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American Journal of Respiratory and Critical Care Medicine Vol 165. pp. 1280-1284, (2002)
© 2002 American Thoracic Society

Original Article

Effect of Age on Allergen-induced Structural Airway Changes in Brown Norway Rats

Els Palmans, Nele J. Vanacker, Romain A. Pauwels and Johan C. Kips

Department of Respiratory Diseases, Ghent University Hospital, Ghent, Belgium

Correspondence and requests for reprints should be addressed to Els Palmans, M.D., Department of Respiratory Diseases, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. E-mail: els.palmans{at}hogent.be


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
It remains to be fully established whether allergen-induced airway inflammation and remodeling are influenced by age. The aim of the present study was to compare allergen-induced airway changes in young and adult rats. Brown Norway rats were sensitized at 4 weeks of age (young) or 13 weeks of age (adult) and exposed to aerosolized ovalbumin (OA) or phosphate-buffered saline for 2 weeks. In both age groups OA exposure induced an increase in OA-specific Immunoglobulin E and in the number of peribronchial eosinophils. OA-challenged animals also developed an increase in total airway wall area, enhanced fibronectin deposition, and goblet cell hyperplasia. Both inflammatory and structural alterations were more pronounced in the airways of young compared with adult OA-exposed rats. The number of peribronchial eosinophils was increased in young animals (685.4 ± 75.0 versus 389.9 ± 37.8/mm2 in adult rats; p < 0.001). A higher degree of goblet cell hyperplasia was observed in young rats (65.37 ± 4.68 versus 34.74 ± 3.68/mm basement membrane in adult rats; p < 0.001) and area of fibronectin deposition in the airway wall was higher in young compared with adult animals (5.08 ± 0.46 versus 3.62 ± 0.29 µm2/µm basement membrane; p < 0.005). In conclusion, in young rats airways are more susceptible to allergen-induced inflammatory and structural airway changes.

Key Words: age • airway • inflammation • rat • structure


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Asthma is an inflammatory disorder of the airways, and several studies have confirmed a similar type of inflammation in children and adults with asthma (1–3). However, it is unknown whether developing airways in children are more prone to the development of allergic inflammation, nor has it been fully established whether a similar environmental exposure will induce a similar severity of airway inflammation in children and adults. Part of the inflammatory process in asthmatic airways consists of structural airway changes, the so-called airway remodeling. This is thought to result from attempts at repair in response to repetitive bouts of allergen-induced inflammation and tissue injury (4). Again, it is unknown whether developing airways in children are more susceptible to remodeling. This aspect would seem particularly relevant for the natural history of asthma as remodeling is thought to have important functional consequences on lung function, contributing to loss of airway distensibility and bronchial hyperresponsiveness (5, 6). Both low baseline FEV1 and severe bronchial hyperresponsiveness are known risk factors for the persistence of asthma into adulthood (7–9).

Representative in vivo animal models might provide interesting information in this respect. We and others have previously shown that structural airway changes can be induced in Brown Norway (BN) rats after sensitization and chronic exposure to the allergen ovalbumin (OA) (10–12). In the present study we compared the allergen-induced airway changes in prepubertal and adult rats. The results indicate that sensitized rats exposed to allergen before they reach puberty develop more profound inflammatory and structural airway changes.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Immunization and Exposure of Animals
Specific pathogen-free, male BN rats (Rattus norvegicus; Harlan CPB, Zeist, The Netherlands) were actively sensitized by intraperitoneal injection of ovalbumin (OA) (4 mg/kg body weight) (Grade III; Sigma, Poole, Dorset, UK) together with Al(OH)3 (800 µg/kg body weight) in 0.5 ml of 0.9% NaCl on Day 0 and Day 7. On Day 0 one group of rats (n = 20) was 4 weeks of age (young rats) and another group of rats (n = 19) was 13 weeks of age (adult rats). From Day 14 to Day 28 animals were exposed seven times to aerosolized OA or phosphate-buffered saline (PBS).

Outcome Measures
On Day 29, 24 hours after the last exposure to OA or PBS, rats were weighed before instrumentation and anesthetized by intraperitoneal injection of 60 mg/kg pentobarbital (Sanofi, Libourne, France). Bronchoalveolar lavage was performed for analysis of total and differential cell count; blood was collected for the measurement of OA-specific Immunoglobulin E (IgE).

Histological analysis of lung tissue.
After lavage, lungs were fixed with 4% paraformaldehyde, slices from different lobes were embedded in paraffin, and cut in 2-µm-thick sections. Histological changes were evaluated on sections stained with hematoxylin and eosin. In addition, Congo red was used to determine the number of eosinophils in the bronchial wall and the number of goblet cells in epithelium was assessed in sections stained with periodic acid–Schiff reagent. Fibronectin was stained immunohistochemically. Details of the methodology used have been previously described (10).

Analysis of airway morphometry and fibronectin deposition.
Hematoxylin- and eosin-stained tissue sections were examined by light microscopy and morphometric measurements were performed on three sections per animal, using a Zeiss Axiophot microscope (Zeiss, Oberkochen, Germany) as previously described (10). The perimeter of epithelial basement membrane (Pbm) and the total bronchial wall area (WAt) were measured in all large airways (Pbm > 2 mm) cut in reasonable cross-sections (ratio of minimal to maximal internal diameter greater than 0.5). Smooth muscle area (WAm) was measured by specifically tracing around the smooth muscle bundles.

Fibronectin deposition was examined by light microscopy and quantitative measurements were performed using a computerized image analysis system (LEICA Q500MC; Leica Cambridge, Cambridge, UK). Fibronectin deposition was analyzed in three lung sections per rat as previously described (10). The amount of protein deposited in the total airway wall (WFt) was measured for all large airways cut in reasonable cross-sections.

Data Analysis
Reported values are expressed as means ± standard error of the mean. The weights of young and adult rats were compared with a Mann–Whitney U test. The cellular composition of the bronchoalveolar lavage fluid (BALF) and concentrations of OA-specific IgE in the serum of the different groups were compared via Kruskal–Wallis test for multiple comparisons. When significant differences were observed, pairwise comparisons were made by using a Mann–Whitney U test with Bonferroni corrections.

For analysis of morphometry and fibronectin deposition, the data for the rats in each experimental group were pooled. Measurements were performed in a mean of 27 large airways (range, 24 to 32) for morphometry and in a mean of 23 large airways (range, 17 to 31) for quantification of the fibronectin. To ensure that a similar range of airway sizes was being compared, the frequency distribution of Pbm values between different experimental groups was compared by the Kolmogorov–Smirnov test. The mean values of WAt, WAm, and WFt were normalized to Pbm; the number of goblet cells per millimeter Pbm and the number of eosinophils per square millimeter WAt were compared between the experimental groups, using one-way analysis of variance with post hoc (least significant difference and Scheffé) tests (p values less than 0.05 were considered significant).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Weight
On Day 29, young rats reached a mean weight of 181.0 ± 2.5 g, whereas adult rats weighed 266.6 ± 5.5 g (p < 0.001).

OA-specific IgE
Serum levels of OA-specific IgE were elevated in all sensitized rats exposed to OA compared with control animals (Table 1) . The IgE levels of OA-exposed animals were not different when rats sensitized at 4 weeks were compared with the group of rats sensitized at 13 weeks. Increased levels of OA-specific IgE were observed in adult control animals compared with young control animals (Table 1).


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  		TABLE 1. Ovalbumin-specific immunoglobulin e levels in serum after immunization at different ages and repeated ovalbumin exposure

 
Inflammatory Cell Infiltrate in BALF
More cells were recovered in the BALF from all sensitized and OA-exposed animals compared with those exposed to PBS (Table 2) . In young animals the amount of cells after OA exposure was twice the amount of BALF cells in control animals. In adult rats a 3-fold increase was observed in OA-exposed animals compared with control animals. Moreover, the total cellularity of OA-exposed rats immunized at 13 weeks was significantly increased compared with OA-exposed rats sensitized at the age of 4 weeks (Table 2). The amount of macrophages, eosinophils, and neutrophils changed in both OA-exposed animal groups. In OA-exposed young animals a 3-fold increase in the number of eosinophils was observed compared with PBS-exposed rats ([500.0±121.5] x 103 cells versus [182.4 ± 74.0] x 103 cells; p < 0.05); in OA-exposed adult animals we observed a 10-fold increase in eosinophils ([538.3 ± 85.4] x 103 cells versus [58.1 ± 26.9] x 103 cells in PBS-exposed rats; p < 0.005). The total amount of BALF eosinophils was similar in both age groups ([500.0 ± 121.5] x 103 young rats versus [538.3 ± 85.4] x 103 for adult rats). Total cellularity of BALF was not different between both PBS-exposed control groups. However, the percentage of eosinophils was higher in control rats sensitized at 4 weeks compared with those sensitized at 13 weeks (Table 2).


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  		TABLE 2. Total white blood cell number and cellular composition* in bronchoalveolar lavage fluid

 
Lung Histology
The difference in BALF composition was not reflected by histological analysis. Inflammatory infiltrates were observed in the peribronchial area of sensitized and OA-exposed animals. In addition to mononuclear cells, these infiltrates contained increased numbers of eosinophils. The number of eosinophils was higher around the bronchi of young rats. The number of peribronchial eosinophils was similar in both control groups (Table 3) .


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  		TABLE 3. Number of goblet cells in the epithelium and number of airway wall eosinophilsafter immunization at different ages and repeated ovalbumin exposure

 
There was no epithelial desquamation observed, but OA exposure resulted in goblet cell hyperplasia. The increase in goblet cells was more pronounced in OA-exposed animals immunized at 4 weeks. The number of goblet cells in young and adult control rats was not different (Table 3).

Fibronectin Deposition
Fibronectin deposition in large airways was significantly increased after 2 weeks of allergen exposure (5.08 ± 0.46 versus 1.50 ± 0.26 µm2/µm Pbm in young rats and 3.62 ± 0.29 versus 2.27 ± 0.37 µm2/µm Pbm in adult animals; p < 0.001 and p < 0.01, respectively) (Figure 1A) . The fibronectin deposition after allergen exposure in rats immunized at 4 weeks was higher compared with OA-exposed adult animals (p < 0.005) (Figure 1A). The amount of fibronectin in control animals was similar in both age groups (Figure 1A).



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  		Figure 1. Effect of age at immunization on fibronectin deposition in the airway wall (A) and airway wall area (B) in large airways after OA exposure (closed bars) versus PBS exposure (open bars) (*p < 0.05 versus PBS, +p < 0.01 versus PBS, ++p < 0.001 versus PBS, and §p < 0.005 versus OA immunization at 4 weeks). WAt = total bronchial wall area; Pbm = length of epithelial basement membrane.

 
Morphometry
The total airway wall area was increased in OA-exposed adult animals compared with the control rats (94.04 ± 11.53 versus 73.33 ± 4.27 µm2/µm Pbm; p < 0.05) (Figure 1B). In young animals, the difference in total wall area between control and OA-exposed rats showed a strong trend toward significance (92.89 ± 5.93 versus 70.26 ± 3.89 µm2/µm Pbm; p = 0.056) (Figure 1B). No difference in airway wall thickness was observed between allergen-exposed rats of both age groups. There was no difference between age groups in airway wall thickness in control animals (Figure 1B).

No difference in airway smooth muscle layer thickness was observed between control and OA-exposed adult rats (2.78 ± 0.28 and 2.00 ± 0.26 µm2/µm Pbm, respectively). Although the thickness of the smooth muscle was increased in young animals compared with the adult animals (p < 0.001) no difference was observed between PBS- and OA-exposed young rats (5.83 ± 0.65 versus 4.14 ± 0.55 µm2/µm Pbm).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The main purpose of this study was to evaluate the effect of age on the development of structural airway changes in BN rats after allergen sensitization and exposure. Synthesis of allergen-specific IgE was similar in both OA-exposed groups. However, in young animals sensitization and repeated exposure to aerosolized allergen resulted in the development of more pronounced acute inflammation reflected by increased peribronchial eosinophils as well as more structural alterations, including goblet cell hyperplasia and fibronectin deposition.

Several elements could contribute to the different responses observed in young and adult BN rats. A first potentially confounding factor is a technical one. In view of the weight difference that we observed between young and adult rats, it is likely that the lung size in both groups was also different. We therefore cannot exclude the possibility that airways of slightly different generations are compared between both groups. However, we have previously shown that the extent of alterations in small, medium, and large airways of sensitized BN rats after OA exposure was similar (10). This indicates that allergen-induced airway changes are uniformly distributed throughout the bronchial tree and that comparison of airways in both age groups can provide valid data. In addition, an increased lung size could also result in a larger lung surface being sampled by the BAL procedure. Yet, as was also reported by Yagi and coworkers (13), the total cell number in BALF was not different between young and adult rats. To us, these results indicate that lung size differences do not significantly influence the results obtained.

Another element that needs to be considered is a possible difference in the immune response to sensitization in both age groups. It is known that experimental animals fail to develop helper T cell type 2-induced allergic responses at an older age (13–15). Throughout the age range chosen in the present study, however, the immune response to inhaled allergen is helper T cell type 2 driven (16, 17). The observation that young and adult rats develop similar IgE serum levels is also an indirect argument that differences in the susceptibility of the airway mucosa rather than the immune response explain the observed results.

The pathogenesis of remodeling remains to be established, but it is thought to result from attempts at tissue repair after bouts of repetitive injury caused by allergen inhalation (4). A characteristic feature of allergen-induced acute airway inflammation is the occurrence of airway eosinophilia. The present study indicates that for a same intensity of allergen exposure, the airways of young animals are infiltrated with larger numbers of eosinophils than those of adult rats. A previous study, using a different experimental protocol, reported similar findings (13). Comparative studies of human asthma are hardly available in this respect. The data available indicate that cellular composition of the inflamed airway in children resembles that observed in adults with asthma (1–3). Similarly, analysis of induced sputum in children with asthma showed, as in adults, an increase in the percentage of eosinophils (1, 2). From the limited studies currently available, sputum eosinophilia in untreated children with asthma also falls within a similar wide range compared with adults (1, 3). To what extent this fully reflects tissue eosinophilia is, however, unknown (18). Of note is that in the present study the difference in eosinophils in the airway wall between both age groups was not reflected in BALF counts.

Airways in young rats develop a more pronounced remodeling as indicated by the number of goblet cells and fibronectin deposition. Biopsy studies have confirmed the presence of remodeling in airways of children (19, 20). A preliminary report even indicates that remodeling might be present before the development of asthma symptoms (21). This challenges somewhat the concept that remodeling results from inflammation, but raises the idea that eosinophilic airway inflammation and remodeling might be two independent processes (21). The present study confirms that remodeling is induced by allergen exposure, but obviously does not prove a causal role of the eosinophils in this process.

The age-dependent difference between animals in terms of infiltrating inflammatory cells and structural changes is concordant with observations relating to other repair processes. During healing of cutaneous punch biopsies in humans, the inflammatory response was delayed in adult compared with young subjects (22). In vivo models of wound healing also showed that repair processes are associated with increased amounts of inflammatory cells in young compared with older animals (23, 24). In young rabbits excision of tissue in the ear resulted in a higher amount of proliferative cells in the healing dermis compared with old animals (24). In mice, the inflammatory response to cutaneous incisional wounds was less pronounced in older animals, as was the deposition of the extracellular matrix (ECM) components fibronectin and collagen types I and III (23).

That young animals develop more pronounced remodeling in response to allergen exposure could have profound implications. To date, the functional consequences of remodeling have been related mainly to altered airway behavior (25). Although it is generally assumed that remodeling contributes to bronchial hyperresponsiveness, it has been shown that, depending on the exact extent and location, changes in ECM can also protect against bronchial hyperresponsiveness (10, 26, 27). We have previously reported that the degree of fibronectin deposition after exposing adult rats to OA for 12 weeks is three times higher than in animals exposed for 2 weeks. This coincided with a change from airway hyperresponsiveness at 2 weeks to hyporesponsiveness after 12 weeks of exposure (10). In the present study, we did not measure airway responsiveness. However, the difference between the intensity in fibronectin deposition is only 1.5. We would therefore speculate that this relatively limited difference is insufficient to significantly influence lung function.

ECM proteins in the airway wall not only determine the structural integrity and mechanical properties of the airway wall, they can also interact with inflammatory cells (28). The components of the ECM can affect migration, proliferation, differentiation, and activation state of inflammatory cells and enhance their survival (29–33). Modulation of the ECM by remodeling its structure can therefore affect the behavior of cells residing within it, and the changes in ECM composition could have an important influence on the persistence of the allergic inflammation, anchoring it firmly within the airway wall. The matrix adhesion molecule fibronectin promotes recruitment and attachment of cells (34). As in the current model, asthmatic airways have increased levels of fibronectin (35, 36). Fibronectin is known to be released by proinflammatory cytokines and is thought to play an important role in epithelial repair (37). In addition, however, the presence of fibronectin in the ECM facilitates the adhesion of inflammatory cells and prolongs eosinophil survival (32). The more pronounced remodeling in response to allergen exposure at a young age might therefore increase the vulnerability of the lower airways to the development of a persistent allergic inflammation. This also fits with the observation that sensitization at a young age increases the likelihood of developing asthma in adulthood compared with those who become sensitized later (7, 38, 39). As remodeling promotes the ongoing inflammatory process, the current observations further strengthen the importance of avoiding stimuli that can induce remodeling in young children; this includes not only allergens, but also stimuli such as cigarette smoke (40).

In vivo animal models obviously have limitations, one of which is to what extent the observations can be extrapolated to human asthma. However, the observations that allergen avoidance measures are far more effective at a young age than in adults would seem to support the idea that the increased susceptibility to allergen-induced airway changes observed in the present model might also apply in humans.


   Acknowledgments
 
The authors thank E. Castrique, C. Snauwaert, K. De Saedeleer, A. Neesen, I. De Borle, and M.-R. Mouton for technical assistance.


   FOOTNOTES
 
Supported in part by the Concerted Research Initiative of Ghent University (grant G.O.A. 98-6) and GlaxoWellcome (courtesy of Dr. Malcolm Johnson). N. J. V. is funded by the FWO-Flanders (Fund for Scientific Research, Flanders).

Received in original form September 5, 2001; accepted in final form February 11, 2002


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 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
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