ToxSci Advance Access originally published online on April 11, 2006
Toxicological Sciences 2006 92(1):321-328; doi:10.1093/toxsci/kfj191
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Topical Application versus Intranasal Instillation: A Qualitative Comparison of the Effect of the Route of Sensitization on Trimellitic Anhydride–Induced Allergic Rhinitis in A/J Mice
* Department of Pharmacology and Toxicology and Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan 48824
2 To whom correspondence should be addressed at 315 Food Safety and Toxicology Building, Michigan State University, East Lansing, MI 48824. Fax: (517) 432-3218. E-mail: kamins11{at}msu.edu.
Received January 30, 2006; accepted March 29, 2006
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ABSTRACT |
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Allergic airway diseases caused by low–molecular weight chemicals including trimellitic anhydride (TMA) have been linked to Th2 cytokines and are characterized by mucus hypersecretion and infiltration of lymphocytes and eosinophils into the airways. The most common route of human exposure to chemical respiratory allergens is inhalation. Most murine models, however, use topical exposure to sensitize mice. The present study tests the hypothesis that topical sensitization on the ears of mice with TMA will induce a qualitatively similar immunologic and pathologic response in the nasal airways after intranasal challenge to that induced after intranasal sensitization and challenge. A/J mice were sensitized topically or by intranasal instillation followed by intranasal challenge with TMA in an ethyl acetate/olive oil vehicle. Intranasal challenge with TMA in mice that were either topically or intranasally sensitized with TMA caused a marked allergic rhinitis, of similar severity, characterized by an influx of eosinophils and lymphocytes. Both the topical and intranasal routes of sensitization also caused significant increases in total serum IgE after intranasal challenge with TMA. In addition, both the topical and intranasal routes of sensitization caused significant increases in the mRNA expression of the Th2 cytokines IL-4, IL-5, and IL-13. Collectively, these findings suggest that topical application is effective in sensitizing mice to TMA and induces a nasal airway lesion and associated immune response after intranasal challenge, which is qualitatively similar to that induced by intranasal sensitization and challenge. Skin exposure may be a potential route of sensitization of the respiratory tract to chemical allergens.
Key Words: trimellitic anhydride; A/J mice; intranasal instillation; topical application; allergic rhinitis; route of exposure.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONSUPPLEMENTAL DATAREFERENCES |
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Low–molecular weight chemicals including toluene diisocyanate and trimellitic anhydride (TMA) have been extensively studied for their allergenic behavior. Chemical-induced allergic respiratory diseases such as asthma are pervasive in occupational settings and increasing in prevalence (Petsonk, 2002
). The cellular and molecular mechanisms underlying the pathogenesis of these diseases have not been fully determined. Inhalation is the most common and relevant route of exposure to chemicals linked to human airway allergy. However, the high incidence of skin exposure to chemical allergens, especially in occupational settings, has led some investigators to speculate that the skin may represent an important route of exposure that can induce sensitization of the respiratory tract. Only scattered reports exist, however, that demonstrate a link between skin exposure to chemical allergens and sensitization of the respiratory tract (Karol, 1986). This is further complicated by the fact that dermal exposure is often accompanied by inhalation of the chemical vapor. Despite the lack of any concrete link between skin exposure and respiratory sensitization, many laboratories use topical application of chemical allergens to sensitize rodents in experimental models of chemical-induced allergic airway disease. For example, it has been shown that some of the characteristic features of chemical-induced allergic airway disease including airway inflammation can be elicited using topical sensitization followed by intraairway challenge in rodent models (Hayes et al., 1992; Herrick et al., 2002; Regal et al., 2001). In contrast, a recent study showed that topical sensitization followed by intraairway challenge with TMA in rats failed to elicit the increase in macrophages, granulocytes, and dendritic cells in the lung observed after intraairway sensitization and challenge (Vohr et al., 2002). This suggests that the route of exposure may influence the allergic response within the respiratory tract and raises the possibility that topical exposure to chemical allergens in rodents may not adequately model human allergic airway disease that results exclusively from inhalation exposure to chemicals.
An alternative method of sensitization and one that more closely resembles inhalation is intranasal instillation. In a previous study, we found that intranasal sensitization and challenge with the protein ovalbumin in a saline vehicle was a simple, inexpensive, and noninvasive method of inducing IgE-mediated allergic airway disease in the upper and lower respiratory tract of the A/J mouse (Farraj et al., 2003). Subsequently, we applied this method of administration to chemicals and found that intranasal sensitization and challenge with TMA in a 1:4 ethyl acetate/olive oil vehicle elicited an eosinophilic allergic rhinitis and a local Th2 cytokine mRNA increase in the nasal airways of the A/J mouse (Farraj et al., 2004). It is not clear, however, whether topical sensitization followed by intranasal challenge with a known chemical respiratory allergen will induce IgE-mediated allergic airway disease in the nasal airway.
The primary objective of this study was to determine if the route of exposure used to sensitize A/J mice will qualitatively influence the pathologic and immunologic characteristics of allergic rhinitis that take place after intranasal challenge with TMA. Topical application on the ears, using an established method of topical application (Dearman and Kimber, 1992), was compared to intranasal instillation in its capacity to induce a qualitatively similar pathologic and cytokine response in the nasal airway after intranasal challenge.
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MATERIALS AND METHODS |
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Animals and chemical sensitization and challenge.
Male A/J mice (Jackson Laboratories, Bar Harbor, ME), 6 weeks of age, were randomly assigned to one of several experimental groups (n = 10). Mice were free of pathogens and respiratory disease and used in accordance with guidelines set forth by the All University Committee on Animal Use and Care at Michigan State University. Animals were housed six per cage in polycarbonate boxes, on Cell-Sorb Plus bedding (A&W Products, Cincinnati, OH) covered with filtered lids and had free access to water and food. Room lights were set on a 12-h light/dark cycle beginning at 6:00 A.M., and the temperature and relative humidity were maintained between 21°C and 24°C and 40–55% humidity, respectively. Figure 1 depicts the exposure regimen used for the intranasal sensitization and challenge of the mice.
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= time after challenge when mice were sacrificed.Mice were anesthetized with 4% halothane and 96% oxygen and then exposed to TMA (Sigma-Aldrich, St Louis, MO). TMA was dissolved in a 1:4 ethyl acetate/olive oil vehicle combination when administered via intranasal instillation. TMA was dissolved in a 4:1 ethyl acetate/olive oil combination when administered via topical application onto the ear. The mice were sensitized on days 1 and 3 via either single intranasal instillations of 60 µl of 0.125% TMA or single applications of 12.5 µl of 10% TMA on each ear. The doses selected for this study were taken from reports that showed effective topical or intranasal sensitization of the respiratory tract (Dearman and Kimber, 1992
; Farraj et al., 2004). The mice were then challenged with TMA via single intranasal or topical applications using the same appropriate volumes and concentrations as in the sensitization on day 17 and again on day 27. There were 11 different treatment groups: (1) untreated naive group; (2 and 3) mice intranasally sensitized and challenged with TMA or vehicle alone; (4 and 5) mice intranasally sensitized and then topically challenged twice with TMA or vehicle alone; (6 and 7) mice that were topically sensitized and then administered a topical challenge on day 17 and then an intranasal challenge on day 27 with TMA or vehicle alone; (8 and 9) mice topically sensitized and then intranasally challenged twice with TMA or vehicle alone; and (10 and 11) mice that were topically sensitized and challenged with TMA or vehicle alone. All mice were sacrificed 48 h (day 29) after the final challenge. The 48-h time point was selected based on our previous time course study (Farraj et al., 2003) where we determined that both elevated Th2 cytokine responses and airway pathology were evident 48 h after allergen challenge.
Necropsy, blood sample collection, and tissue preparation.
Mice were deeply anesthetized via ip injection of 0.1 ml of 12% pentobarbital in saline. Blood samples (0.1–0.5 ml) were taken from the abdominal aorta. Serum samples were collected and stored at – 20°C after the blood samples were centrifuged to remove cells. The abdominal aorta and renal artery were then severed to exsanguinate the mice. Immediately after death, the trachea was cannulated and the heart/lung block removed. The right bronchus was then clamped using suture thread. All four right lung lobes were placed in 2 ml of TRI Reagent (Molecular Research Center, Cincinnati, OH), homogenized, and stored at – 80°C.
After removal of the right lung lobes, the left lung lobe was intratracheally perfused with 10% neutral buffered formalin at a constant intraairway pressure of 30 cm of fixative. After 1 h, the trachea was ligated and the inflated left lung lobe immersed in a large volume of the same fixative for 24 h. After fixation, the left lung lobe was microdissected along the axial airways, and sections were then excised at the level of the 5th (proximal airway) and 11th (distal airway) airway generation (Supplemental Fig. 1), as has been described previously in detail (Steiger et al., 1995).
The head of each mouse was excised from the carcass, and the eyes, skin, skeletal muscle, and lower jaw were removed. Half the mice in each group were reserved for nasal airway microdissection and the other half for nasal airway histopathology. In preparation for histopathologic analysis, the heads were immersed in 10% neutral buffered formalin for 24 h. After fixation, the heads were decalcified in 13% formic acid for 7 days and then rinsed in tap water for at least 4 h. The nasal cavity of each mouse was transversely sectioned at three specific anatomic locations according to a modified method of Young (1981). The most proximal nasal section was taken immediately posterior to the upper incisor teeth (proximal, T1), the middle section was taken at the level of the incisive papilla of the hard palate (middle, T2), and the most distal nasal section was taken at the level of the second palatal ridge (distal, T3) (Supplemental Fig. 1). These tissue blocks were embedded in paraffin, sectioned at a thickness of 5 µm, and then stained with hematoxylin and eosin for light microscopic examination. Other paraffin sections were stained with Alcian Blue/Periodic Acid Schiff's sequence to identify intraepithelial mucosubstances.
For the analysis of cytokine mRNA expression in the nasal mucosa, the heads of five mice from each group were split in a sagittal plane adjacent to the midline exposing the mucosal surfaces lining the nasal lateral wall and septum. The nasoturbinate and maxilloturbinate from each nasal airway and the proximal septum were microdissected. The excised tissues from each animal were placed in 1 ml of Tri Reagent, homogenized, and stored at – 80°C.
ELISA for total serum IgE.
Total serum IgE was measured using a 96-well Immulon ELISA plate (Dynex, Technologies, Chantilly, VA) coated with 2 µg/ml anti-mouse IgE (purified rat anti-mouse IgE monoclonal Ab, Pharmingen, San Diego, CA) and incubated overnight at 4°C. After washing, the plates were incubated in 3% bovine serum albumin (Calbiochem, La Jolla, CA) at 37°C for 1 h. Serum samples at 1:10 dilution were then added followed by incubation at 37°C for 1 h. After washing, biotinylated anti-mouse IgE (biotin-conjugated rat anti-mouse IgE monoclonal Ab, Pharmingen) was then added at 2 µg/ml and allowed to incubate at 25°C for 1 h. After washing, 1.5 µg/ml of streptavidin peroxidase was added followed by incubation at 25°C for 1 h. After washing, tetramethylbenzidine (TMB) substrate (12.5 ml citric-phosphate buffer + 200 µl of TMB stock solution [6 mg/ml in DMSO] + 100 µl 1% H2O2; Fluka Chemical Co., Ronkonkoma, NY) was added to produce a color reaction. The reaction was terminated by the addition of 6 N H2SO4. Optical density was determined at 450 nm using an EL-808 microplate reader (Bio-Tek Instruments, Winooski, VT). In previous studies, we determined that the maximum limit of detection is a mean optical density of approximately 2.0. The blank was a saline control. The mean optical density of the blank was subtracted from every group including the naive and vehicle controls.
Real-time RT-PCR.
Total RNA was isolated from nasal airway tissue using the TRI Reagent method following the manufacturer's protocol. The evaluation of the relative mRNA expression levels of the cytokines IL-4, IL-5, IL-10, IL-13, and IFN-
was determined using the TaqMan one-step real-time multiplex RT-PCR with TaqMan predeveloped primers and probe using the manufacturer's recommended protocol (Applied Biosystems, Foster City, CA). Briefly, aliquots of isolated tissue RNA (100 ng total RNA) were added to the RT-PCR mixture, which included the target gene (IL-4, IL-5, IL-10, IL-13, or IFN-) primers and probe, endogenous reference primers and probe (18S ribosomal RNA), AmpliTaq DNA polymerase, and Multiscribe reverse transcriptase (MuLV). The probes are designed to exclude detection of genomic DNA. RNA samples were first reverse transcribed and then immediately amplified by PCR. Following the PCR, amplification plots (change in dye fluorescence vs. cycle number) were examined, and a dye fluorescence threshold within the exponential phase of the reaction was set separately for the target gene and the endogenous reference (18S). The cycle number at which each amplified product crosses the set threshold represents the CT value. The amount of target gene normalized to its endogenous reference was calculated by subtracting the endogenous reference CT from the target gene CT (
CT). Relative mRNA expression was calculated by subtracting the mean CT of the control samples from the CT of the treated samples (CT). The amount of target mRNA normalized to the endogenous reference and relative to the calibrator (i.e., RNA from control) is calculated by using the formula 
Statistics.
The data obtained from each experimental group were expressed as a mean group value ± the SEM. The differences among groups were determined by one-way or two-way ANOVA and an All Pairwise Comparison Test (Tukey), using SigmaStat software from Jandel Scientific (San Rafael, CA).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONSUPPLEMENTAL DATAREFERENCES |
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Airway and Ear Pathology
Both topical and intranasal sensitization with TMA induced qualitatively similar airway lesions after intranasal challenge. TMA-induced airway alterations in these mice were restricted to the nasal airways. No exposure-related alterations were microscopically evident in the lungs of any of these mice. The principal morphologic alteration in the mice sensitized and challenged with TMA was a moderate-marked allergic rhinitis characterized by a conspicuous influx of mixed inflammatory cells predominated by eosinophils and accompanied by lesser numbers of mononuclear cells (lymphocytes and plasma cells) (Fig. 2). The inflammatory cell influx was bilateral and most severe in the nasal mucosa lining the proximal lateral meatus and the midseptum in T1. Accompanying the nasal inflammation was a moderate to marked regenerative hyperplasia with areas of degeneration and individual cell necrosis of the nasal transitional epithelium in these proximal nasal airways. Similar, but less severe, mucosal inflammation was present in the more distal nasal airways in T2 and T3. In these latter two sections, the inflammation was restricted to the respiratory mucosa lining the middle and lateral meatus in T2 and the nasopharyngeal meatus in T3. In addition, there was moderate lymphoid hyperplasia of the nasal-associated lymphoid tissue in T3 of these mice. There was no evidence of mucus overproduction or mucous cell metaplasia (data not shown).
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A similar airway lesion was evident in mice that were topically sensitized with TMA, topically challenged on day 17 and then intranasally challenged on day 27. However, no airway lesions were evident in mice that were topically sensitized and challenged or mice that were intranasally sensitized and topically challenged twice with TMA.
Topical sensitization and challenge with TMA caused an allergic contact dermatitis in the skin of the ear that was characterized by a marked dermal edema accompanied by an inflammatory cellular influx consisting of mononuclear cells, lymphocytes, neutrophils, and eosinophils (Fig. 3). In addition, there was a mild to moderate hyperplasia of the epidermis. Similar lesions were evident in ears of mice that were intranasally sensitized and topically challenged twice with TMA. No lesions were evident on the ears of mice that were intranasally challenged twice with TMA.
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Total Serum IgE
All groups exposed to TMA had significant increases in total serum IgE relative to the naive control irrespective of the exposure regimen used. Mice intranasally sensitized and challenged with TMA had a 4-fold increase in total serum IgE relative to the naive controls (Fig. 4). Mice topically sensitized and intranasally challenged twice had a 13-fold increase in total serum IgE relative to the naive controls. Mice intranasally sensitized and topically challenged twice had a 16-fold increase in total serum IgE relative to the naive controls. Mice that were topically sensitized and then topically challenged once and then administered an intranasal instillation during the second challenge had an 18-fold increase in total serum IgE relative to the naive controls. Mice that were topically sensitized and challenged also had an 18-fold increase in total serum IgE relative to the naive controls. Mice that received topical applications of TMA in two different periods had significantly greater serum IgE levels than mice that received one or less. Mice that were topically sensitized and intranasally challenged with TMA had significantly greater serum IgE levels than mice that were intranasally sensitized and challenged. No significant increase in total serum IgE was observed in the vehicle control groups relative to the naive control.
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Nasal Airway Cytokine Gene Expression
IL-4.
Mice intranasally sensitized and challenged with TMA had a 5-fold increase in IL-4 mRNA levels relative to the naive controls (Fig. 5). Mice topically sensitized and intranasally challenged twice with TMA had a 7-fold increase in IL-4 mRNA levels relative to the naive controls. Mice that were topically sensitized, topically challenged once, and then administered an intranasal instillation during the second challenge with TMA had a 2.4-fold increase in IL-4 mRNA levels relative to the naive controls. These differences were all statistically significant (p < 0.05).
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IL-5.
Mice intranasally sensitized and challenged with TMA had a 3-fold increase in IL-5 mRNA levels relative to the naive controls (Fig. 6). Mice topically sensitized and intranasally challenged twice with TMA had a 4-fold increase in IL-5 mRNA levels relative to the naive controls. Mice that were topically sensitized, topically challenged once, and then administered an intranasal instillation during the second challenge with TMA also had a 4-fold increase in IL-5 mRNA levels relative to the naive controls, but this was not statistically significant.
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IL-13.
Mice intranasally sensitized and challenged with TMA had a 7-fold increase in IL-13 mRNA levels relative to the naive controls (Fig. 7). Mice topically sensitized and intranasally challenged twice with TMA had an 11-fold increase in IL-13 mRNA levels relative to the naive controls. Mice that were topically sensitized, topically challenged once, and then administered an intranasal instillation during the second challenge with TMA also had an 11-fold increase in IL-13 mRNA levels relative to the naive controls. These differences were all statistically significant (p < 0.05).
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There were no significant increases in IL-4, IL-5, or IL-13 mRNA levels in mice that were intranasally sensitized and then topically challenged twice with TMA, in mice that were topically sensitized and challenged with TMA, or in the vehicle control groups relative to the naive group.
IL-10 and IFN-.
There were no significant differences in the expression of IL-10 or IFN- mRNA in any of the treatment groups relative to the naive or vehicle controls (Supplemental Figs 2 and 3).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONSUPPLEMENTAL DATAREFERENCES |
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Although data demonstrating a link between dermal exposure to chemical allergens and respiratory sensitization is sparse, the demonstration that the skin is a route of exposure that can lead to sensitization of the respiratory tract to chemical allergens in animals has at least two important implications. One is that, in addition to controlling the atmospheric concentrations of chemical respiratory allergens in occupational settings to limit inhalation, it is also crucial to minimize dermal exposure in order to prevent airway allergy. The second is that topical application of chemical allergens in experimental models is an adequate method of sensitization of the respiratory tract and thus represents a valid model with which to investigate the mechanisms of chemical-induced airway allergy.
TMA-induced allergic airway disease as a result of inhalation of TMA vapors is relatively common in industries that use TMA to manufacture products including epoxy resins. In addition to being a respiratory allergen, TMA is also a contact allergen that can induce contact hypersensitivity reactions in the skin (Cumberbatch et al., 1992). As a positive control for the allergenicity of TMA, the histopathology of the ear was examined at the site of topical application. TMA caused a contact dermatitis in the ear that was characterized by dermal edema, mononuclear and eosinophil cellular influx, and an epidermal hyperplasia. This response required topical sensitization and challenge or two topical challenges with TMA.
Work-related occupational asthma is often accompanied by allergic rhinitis (Leynaert et al., 2000). TMA-induced allergic rhinitis precedes and may be more common than occupational asthma (Bernstein and Brooks, 1993; Grammer et al., 2002). The main symptoms of TMA-induced allergic rhinitis are itching, sneezing, watery discharge, and obstructed nose (WHO, 1999). The pathologic features of TMA-induced allergic rhinitis are similar to nonoccupational allergic rhinitis and include plasma exudation, hypersecretion of mucus, and cellular infiltrates consisting of T and B lymphocytes, eosinophils, and plasma cells in the nasal airway (WHO, 1999). In the present study, mice that were intranasally sensitized and challenged with TMA had a marked allergic rhinitis characterized by an influx of eosinophils, lymphocytes, and plasma cells, after the second challenge. The predominant inflammatory cell type was the eosinophil with fewer numbers of lymphocytes. In addition, mice topically sensitized and then challenged either once or twice via intranasal instillation also had an allergic rhinitis that was qualitatively similar to that elicited by intranasal sensitization and challenge. The inflammatory response that resulted after both routes of sensitization in mice that were intranasally challenged with TMA was similar to that described in humans with TMA-induced allergic rhinitis (WHO, 1999).
Th2 cytokines, including IL-4, IL-5, and IL-13, play an important role in the development of key features of allergic rhinitis and asthma, contributing to the development of airway hyperreactivity, mucus production, and eosinophil recruitment (Busse and Holgate, 2000; Frew, 1996; Shim et al., 2001; Yssel and Groux, 2000). Th2 cytokines have also been linked to the pathogenesis of chemical-induced asthma (Maestrelli et al., 1997). Several groups have shown that lymph node cells draining the site of topical application in murine models of TMA-induced asthma preferentially secrete Th2 cytokines including IL-4, IL-5, and IL-13 (Dearman et al., 2003; Plitnick et al., 2002; Vandebriel et al., 2000). In addition, we recently demonstrated a link between TMA-induced allergic rhinitis and the upregulation of Th2 cytokines in A/J mice (Farraj et al., 2004). In the present study, mice that were intranasally sensitized and challenged with TMA had an increase in nasal airway–derived mRNA levels of the Th2 cytokines IL-4, IL-5, and IL-13 and no change in the levels of IL-10 or the Th1 cytokine IFN-. Mice that were topically sensitized and intranasally challenged once or twice had similar increases in Th2 cytokine mRNAs and no change in IFN-. Thus, both routes of sensitization induced a qualitatively similar pattern of Th2 cytokine mRNA expression.
Both topical and intranasal sensitization failed to induce an immune response in the lung as evidenced by the absence of any pulmonary airway lesions after intranasal challenge. This result is similar to our previous findings that showed the intranasal instillation of chemical allergens in an ethyl acetate/olive oil vehicle does not result in sufficient distribution of the chemical allergen to the pulmonary airways (Farraj et al., 2004).
The role of serum IgE levels in chemical-induced allergic airway disease is controversial. The presence of elevated serum IgE levels, however, may be suggestive of an allergic response. In the present study, mice intranasally sensitized and challenged with TMA had an increase in total serum IgE. Mice topically sensitized with TMA and intranasally challenged once or twice with TMA also had increases in total serum IgE. It is important to note that while topical application of TMA caused a more significant increase in total serum IgE levels than intranasal instillation of TMA, the dose of TMA applied topically was several-fold greater than that administered via intranasal instillation and thus may account for the disparity in IgE levels. Alternatively, this may suggest that topical exposure is more effective in eliciting an IgE response than inhalation, thus further emphasizing that topical application may be a viable route of exposure to chemical allergens. It is possible that lipophilic chemical haptens have greater accessibility to Langerhans cells in the hydrophobic environment of the skin than to the corresponding antigen-presenting cells in the hydrophilic environment of the airways. Nonetheless, the data suggest that both routes of sensitization are effective in eliciting an increase in IgE. An increase in total serum IgE, however, was not limited to mice that were intranasally challenged with TMA as topical sensitization and challenge also caused a significant increase in total serum IgE. While the development of a pathologic and cytokine response in the airway was dependent on an airway challenge, increases in serum IgE levels were independent of the route of sensitization and challenge. The significance of these findings is unclear. Further studies with other chemical respiratory sensitizers and nonsensitizers need to be conducted in order to determine the relevance of enhanced circulating IgE levels in chemical-induced allergic airway disease.
The present study illustrated that topical application of the chemical allergen TMA is an effective method of sensitization to TMA in a murine model of allergic airway disease and induces a nasal airway lesion and associated immune response after intranasal challenge that is qualitatively similar to that induced by intranasal sensitization and challenge (Table 1). The sensitization of the respiratory tract of mice to TMA using topical application suggests that the skin may be an important route of sensitization of the human respiratory tract to TMA and potentially other chemical allergens.
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SUPPLEMENTAL DATA |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONSUPPLEMENTAL DATAREFERENCES |
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Supplemental Figures 1–3 and supplementary data are available online at www.toxsci.oxfordjournals.org.
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NOTES |
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1 Present address: Experimental Toxicology Division, US Environmental Protection Agency, Research Triangle Park, NC 27711.
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ACKNOWLEDGMENTS |
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This study was supported in part by the American Chemistry Council Grant 0051.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONSUPPLEMENTAL DATAREFERENCES |
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Bernstein, I. L., and Brooks, S. M. (1993). Metals. In Asthma in the Workplace (I. L. Bernstein, M. Chan-Yeung, J. L. Malo, and D. I. Bernstien, Eds.), pp. 459–479. Marcel Dekker, New York.
Busse, W. W., and Holgate, S. T., Eds. (2000). Allergic and non-allergic rhinitis. In Asthma and Rhinitis, pp. 223–244, Vol. 1, 2nd ed. Blackwell Science Ltd, Osney Meade, Oxford.
Cumberbatch, M., Gould, S. J., Peters, S. W., Basketter, D. A., Dearman, R. J., and Kimber, I. (1992). Langerhans cells, antigen presentation, and the diversity of responses to chemical allergens. J. Invest. Dermatol. 99, 107S–108S.[CrossRef][Medline]
Dearman, R. J., Betts, C. J., Humphreys, N., Flanagan, B. F., Gilmour, N. J., Basketter, D. A., and Kimber, I. (2003). Chemical allergy: Considerations for the practical application of cytokine profiling. Toxicol. Sci. 71, 137–145.
Dearman, R. J., and Kimber, I. (1992). Divergent immune responses to respiratory and contact chemical allergens: Antibody elicited by phthalic anhydride and oxazolone. Clin. Exp. Allergy 22, 241–250.[CrossRef][ISI][Medline]
Farraj, A. K., Harkema, J. R., Jan, T.-R., and Kaminski, N. E. (2003). Immune responses in the lung and local lymph node of A/J mice to intranasal sensitization and challenge with adjuvant-free ovalbumin. Toxicol. Pathol. 31, 432–447.[CrossRef][ISI][Medline]
Farraj, A. K., Harkema, J. R., and Kaminski, N. E. (2004). Allergic rhinitis induced by intranasal sensitization and challenge with trimellitic anhydride but not with dinitrochlorobenzene or oxazolone in A/J mice. Toxicol. Sci. 79, 315–325.
Frew, A. J. (1996). The immunology of respiratory allergies. Toxicol. Lett. 86, 65–72.[CrossRef][ISI][Medline]
Grammer, L. C., Ditto, A. M., Tripathi, A., and Harris, K. E. (2002). Prevalence and onset of rhinitis in subjects with occupational asthma caused by trimellitic anhydride. J. Occup. Environ. Med. 44, 1179–1181.[ISI][Medline]
Hayes, J. P., Daniel, R., Tee, R. D., Barnes, P. J., Taylor, A. J., and Chung, K. F. (1992). Bronchial hyperreactivity after inhalation of trimellitic anhydride dust in guinea pigs after intradermal sensitization to the free hapten. Am. Rev. Respir. Dis. 146(5 Pt 1), 1311–1314.[ISI][Medline]
Herrick, C. A., Xu, L., Wisnewski, A. V., Das, J., Redlich, C. A., and Bottomly, K. (2002). A novel mouse model of diisocyanate-induced asthma showing allergic-type inflammation in the lung after inhaled antigen challenge. J. Allergy Clin. Immunol. 109, 873–878.[CrossRef][ISI][Medline]
Karol, M. H. (1986). Respiratory effects of inhaled isocyanates. Crit. Rev. Toxicol. 16, 349–379.[Medline]
Leynaert, B., Neukirch, F., Demoly, P., and Bousquet, J. (2000). Epidemiologic evidence for asthma and rhinitis comorbidity. J. Allergy Clin. Immunol. 106, S201–S205.[Medline]
Maestrelli, P., Occari, P., Turato, G., Papiris, S. A., Di Stefano, A., Mapp, C. E., Milani, G. F., Fabbri, L. M., and Saetta, M. (1997). Expression of interleukin (IL)-4 and IL-5 proteins in asthma induced by toluene diisocyanate (TDI). Clin. Exp. Allergy 27, 1292–1298.[CrossRef][ISI][Medline]
Petsonk, E. L. (2002). Work-related asthma and implications for the general public. Environ. Health Perspect. 110(Suppl. 4), 569–572.
Plitnick, L. M., Loveless, S. E., Ladics, G. S., Holsapple, M. P., Selgrade, M. J., Sailstad, D. M., and Smialowicz, R. J. (2002). Cytokine profiling for chemical sensitizers: Application of the ribonuclease protection assay and effect of dose. Toxicol. Appl. Pharmacol. 179, 145–154.[CrossRef][ISI][Medline]
Regal, J. F., Mohrman, M. E., and Sailstad, D. M. (2001). Trimellitic anhydride-induced eosinophilia in a mouse model of occupational asthma. Toxicol. Appl. Pharmacol. 175, 234–242.[CrossRef][ISI][Medline]
Shim, J. J., Dabbagh, K., Ueki, I. F., Dao-Pick, T., Burgel, P.-R., Takeyama, K., Tam, D. C.-W., and Nadel, J. A. (2001). IL-13 induces mucin production by stimulating epidermal growth factor receptors and by activating neutrophils. Am. J. Physiol. Lung Cell. Mol. Physiol. 280, L134–L140.
Steiger, D., Hotchkiss, J., Baja, L., Harkema, J., and Basbaum, C. (1995). Concurrent increases in the storage and release of mucin-like molecules by rat airway epithelial cells in response to bacterial endotoxin. Am. J. Respir. Cell Mol. Biol. 12, 307–314.[Abstract]
Vandebriel, R., De Jong, W. H., Spiekstra, S. W., Van Dijk, M., Fluitman, A., Garssen, J., and Van Loveren, H. (2000). Assessment of preferential T-helper 1 or T-helper 2 induction by low molecular weight compounds using the local lymph node assay in conjunction with RT-PCR and ELISA for interferon- and interleukin-4. Toxicol. Appl. Pharmacol. 162, 77–85.[CrossRef][ISI][Medline]
Vohr, H.-W., Pauluhn, J., and Ahr, H. J. (2002). Respiratory hypersensitivity to trimellitic anhydride in brown Norway rats: Evidence for different activation pattern of immune cells following topical and respiratory induction. Arch. Toxicol. 76, 538–544.[CrossRef][ISI][Medline]
World Health Organization (WHO) (1999). Clinical aspects of the most important allergic diseases: Allergic rhinitis and conjunctivitis. In Principles and Methods for Assessing Allergic Hypersensitization Associated with Exposure to Chemicals, pp. 181–186. International Program on Chemical Safety, Environmental Health Criteria 212. World Health Organization, Geneva.
Young, J. T. (1981). Histopathologic examination of the rat nasal cavity. Fundam. Appl. Toxicol. 1, 309–312.[Medline]
Yssel, H., and Groux, H. (2000). Characterization of T cell subpopulations involved in the pathogenesis of asthma and allergic diseases. Int. Arch. Allergy Immunol. 121, 10–18.[CrossRef][ISI][Medline]
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