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Psychosomatic Medicine 66:564-571 (2004)
© 2004 American Psychosomatic Society

ORIGINAL ARTICLES

Neurokinin-1 Receptor Mediates Stress-Exacerbated Allergic Airway Inflammation and Airway Hyperresponsiveness in Mice

Ricarda A. Joachim, MD, Viktoriya Sagach, MD, David Quarcoo, MD, Q. Thai Dinh, MD, Petra C. Arck, MD and Burghard F. Klapp, MD

From the Department of Internal Medicine and Psychosomatics, Charité, Universitätsmedizin Berlin (R.A.J., V.S., T.D., P.C.A., B.F.K.) and the Department of Paediatric Pneumology and Immunology, Charité, Universitätsmedizin Berlin (D.Q.), Berlin, Germany.

Address correspondence and reprint requests to Ricarda Joachim, MD, Charité, Campus Virchow, Biomedizinisches Forschungszentrum, R. 2.0549, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail: ricarda.joachim{at}charite.de


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 ACKNOWLEDGMENTS
 REFERENCES
 
BACKGROUND: A wealth of clinical observation has suggested that stress and asthma morbidity are associated. We have previously established a mouse model of stress-exacerbated allergic airway inflammation, which reflects major clinical findings.

OBJECTIVE: The aim of the current study was to investigate the role of the neurokinin- (NK-)1 receptor in the mediation of stress effects in allergic airway inflammation.

METHODS: BALB/c mice were systemically sensitized with ovalbumin (OVA) on assay days 1, 14, and 21 and repeatedly challenged with OVA aerosol on days 26 and 27. Sound stress was applied to the animals for 24 hours, starting with the first airway challenge. Additionally, one group of stressed and one group of nonstressed mice received the highly specific NK-1 receptor antagonist RP 67580. Bronchoalveolar lavage fluid was obtained, and cell numbers and differentiation were determined. Airway hyperreactivity was measured in vitro by electrical field stimulation of tracheal smooth-muscle elements.

RESULTS: Application of stress in sensitized and challenged animals resulted in a significant increase in leukocyte number in the bronchoalveolar lavage fluid. Furthermore, stressed animals showed enhanced airway reactivity. The increase of inflammatory cells and airway reactivity was blocked by treatment of animals with the NK-1 receptor antagonist.

CONCLUSION: These data indicate that the NK-1 receptor plays an important role in mediating stress effects in allergen-induced airway inflammation.

Key Words: sound stress, • allergy, • eosinophils, • neurokinin-1 receptor, • substance P, • mouse.

Abbreviations: NK = neurokinin,; NKA = neurokinin A,; OVA = ovalbumin,; SP = substance P,; IL = interleukin,; BAL = bronchoalveolar lavage,; NK-1-RA = neurokinin-1 receptor antagonist,; PBS = phosphate-buffered saline,; ELISA = enzyme-linked immunosorbent assay,; IgE = immunoglobulin E,; EFS = electrical field stimulation,; AHR = airway hyperreactivity,; AR = airway reactivity,; NGF = nerve growth factor (NGF).


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Bronchial asthma is one of the most common chronic diseases of the airways. Although the prevalence of asthma in western countries is increasing dramatically, the underlying pathophysiology is not entirely understood. Genetic factors are believed to play an important role in rendering an individual susceptible to bronchial asthma, but environmental factors such as viral and bacterial infections, air pollution, and lifestyle trigger the onset of the disease. One frequently reported factor leading to acute exacerbation of asthma is stress. Various clinical studies have demonstrated an association between distressful experiences and the onset of asthma symptoms (1–3). Because of the observation of intense cross-talk between the neural and immune systems, involved mediators have been under scrutiny.

In the airways, afferent nerve fibers lining the mucosal epithelium secrete tachykinins such as substance P (SP) and neurokinin A (NKA) (4,5). Additionally, immune cells such as eosinophils (6–8) macrophages (9), lymphocytes (10) and dendritic cells (11) are able to secrete these mediators in response to various stimuli. Because of their capacity to induce neurogenic inflammation, bronchoconstriction, and vascular leakage, tachykinins have been proposed to play an important role in the pathophysiology of asthma.

The effects of tachykinins on the airways are mediated by neurokinin (NK) receptors. Two of the three tachykinin receptors, namely, the NK-1 and NK-2 receptors, have been detected in human bronchi and subpleural lung (12). In situ hybridization experiments have indicated that the NK-1 receptor mRNA is expressed in submucosal glands and airway epithelial cells (13). The NK-1 receptor is also present on mast cells (14), lymphocytes (15), and macrophages (16,17) in rodents.

Contraction of airway smooth muscles in the guinea pig is mediated mainly by NK-2 receptors (18,19), whereas the NK-1 receptor mediates proinflammatory and vascular effects (20–22). SP, which acts mainly on the NK-1 receptor, has been shown to degranulate mast cells (23), to induce chemotaxis on eosinophils, neutrophils (24–26), and lymphocytes (27), and to enhance interleukin (IL)-2 production of human and murine T-cells (28,29).

In allergen-induced airway inflammation, tachykinins are released into the airways after exposure to allergen. Higher levels of SP have been found in bronchoalveolar lavage (BAL) fluid of atopic subjects compared with nonatopic individuals. These differences were further increased by allergen provocation (30). In a guinea pig model of allergic airway inflammation, a significant increase in SP and NKA was detected in lung tissues after allergen challenge. In addition, higher expression of preprotachykinin-I mRNA (encoding SP and NKA) was found in the nodose ganglia of allergen-challenged animals (31).

Enhanced expression of the NK-1 receptor (13) as well as of the NK-2 receptor (12) has been observed in lung tissue taken from asthmatic subjects. In another study, asthmatic subjects demonstrated an increased expression of NK-1 receptor, which correlated well with enhanced mucus production in the airway epithelium as compared with normal control (32). Both SP and NKA were shown to cause enhanced bronchoconstriction in asthmatics (33–35) but only SP, and not NKA, induced airway hyperreactivity to methacholine in asthma patients (34,35). This observation suggests that NK-1 receptor stimulation by SP may be important in the development of airway hyperreactivity (AHR).

Stress has been defined as a stimulus that activates both the hypothalamic pituitary adrenal axis and the sympathetic nervous system, thereby inducing neuronal and humoral changes that may finally lead to an adaptation of the individual to the changed environment (36). Animal studies reveal that stress may further lead to the release of neuropeptides, especially the tachykinin substance P, by sensory neurons, and induce or exacerbate an inflammatory process (37–40).

In a murine model of allergen-induced airway inflammation, we have recently demonstrated that exogenously applied stress enhanced the allergen-induced airway inflammation and airway hyperreactivity (41). In the present study, we investigated whether the stress-induced increase in airway inflammation and hyperreactivity is mediated by tachykinins. To do this, we employed the highly specific nonpeptide NK-1 receptor antagonist (NK-1-RA) RP 68750 (42) in a combined mouse model of allergen-induced airway inflammation and stress.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Animals
BALB/c mice were purchased from the Federal Institute for Health Protection of Consumers and Veterinary Medicine (BgVV, Berlin, Germany) and maintained on a 12-hour light/dark cycle. Animal care and experimental procedures were followed according to institutional guidelines and conformed to the requirements of the state authority for animal research conduct (LaGetSi, Berlin).

Protocol of Sensitization
BALB/c mice were sensitized by intraperitoneal (i.p.) injection of 10 µg chicken ovalbumin (OVA, Grad VI, Sigma Chemie, Deisenhofen, Germany) emulsified in 1.5 mg Al(OH)3 (Alum Imject Pierce, Rockford, IL) on days 0, 14, and 21. Mice were challenged twice with OVA aerosol (1% OVA diluted in phosphate buffered saline (PBS)) via the airways on days 26 and 27, as described previously (43).

Stress Treatment/NK-1 Receptor Antagonist Application
After i.p. sensitization, mice were randomized in four different experimental groups (Table 1). Coinciding with the first OVA aerosol challenge, two groups were exposed to sound stress for a single 24-hour period, while the other groups remained undisturbed (Figure 1). The sound stress was emitted by a rodent repellant device (Conrad Electronics, Berlin, Germany) at a frequency of 300 Hz (sound pressure level 75–80 dB) for 1 second each time, in intervals of 15 seconds. The stress device was placed in the mouse cage so that the mice could not escape perception of the sound. While stressed animals experienced exposure to the stressor in their home cage, they were kept in a different room from nonstressed animals so that the groups were separated. One group of nonstressed and one group of stressed animals (groups III and IV, see Table 1) received IP injections of the NK-1 receptor antagonist (NK-1-RA) RP 67580 (Rhone-Poulenc, France, 200 µg/200 µl PBS/mouse) before airway challenges, groups II and I received PBS injections before challenge. In a pilot study, we found that stress did not influence the examined variables airway inflammation (including cytokine production) and airway reactivity in nonsensitized animals; therefore, we did not include naive animals as control groups.


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  		TABLE 1. Experimental Groups and Substances Used for Sensitization, Pretreatment, and Challenge
 


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  		Figure 1. Experimental protocol. After systemic sensitization on days 0, 14, 21 (ovalbumin (OVA) i.p.) mice were challenged twice with OVA aerosol on days 26 and 27. Coinciding with the first challenge, the stress groups (II and IV) were exposed to sound stress for 24 hours, while nonstressed mice remained undisturbed. On days 26 and 27, groups III and IV received an IP injection of the neurokinin (NK)-1 receptor antagonist before airway challenge.

 
Determination of Allergen Specific Antibodies
Blood was sampled from the lateral caudal veins on day 28 of sensitization before animals were sacrificed. Blood was clotted at room temperature and centrifuged. Total IgE and allergen-specific IgE antibody titers were determined in sera by enzyme linked immunosorbent assay (ELISA) as described previously (43). Anti-mouse IgE antibodies were obtained from Pharmingen, Hamburg, Germany. The anti-OVA IgE antibody titers of the samples were related to pooled standard sera that were generated in the laboratory. Detection limits were 1.95 ng/ml for total IgE and 15 EU/ml for anti-OVA IgE.

Bronchoalveolar Lavage
BAL fluid was obtained 24 hours after the second airway challenge (day 28). Animals were sacrificed and tracheas were cannulated. Airways were lavaged twice with 0.8 ml ice-cold PBS, and the total number of cells in BAL fluid was determined as previously described (43). Cytospins were prepared for each sample by centrifugation of 50 µl BAL fluid. After fixation, cytospins were stained with Diff Quik (Dade Behring, Marburg, Germany) and differential cell counts were performed. Cells were classified as neutrophils, eosinophils, lymphocytes, or macrophages using standard morphological criteria and counting at least 100 cells per cytospin.

Determination of Airway Responsiveness
Airway reactivity (AR) was evaluated 24 hours after the last OVA challenge (day 28). AR was assessed in vitro by electrical field stimulation (EFS) of tracheal smooth muscle elements as previously described (43,44). In brief, animals were sacrificed and tracheal smooth-muscle segments were prepared and placed in organ baths containing Krebs-Henseleit buffer (Sigma, Steinheim, Germany), and suspended by triangular supports transducing the force of contractions. EFS was delivered by an HSE-Harvard Stimulator I-4Z (HSE Harvard Electronics, Hugstetten, Germany) using 12-V, 2-millisecond pulse duration and 0.5 to 30-Hz frequencies. Each stimulation was maintained until peak contractile responses were obtained. The contraction in response to EFS was measured, and the frequency that caused 50% of the maximal contraction was calculated from logarithmic plots of the contractile response vs. the frequency of EFS and expressed as ES50. Mean ES50 from nonstressed animals was set as 100%. Seven to 9 mice per group were examined in two independent experiments.

Statistics
Results are presented as mean values ± SEM. Nonparametric tests were used because of nonnormal distribution of the results (Kolmogorov-Smirnov). Significance of differences between groups was determined using the nonparametric Kruskal-Wallis test. Significance was set at p ≤ .05. The Mann-Whitney U test was used for multiple comparisons and the {alpha} level was adjusted by Bonferroni correction.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Airway Inflammation
To determine the cell types of leukocytes infiltrating the animals’ airways, BAL fluids were analyzed. A significantly higher number of total leukocytes was found in sensitized and stressed animals (group II, mean 317 ± 42 x 103/ml) compared with sensitized, nonstressed mice (group I, 176 ± 23 x 103/ml, Mann-Whitney z –2.707, {alpha} = 0.017 for 3 comparisons, p < .007, Figure 2). Cell type identification revealed that the difference between the two groups was predominantly based on an increased number of eosinophils (173 ± 32 x 103/ml vs. 98 ± 16 x 103/ml, Mann-Whitney z –2.242, {alpha} = 0.017 for 3 comparisons, p < .02, Figure 2).



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  		Figure 2. Total leukocyte number and cell type identification in bronchoalveolar lavage (BAL) fluids of OVA-sensitized and airway-challenged BALB/c mice. BAL was performed 24 hours after last allergen aerosol challenge. Stressed mice that were treated with phosphate-buffered saline (PBS) showed significantly higher total cell numbers than nonstressed PBS-injected mice, *p < .017. Application of neurokinin-1 receptor antagonist (NK-1-RA) in stressed mice abrogated the stress-induced increase, #p = .023. Columns represent mean and SEM (Leuko = leukocytes, Lympho = lymphocytes, Eos = eosinophil granulocytes, Gran = neutrophil granulocytes, Macro = Macrophages).

 
The application of NK-1-RA in nonstressed animals had no significant effect on total leukocyte numbers (group III, mean 221 ± 30 x 103/ml, Mann-Whitney z –1.023, p < .3) compared with nonstressed mice (group I). In contrast, the dramatic stress-induced increase in total leukocyte numbers was abrogated when the NK-1-RA was applied shortly before stress/challenge (group IV, mean 195 ± 43 x 103/ml, Mann-Whitney z –2.278, p < .023 vs. stressed animals without NK-1-RA application, group II, Figure 2).

This was associated with a significantly lower number of eosinophils in BAL fluid from stressed animals after NK-1-RA application (group IV, mean 81 ± 16 x 103/ml) compared with stressed animals without NK-1-RA application (group II, Mann-Whitney z –2.523, p < .01, Figure 2)

Airway Responsiveness
The AR was measured by EFS of tracheal smooth-muscle elements. Twenty-four hours after the second allergen challenge, both stressed and nonstressed sensitized mice showed airway reactivity. The ES50 was 1.56 Hz in the nonstressed group I and set as 100% (±15.6%). AR was further increased by 33% (±6.1%) in the stressed group II, and ES50 was reached at a mean of 1.04 Hz (Mann-Whitney z –2.264, {alpha} = 0.017 for 3 comparisons, p < .024, Figure 3).



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  		Figure 3. Effect of stress on airway reactivity measured in ovalbumin (OVA)-sensitized and airway-challenged BALB/c mice. The frequency that caused 50% of maximal contraction (ES50) was calculated. Mean ES50 from the nonstressed group I was set as 100%. Airway reactivity was higher in stressed mice treated with phosphate-buffered saline (PBS) compared with nonstressed mice, #p = .024. Application of neurokinin-1 receptor antagonist (NK-1-RA) in stressed mice significantly abrogated the stress-induced increase. *p < .017. Indicated are mean and SEM from 7 to 9 mice per group.

 
When the NK-1-RA was applied in nonstressed animals (group III) a 15% reduction (±16.6%) of the AR was detected (ES50 1.79 Hz) compared with group I, without reaching significance (Mann-Whitney z –0.689, p < .49). In stressed animals, the application of the antagonist resulted in a significant decrease of AR by 35% (±11.4%, group IV; ES50 1.58 Hz, Mann-Whitney z –2.430, p < .015) compared with stressed animals without treatment (Figure 3).

OVA Sensitization and Immunoglobulin Synthesis
BALB/c mice sensitized to OVA by intraperitoneal injections developed high anti-OVA IgE antibody titers and increased total IgE as evaluated by ELISA (groups I – IV, Table 2). No difference was detected between the four sensitized groups (IgE Kruskal-Wallis 0.193; p = .979; OVA IgE Kruskal-Wallis 2.719, p = .437).


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  		TABLE 2. Blood Serum Immunoglobulin Titers in BALB/c Micea
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 ACKNOWLEDGMENTS
 REFERENCES
 
The stress response in a healthy organism is generally viewed as a protective reaction to an external threat. However, under certain circumstances, such as in the presence of underlying pathologies, these reactions might not only be ineffective, but may even actually worsen a given condition. We have recently shown in a combined mouse model of stress and allergen-induced airway inflammation that the application of sound stress enhances airway inflammation and increases airway reactivity (41). Here we demonstrate that the effect of stress-aggravated airway inflammation and hyperreactivity is mediated in part by the NK-1 receptor.

Airway Inflammation
In patients with bronchial asthma, increased total leukocyte and eosinophil numbers in bronchial biopsies and in bronchoalveolar lavage fluid testify to airway inflammation (45–47). Similarly, in murine models, allergic airway inflammation can be assessed by measurement of these parameters.

After allergen sensitization and challenge, stressed animals showed a marked influx of leukocytes in the airways at significantly higher levels than in nonstressed mice. This stress-induced inflammatory increase was abrogated by the NK-1-RA.

The main ligand for the NK-1 receptor is the tachykinin substance P (SP), which has been shown to be up-regulated in stressful situations in the central nervous system (48) and other tissues. Studies in mice have indicated that substance P is involved in stress-mediated abortion (37). In rats, acute immobilization stress triggered mast cell activation and degranulation via SP released from primary afferent fibers in the skin (40) and the bladder (39). Neonatal denervation of afferent SP-containing nerve fibers with capsaicin reduced stress-induced activation of mast cells, which appear to play a significant role in the pathophysiology of stress-sensitive skin disorders and interstitial cystitis. Likewise, the effectiveness of NK-1-RA in reducing airway inflammation in stressed animals suggests a stress-induced upregulation of tachykinins in the model presented here.

Although increased amounts of tachykinins have been detected in the airways of asthmatic individuals (30,49), there has been debate about the possible increase in number of SP-containing nerves in individuals with asthma. In tissue obtained from autopsy, after lobectomy or from bronchoscopy, both the number and the length of SP-immunoreactive nerve fibers were increased in airways of subjects with asthma, when compared with airways of subjects without asthma (50). However, Howarth and co-workers could not identify any SP-containing nerves in endobronchial biopsies from patients with mild asthma (51). More recently, Chanez and colleagues did not find evidence of an increase in the number of SP-containing nerves in asthma (52). Nevertheless, there remains strong functional evidence that in large mammals the bronchi are innervated by neuropeptide-containing sensory nerves (53–56). This suggests that the failure to find SP-positive fibers may have been methodological (57). Standard histology, which uses thin sections, is not suited to the following of nerve pathways, which have a complex three-dimensional arrangement. Using confocal laser scanning microscopy, Lamb and Sparrow demonstrated the distribution of epithelial SP-immunoreactive nerves in human bronchi (57). In the airways, NK-1 receptors are localized to bronchial vessels, bronchial smooth muscle, epithelial cells, and submucosal glands (13,58), but NK-1 receptors have also been demonstrated on immune cells (14–16,59). The observed effect of stress on cell influx into the airways might be a result of tachykinins acting on structural cells of the lung, or a consequence of their influence on immune cells. A wealth of data demonstrate an influence of SP on structural tissues in the lung. SP stimulates mucus secretion from submucosal glands in human airways in vitro (60–62). Proliferation and chemotaxis of human lung fibroblasts after SP stimulation suggest that tachykinins may contribute to the fibrotic process in chronic asthma (63). Inhaled SP increases microvascular leakage and lung resistance in guinea pigs (62). Baluk and co-workers (64) have shown in vivo that SP induces adhesion of neutrophils and eosinophils in blood vessels of rat tracheal mucosa and that this effect is mediated by NK-1 receptors.

On the other hand, in vitro data have demonstrated a significant action of SP on immune cells. SP activates and degranulates mast cells, leading to the release of proinflammatory mediators (23,65). In healthy subjects, SP enhances lymphocyte proliferation (66) and IL-2 production (28). Furthermore, SP induces chemotaxis in neutrophils, eosinophils, monocytes, and lymphocytes in vitro (24–27,67). Further studies are necessary to determine the relative importance of different cell populations in the response to stress-induced tachykinins.

Tachykinin receptor antagonists have been tested extensively in rodent models of inflammatory responses, demonstrating an effect of NK-1 receptor blockage on allergen-induced airway inflammation. Recently, Kaltreider and co-workers showed the inhibitory effect of NK-1-RA CP-96,345 on antigen-induced influx of granulocytes and lymphocytes in BAL fluid, in a murine model of immune inflammation in the lung (17). In a guinea pig model, the NK-1-RA SR140333 significantly inhibited antigen-induced infiltration of eosinophils, neutrophils, and lymphocytes (68). On the other hand, Costello and co-workers (69) have found that the NK-1-RA induced inhibition of antigen-induced infiltration of other immune cells, but only slightly reduced airway eosinophilia. This difference might be due to different species, treatment protocols, or the NK-1-RA used. The above-mentioned observations are in line with the present study, which by applying an external stressor has provided additional information about the specific effects of antagonizing NK-1 receptors in the airways. The NK-1-RA has abrogated the component of airway inflammation that equaled the amount of cell influx induced by sound stress. Therefore, the effect of NK-1-RA in airway inflammation might also depend on the level of stress experienced by the animals in the different experimental protocols.

Based on our recent data, the question arises of how stress might lead to an upregulation of SP in the airways. Stress and stress-induced activation of the hypothalamic–pituitary–adrenal axis induce various mediators involved in the execution of stress effects. After external stress, nerve growth factor (NGF) has been found to be increasingly expressed (70,71). Aggressive behavior, a form of social stress, has been demonstrated to increase serum and hypothalamic NGF levels (72–74). NGF has been shown to induce SP in airway sensory nerves (75); thus, exposure to sound stress may lead to an upregulation of SP in the airways via NGF. Future investigation will identify the exact role NGF plays and other mediators involved in the transmission of stress-induced effects.

Airway Reactivity
Much of the current understanding of the mechanisms of allergic airway inflammation stems from studying animal models, especially murine models (76,77). Many of the therapeutic targets have emerged from studies in murine models, including cytokine targets or their receptors, mediator inhibitors or signaling molecules, and even recent trials with immunostimulatory sequences were derived from basic studies in mice (78). However, as is true for every model, the murine models have their limitations. In particular, the modeling of airway hyperreactivity and the methods used for its measurement have been questioned recently (79,80). In this study, we used an ex vivo technique to examine the contractility of tracheal smooth muscle stimulated by electric impulses. This technique is best suited to dissecting neuronal regulation of the airways (44).

Confirming the results of our previous study, we found that stress increases AHR in sensitized and challenged mice (41). Enhanced AHR was attenuated by using a NK-1-RA in sensitized and challenged stressed animals, indicating that pathways using the NK-1 receptor might also be involved in stress-related increase of AHR; this is a result of either direct neuronal involvement or of the above-discussed NK-1 receptor-linked increase in airway inflammation.

Although ample data have suggested that NK-1 receptors mediate events in early and late allergic inflammatory reactions, conflicting data exist concerning the role of NK-1 in AHR. A relaxing effect mediated by NK-1 receptors has been described for smooth-muscle cells in mouse (81) and rat (82,83) airways under the condition that tracheal elements were artificially precontracted. On the other hand, Tournoy and co-workers have shown that in NK-1 receptor –/– mice, tracheal contractility triggered by EFS was significantly lower as compared with NK-1 wt controls (84). They found decreased acetylcholine release from the airways of NK-1 receptor –/– mice. Pretreatment with the NK-1-RA SR 140333 significantly reduced contractility in wt, but not in –/– animals, indicating that the NK-1 receptor augments cholinergic neurotransmission in mouse trachea. These findings are in line with the present data, where a contractility-reducing effect was found with NK-1-RA application. A possible mechanism has been suggested by Costello, who demonstrated that the NK-1-RA CP 99994, SR 140333, and CP 96345, when given before antigen challenge, prevented the development of vagal hyperreactivity and neuronal muscarinic M2 receptor dysfunction in sensitized guinea pigs, without influencing airway eosinophilia (69).

Only few clinical data are currently available on the effect of tachykinin NK-1 receptor antagonists on allergic bronchial asthma. Studies have focused on the antagonist’s effect on bronchoconstriction, which has been rather poor (85,86), whereas influence on airway inflammation has not been examined. The results of the present study suggest that NK-1 receptor antagonists might attenuate the stress-induced component of airway reactivity. Further studies will be necessary to provide evidence for a similar regulation in humans, possibly resulting in new treatment options.

Many data indicate the severity of airway inflammation to be linked to the expression of AHR. Eosinophilic inflammation is clearly a hallmark of allergic asthma, and considerable evidence suggests that there is an association between pulmonary eosinophil infiltration and AHR in human asthma (87). In murine models of allergic airway inflammation, a temporal association between Th2 cytokine production, tissue eosinophil infiltration and activation, and both the development and resolution kinetics of AHR has been identified (88). A causal relation has been suggested by blocking experiments, in which prevention of eosinophilic airway inflammation with anti-IL-5 before airway allergen challenge also prevented AHR (89). Thus, in the present model, NK-1 receptor-mediated increased airway inflammation in stressed animals might have led to increased AHR.

Immunoglobulins
No differences in total and allergen-specific IgE levels have been found in this study. IgE production was initialized by repeated i.p. sensitization and boosted by OVA aerosol challenge. Stress was applied at the time of aerosol challenge, when IgE production was already under way. The time elapsed between stress induction and analysis was too short to observe differences in IgE production.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
ACKNOWLEDGMENTS
 REFERENCES
 
In conclusion, our work provides further evidence that stress-induced changes mediated by NK-1 receptors play a crucial role in exacerbation of allergic airway inflammation and airway reactivity.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 ACKNOWLEDGMENTS
REFERENCES
 
This study was supported by a grant from the German Research Association to Dr. Joachim (DFG Jo 365/2–1).

We thank Dr. Otto Walter for his expertise in statistical analysis.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 ACKNOWLEDGMENTS
 REFERENCES
 

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