to cigarette smoke in this study, we selectively blocked NK2 receptors with the administration of SR-48968, which alone abolished >90% of the increase of the bronchoconstrictive response to smoke after O3 exposure. In contrast, administration of CP-99994 alone reduced the response by only 3%. Hence, we conclude that the activation of NK2 receptors is primarily responsible for mediating this response.
It has been shown that airway inflammation induced by O3 and by other causes can inhibit the enzyme activity of neutral endopeptidase (NEP), which is present in the membranes of epithelium and nerve fibers and cleaves tachykinins immediately after their release (3, 7, 23, 26). Thus, reduced NEP activity after O3 exposure (26) may play a part in potentiating the bronchoconstrictive effect of tachykinins, which are known to be released by inhaled cigarette smoke (19). Indeed, it has been shown that O3 induced the bronchial hyperresponsiveness to SP and capsaicin, and the enhanced responses can be reversed by administration of exogenous NEP (26).
An alternative explanation is that the excitability of the C-fiber afferents is enhanced by the airway epithelial injury and mucosal inflammation resulting from the exposure to O3 (14, 26, 31). Thus a given dose of cigarette smoke evokes a greater discharge of the afferent endings and triggers the release of a larger quantity of tachykinins, which in turn renders a more severe bronchoconstriction. Indeed, a possible increase in excitability of these sensory endings has been reported (10); the increased bronchomotor responsiveness to histamine in healthy humans after exposure to O3 is consistently associated with symptoms of airway irritation. For example, some of these subjects coughed on deep inspiration after O3 exposure but did not do so before exposure (10). Because hyperinflation of the lungs is known to be a relatively weak stimulus to the bronchopulmonary C-fiber afferents in healthy lungs (6), these findings indicate that, after O3 exposure, airway irritation can be evoked by an otherwise subthreshold stimulus. This postulation is also in general agreement with our preliminary observation in anesthetized rats that the pulmonary chemoreflexes elicited by right atrial injection of certain specific stimulants of pulmonary C-fiber afferents (e.g., capsaicin, phenyl biguanide) are augmented after exposure to O3 (8); the exaggerated response can be completely abolished by a perineural capsaicin treatment of both cervical vagi, which selectively blocks the conduction of C fibers. These findings suggest a possible involvement of pulmonary C-fiber afferents. In addition, we cannot totally rule out the possibility that rapidly adapting receptors may be also involved in triggering the observed responses, since it has been suggested that tachykinins released locally in the lung can stimulate rapidly adapting receptors and elicit reflex bronchoconstriction (2, 29).
Recent studies carried out in our laboratory have shown that inhalation of three breaths of cigarette smoke evokes an acute bronchoconstriction in anesthetized guinea pigs. The response consists of two distinct phases that are different in time course and underlying mechanisms (12). The first phase is induced by a cholinergic reflex and a tachykinin release, whereas the second phase is caused by the action of arachidonic acid metabolite(s) of the cyclooxygenase pathway. Indeed, pretreatment of the animals with atropine, CP-99994, and SR-48968 completely abolished the first-phase response but did not alter the mild increase in RL and decrease in Cdyn during the second phase (12). Furthermore, the first-phase response is primarily induced by activation of bronchopulmonary C-fiber afferents, and nicotine is the primary causative agent responsible for evoking the response (11, 12). Previous studies carried out in our laboratory, using a "single-fiber" electrophysiological recording technique, have demonstrated that the vagal pulmonary C fibers are activated by inhaled cigarette smoke (18) and by right atrial injection of nicotine (16) in anesthetized dogs. Hexamethonium completely abolishes the stimulatory effects of cigarette smoke and nicotine on these endings but does not significantly alter their afferent response to capsaicin, suggesting that nicotinic ACh receptors are present on the terminal membrane of these sensory endings (18). In the present study, inhalation of a relatively smaller volume (7 ml) and lower concentration (33%) of cigarette smoke failed to produce any detectable first-phase response and produced only a mild second-phase bronchoconstriction before O3 exposure (Figs. 2 and 3). In sharp contrast, the same smoke inhalation challenge evoked a very intense first-phase bronchoconstriction in the same animals after O3 exposure (Figs. 2 and 3), lending additional support to the notion that the excitability of pulmonary C fibers is enhanced after O3 exposure.
Stimulation of these afferents is also known to elicit a reflex bronchoconstriction mediated through the cholinergic pathway (6). Therefore, it was somewhat surprising to find that the bronchoconstrictive effect of cigarette smoke mediated by the cholinergic reflex was not enhanced after O3 exposure, because the augmented response to smoke was completely abolished by pretreatment with NK1- and NK2-receptor antagonists (Figs. 7 and 8). In contrast, O3-induced airway hyperresponsiveness to inhaled bronchoconstrictive substances is significantly attenuated by atropine in larger mammals (10, 17). This discrepancy in the relative contribution of the cholinergic mechanism and endogenously released tachykinins to the O3-induced airway hyperresponsiveness is probably related to species differences (6).
After exposure to O3, the baseline RL did not change, but Cdyn decreased by 27% from the pre-O3 baseline in this study. This decrease in Cdyn occurred immediately after O3 exposure and persisted for >3 h (Figs. 3 and 4). This change could not be reversed by the administration of NK1- and NK2-receptor antagonists (Figs. 7 and 8) and persisted even after the higher dose of these antagonists (1 mg/kg of SR-48968 and 1 mg/kg of CP-99994) had been administered to six guinea pigs (unpublished data). The reduction in Cdyn was not caused by the time factor or the experimental procedures, because Cdyn did not change significantly after sham exposure (Figs. 5 and 6). Similar changes have been reported by others in guinea pigs after exposure to a lower concentration (1 ppm) of O3, and the cause was not known (25). Extravasation of macromolecules and mucosal edema have been reported in guinea pig airways after exposure to O3 (14, 15). Whether these effects can account for the changes in the baseline Cdyn observed in our study is not known.
In conclusion, the results of this study show that the bronchoconstrictive effect of inhaled cigarette smoke is augmented after exposure to O3 in guinea pigs. The enhanced bronchomotor response to smoke results primarily from an increased bronchoconstrictive effect of endogenous tachykinins. We believe that the potentiated effect of tachykinins is probably associated with the O3-induced inflammation of airway mucosa, which enhances the excitability of bronchopulmonary C-fiber endings and/or inhibits the enzyme activity of NEP.
ACKNOWLEDGEMENTS
The authors are grateful to Dr. Mary K. Rayens for statistical analysis. The authors thank Sanofi Recherche (Montpelliex Cedex, France) and Pfizer (Groton, CT) for the supply of SR-48968 and CP-99994, respectively.
FOOTNOTES
Address for reprint requests: L.-Y. Lee, Dept. of Physiology, University of Kentucky, 800 Rose St., Lexington, KY 40536-0084.
Received 25 February 1997; accepted in final form 8 May 1997.
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