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Psychosomatic Medicine 65:811-815 (2003)
© 2003 American Psychosomatic Society

ORIGINAL ARTICLES

Stress Enhances Airway Reactivity and Airway Inflammation in an Animal Model of Allergic Bronchial Asthma

Ricarda A. Joachim, MD, David Quarcoo, MD, Petra C. Arck, MD, Udo Herz, PhD, Harald Renz, MD and Burghard F. Klapp, MD

From the Department of Internal Medicine, Charité-Campus Virchow, Humboldt University (R.A.J., P.C.A., B.F.K.), Berlin; Department of Pediatrics, Charité-Campus Virchow, Humboldt University (D.Q.), Berlin; and Department of Clinical Chemistry and Molecular Diagnostic, Philipps-Universität (U.H., H.R.), Marburg, Germany.

Address reprint requests to: Ricarda Joachim, MD, Charité-Campus Virchow, Biomedizinisches, Forschungszentrum, R. 2.0594, Augustenburger Platz 1, 13353 Berlin, Germany. Email: ricarda.joachim{at}charite.de


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: Despite the long-standing clinical assumption that stress and asthma morbidity are associated, convincing experimental evidence on mechanisms has been unavailable. A wide range of immunological, endocrinological, and neuronal pathways are known to mediate and modulate a systemic stress response. Interestingly, most of these mediators play a crucial role in initiating and perpetuating symptoms associated with bronchial asthma. To explore potential mechanisms linking stress to asthma exacerbation we developed an animal model that combines allergic airway inflammation and exposure to stress.

METHODS: CBA/J mice were sensitized by intraperitoneal injection of ovalbumin (OVA) and challenged with OVA aerosol via the airways. Additionally, some mice were stressed by exposure to an ultrasonic stressor. Airway hyperreactivity (AHR) was measured in vitro by electric field stimulation (EFS) of tracheal smooth muscle elements. Bronchoalveolar lavage fluid (BAL) was obtained and cell numbers determined. Cytokine levels of IL-4, IL-5, and IFN-{gamma} in BAL were determined by ELISA.

RESULTS: Our findings demonstrate that exogenously applied stress dramatically enhances airway reactivity in OVA-sensitized and challenged mice. Further, stress significantly increases allergen-induced airway inflammation identified by increased leukocyte (ie, eosinophil) numbers in bronchoalveolar lavage fluids.

CONCLUSIONS: We found further evidence that stress can indeed exacerbate airway hyperreactivity and airway inflammation in an animal model of allergic bronchial asthma and now introduce a novel murine model to identify stress-triggered pathways, including mediators as neurohormones, neuropeptides, and markers of inflammation.

Key Words: sonic stress, • allergic asthma, • airway inflammation, • airway hyperreactivity, • mouse model.

Abbreviations: AHR = airway hyperreactivity; AR = airway reactivity; BAL = bronchoalveolar lavage; EFS = electrical field stimulation; ELISA = enzyme linked immuno sorbent assay; ES50 = frequency of half maximal tracheal contraction; GM-CSF = granulocyte-macrophage colony-stimulating factor; IFN = Interferon; IL = Interleukin; IP = intraperitoneal; LaGetSi = Landesamt für Arbeitsschutz, Gesundheitsschutz und technische Sicherheit Berlin (authority for animal research conduct); OVA = Ovalbumin; PBS = phosphate buffered saline; Th1/Th2 = T helper cell type 1 and 2; TNF = tumor necrosis factor; VCAM-1 = vascular cell adhesion molecule-1


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Stress has long been suspected as a possible cause of acute asthma exacerbation in humans, even though conclusive experimental evidence is still lacking. For example, anecdotal reports have often associated stressful life events with the onset of reversible airway constriction besides other extrinsic stimulant-like allergens, chemical irritants, acute airway infection, cold air, and exercise. Stress has been associated with asthma morbidity by clinical observation and epidemiological research (1–3), but little is known about its underlying mechanisms.

Stress as a precipitating or provoking factor in men has been implicated in diseases as varied as inflammatory bowel disease (4, 5), cancer (6, 7), and atopic dermatitis (8, 9). There is increasing evidence from psychoneuroimmunological studies in both animals and humans that stress results in concomitant activation of cells from the nervous, endocrine, and immune systems and in the release of diverse biologically active compounds, including glucocorticoids, catecholamines, neuropeptides, and cytokines (10). Many of these have been shown to play a critical role in the pathogenesis of asthma and might be the key for understanding the complex regulation processes that are involved. An animal model was developed to study the psychoneuroimmunological network in a controlled environment. For this purpose we combined two established models (11, 12)–a model of allergic airway inflammation and a stress mouse model. The murine model of allergic airway inflammation reflects major pathophysiological findings of allergic bronchial asthma, namely airway reactivity and airway inflammation (11, 13, 14).

In asthmatic patients, enhanced airway reactivity (AHR) to unspecific stimuli and eosinophilic airway inflammation correlate well with the severity of the disease (15, 16). It has been suggested that both in asthmatic patients as in animals subjected to allergen-induced airway inflammation the development of AHR is based on abnormalities of the neural system of the airways (17–20). Of the different methods to assess airway reactivity in mice, the ex vivo technique of electrical field stimulation of tracheal smooth muscle segments used in this study is best suited to dissect neuronal dysregulation of the airways (21).

In patients with bronchial asthma, increased total leukocyte and eosinophil numbers in bronchial biopsies and in bronchoalveolar lavage fluid are proof of an increased airway inflammation (22–24). Similarly, in mice allergic airway inflammation can be assessed by measuring these parameters.

A wealth of data demonstrates an important role for T helper type 2 cell (Th2) in the allergic inflammation. These activated cells release the cytokines interleukin (IL)-4 (25) and IL-13 (26), which lead to the production of allergen-specific IgE antibodies by plasma-cells, and IL-5, a major regulating factor for growth, differentiation, and activation of eosinophils (27–30). Stress has been proposed to enhance the allergic inflammatory response by altering the Th1/Th2 balance (31).

Sound stress as an effective inductor of stress reactions has been used in various animal models (12, 32–34). The apparatus and the stress protocol used in this study have been adopted from a murine model of stress-induced abortion. Here, a 24-hour period of sound stress induces maximal abortion rates in pregnant CBA/J mice (12). Data from pilot studies in the model of allergen-induced airway inflammation combined with exogenously applied stress suggested that a 24-hour period of sound stress induces the maximal reaction in this model.

The aim of this study was to investigate whether and how exogenously applied stress influences the airway reactivity and to test the hypothesis that stress acts through increased airway inflammation in OVA-sensitized and provoked mice.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animals
CBA/J mice were purchased from Charles River (Sulzfeld, Germany) and maintained in an animal facility with 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
CBA/J mice were sensitized by intraperitoneal injection (IP) 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, USA) on day 0, 14, and 21. To induce a strong local inflammatory response with increased leukocyte numbers in the bronchoalveolar lavage (BAL), mice were challenged twice with OVA aerosol (1% OVA diluted in PBS) via the airways on day 26 and 27, as described previously (11)(Fig. 1).



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  		Fig. 1. Experimental protocol. After systemic sensitization on days 0, 14, and 21, OVA IP mice were challenged twice with OVA aerosol on days 26 and 27. Coinciding with the first challenge, the stress group was exposed to sound stress for 24 hours while controls remained undisturbed.

 
Stress Treatment
After IP sensitization, mice were randomized into two different experimental groups. Coinciding with the first OVA aerosol challenge, one group of mice was exposed to sound stress for a single 24-hour period, while control animals remained undisturbed (Fig. 1). The sound stress was emitted by a rodent repellant device (Conrad Electronics, Berlin, Germany) at a frequency of 300 Hz 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 control animals so that the two groups were separated.

Determination of Allergen-Specific Antibodies
Blood was sampled from the lateral caudal veins on day 0 and 25 of sensitization (ie, before stress application). 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 (11). 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.

Determination of Airway Responsiveness
Airway reactivity (AR) was evaluated 24 hours after the last OVA challenge (day 28). AR as well as airway inflammation reflected by numbers of infiltrating immune cells into the airways have been shown to be maximal between 24 to 48 hours after the last allergen challenge (personal communication, E. Hamelmann). AR was assessed in vitro by electric field stimulation (EFS) of tracheal smooth muscle elements as previously described (11, 21) . In brief, animals were sacrificed and tracheal smooth muscle segments were prepared and placed in organ baths containing Krebs-Henseleit buffer (Sigma, Germany), and suspended by triangular supports transducing the force of contractions. EFS was delivered by a Grass S48 stimulator using 12V, 2 ms 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 stimulus was measured and the frequency that caused 50% of the maximal contraction was calculated from logarithmic plots of the contractile response versus the frequency of EFS and expressed as ES50. Mean ES50 from nonstressed animals was set as 100% and compared with mean ES50 from stressed animals.

Bronchoalveolar Lavage
Bronchoalveolar lavage (BAL) was obtained 24 hours after the second airway challenge (day 28).

Animals were sacrificed and tracheas cannulated. Airways were lavaged twice with 0.8 ml ice-cold PBS and the total number of cells was determined as previously described (11). 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. Cell-free lavage fluids were stored at -20°C until further analysis.

Determination of Cytokines in Bronchoalveolar Lavage Fluids
Interleukin (IL) -4, IL-5, and Interferon (IFN) {gamma} content of BAL fluids was determined by ELISA as described previously (11). Antibodies were obtained from Pharmingen, Hamburg, Germany. Detection limits were 16 pg/ml for IL-4, 27 pg/ml for IL-5, and 40 pg/ml for IFN-{gamma}.

Histological Evaluation
For assessment of airway inflammation, lungs were fixed in situ with 4% formaldehyde via the trachea, then removed and stored in formaldehyde. Paraffin-embedded sections were stained with hematoxylin and eosin (H & E).

Statistics
Significance of differences between groups was determined using the nonparametric Mann-Whitney U-test. Significance was set at p < .05. Results are presented as mean values.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Airway Reactivity
The AR was measured by electric field stimulation (EFS) of tracheal smooth muscle elements. It was previously shown that the base-line ES50 value (electrical stimulation [Hz] required to induce half-maximal constriction of tracheal smooth muscle segments) of untreated mice is around 4 Hz (11, 21). Twenty-four hours after the second allergen challenge both stressed and nonstressed sensitized mice showed airway reactivity. The ES50 was 2.1 Hz in the nonstressed group (N = 8) and set as 100%. AR was further increased by 40% in the stressed group, as ES50 was reached at a mean of 1.3 Hz (N = 8, p < .05) (Fig. 2).



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  		Fig. 2. Effect of stress on AHR measured in OVA-sensitized and airway-challenged CBA/J mice. Indicated are mean and SEM from stressed (N = 8) and nonstressed (N = 8) sensitized CBA/J mice. The frequency that caused 50% of maximal contraction (ES50) was calculated. Airway contractility is expressed as percent of nonstressed control (2.1 Hz). * p < .05.

 
Airway Inflammation
To determine the cellular constituents of leukocytes infiltrating the animals’ airways, lung tissues and bronchoalveolar lavage (BAL) fluids from stressed and nonstressed OVA-sensitized animals were analyzed. Morphologically, all sensitized animals developed signs of airway inflammation with infiltrating mononuclear cells around small blood vessels and lower conducting airways after allergen challenge.

In the BAL fluid a significantly higher number of total leukocytes was found in sensitized and stressed animals (mean 276 x 103/ml, N = 12) compared with sensitized, nonstressed control mice (199 x 103/ml, N = 9, p < .05). Cell differentiation by Diff Quik staining revealed that the difference between the two groups was predominantly based on an increased number of eosinophils (169 x 103/ml vs. 101 x 103/ml) (Fig. 3).



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  		Fig. 3. Total leukocyte number and cell differentiation in BAL fluid of OVA-sensitized and airway-challenged CBA/J mice. Indicated are mean and SD from stressed (N = 12) and nonstressed (N = 9) sensitized animals (Leukos = leukocytes, Lymphos = lymphocytes, Eos = eosinophil granulocytes, Neutros = neutrophil granulocytes, Mono/Mac=Monocytes/Macrophages). * p < .05.

 
To characterize inflammation markers, the cytokines Interleukin (IL)-4, IL-5, and Interferon (IFN)-{gamma} were measured in BAL fluids by ELISA. There was no difference between nonstressed and stressed animals with respect to IL-5 (75 ± 28 pg/ml vs. 60 ± 60 pg/ml), whereas the levels of IL-4 and IFN-{gamma} remained below detection limits.

Ovalbumin Sensitization and Immunoglobulin Synthesis
CBA/J mice sensitized to OVA by intraperitoneal injections developed high anti-OVA IgE antibody titers and increased total IgE as evaluated by ELISA before stress application (Table 1).


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  		TABLE 1. Assessment of Immunoglobulin Production in CBA/J Mice before and after OVA Sensitization
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the present study we demonstrate that exogenously applied stress dramatically enhances airway reactivity in OVA-sensitized and challenged mice. Additionally, the application of stress aggravates the allergen-induced airway inflammation. The increased eosinophil counts in BAL fluid of stressed mice point to a possible mechanism linking stress to the exacerbation of asthma symptoms.

Stress and Airway Reactivity
Assessing the airway reactivity by electrical field stimulation (EFS), we show for the first time that exogenously applied stress increases hyperreactivity of the airways (AHR) in allergen-sensitized and provoked mice. The changes in AHR might originate in an enhanced airway inflammation reflected by higher numbers of inflammatory cells in airways of stressed animals. It has been shown that eosinophils are recruited to the airways and the airway nerves after antigen challenge in animals and in human individuals with asthma (35,36). Prevention of eosinophil recruitment to the airway nerves also prevented airway hyperreactivity in an animal model (37).

On the other hand there is ample data suggesting that AHR is mediated via neuronal pathways and might exist independently of AI. In animal models that lack sensory neurons due to Capsaicin pretreatment AHR does not develop (38, 39), whereas AHR can be detected in asthmatic individuals without signs of airway inflammation (40) or with long-term suppression of inflammation (41). Thus stress might exert a direct influence on neuronal structures resulting in enhanced AHR.

The employed method of EFS utilizes electrical impulses to induce muscle constriction via neuronal structures of the tracheal smooth muscle segments, namely cholinergical and sensory neurons (21). Because of the anatomical seizure of the tracheal segment we can exclude higher neuronal structures as causative for the bronchomotoric action. The exact identification of the neuronal structures that are influenced by stress remains the subject of further investigation.

Stress and Airway Inflammation
Airway inflammation is one of the main characteristics of bronchial asthma, whereby eosinophils and lymphocytes infiltrate the lung tissue and the air-conducting space. Our findings that stress increases eosinophil counts in BAL fluid correlate well with the results of a recently published human study, in which stressful school examinations enhanced eosinophilic airway inflammation of asthmatic college students after antigen challenge (42). The recruitment and migration of eosinophils into inflamed tissue after antigen challenge is thought to be regulated by cytokines and chemokines. In allergic diseases the Th2 cytokines IL-4 and 5 result in an increased allergen-specific IgE production and the migration of leukocytes, namely eosinophils to inflammatory loci through the interaction of the adhesion molecule VCAM-1 (43), the promotion of eosinophil bone marrow precursor cell differentiation, and the prevention of apoptosis (30, 44). On the other hand, several studies have demonstrated reduced production of IFN-{gamma} by T-cells in asthmatic patients (45, 46). In mice aerosolized IFN-{gamma} inhibits allergen-induced eosinophilic airway inflammation, whereas targeted disruption of the IFN-{gamma} receptor results in a prolonged airway eosinophilia in response to allergen (47). Interestingly, when analyzing the cytokine levels of BAL fluids we did not detect differences between stressed and nonstressed groups. This might be due to the time point of analysis because the cytokine summit precedes the influx of immune cells, or the fact that we examined the spontaneous cytokine secretion without prior stimulation of BAL cells. However, it should also be considered that neuronal factors like tachykinins or neurotrophins, which could be the result of a modified neuronal system (18), might be responsible for the observed phenomena without interfering in cytokine levels.

Stress and Th1/Th2 Profile
Today, allergic immune responses are considered to be caused by a Th1/2 imbalance with an increase in Th2 cytokines. Stress has been discussed as a means to alter the Th1/Th2 cytokine balance. Depending on the experimental set-up, there are research groups that found stress to be associated with a Th1-like pro-inflammatory cytokine profile such as TNF-{alpha}, IL-1, and IFN-{gamma} (12, 48, 49). Other studies have shown an opposite effect of stress with a shift toward Th2-type responses (50, 51). In contrast to many published data investigating the sole influence of stress on the Th1/Th2 cytokine balance, we modulated an ongoing Th2-type inflammatory process by applying external stress. Therefore, observing the sum of both factors–the allergic inflammation and the impact of stress–our data suggests an exaggerated Th2-driven allergic response in stressed animals.

In conclusion, we have established an animal model that can be used as a tool to investigate the combination of allergic airway inflammation with the application of exogenous stress. We found stress produced a profound influence on two major aspects of bronchial asthma, namely airway inflammation and airway reactivity, suggesting that stress impacts on a central regulating unit of this disease.

Received for publication July 29, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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