American Journal of Respiratory Cell and Molecular Biology. Vol. 27, pp. 267-272, 2002
© 2002 American Thoracic Society
DOI: 10.1165/rcmb.F248
Modeling Allergic Asthma in Mice
Pitfalls and Opportunities
Rakesh K. Kumar and
Paul S. Foster
Department of Pathology, University of New South Wales, Sydney; and Department of Biochemistry and Molecular Biology, John Curtin School of Medical Research, Australian National University, Canberra, Australia
Address correspondence to: R. K. Kumar, Department of Pathology, University of New South Wales, Sydney, Australia 2052. E-mail: R.Kumar{at}unsw.edu.au
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Abstract
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Studies in murine experimental models have contributed greatly to understanding the mechanisms of allergic inflammation underlying asthma. However, models involving short-term high-level exposure of sensitized animals to antigen have significant limitations for investigating the pathogenesis of the lesions of chronic asthma. Modeling chronic asthma is problematic, because long-term antigenic challenge often triggers widespread pulmonary parenchymal inflammation or leads to eventual downregulation of inflammation and airway hyperreactivity. We have developed an improved murine model in which animals are exposed to low mass concentrations of aerosolized antigen for 6–8 wk. The mice exhibit airway-specific acute-on-chronic inflammation and changes of airway wall remodeling as seen in human asthma, together with hyperreactivity to a cholinergic agonist which can be specifically attributed to airway disease. This more realistic model of asthma offers a number of opportunities for investigation of pathogenetic mechanisms and novel therapeutic agents.
Abbreviations: airway hyperreactivity, AHR • interleukin, IL
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Introduction
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Allergic disease is a major health issue, with the prevalence of allergic rhinoconjunctivitis and asthma increasing steadily worldwide. Much of our understanding of the response to allergens comes from the study of animal models, especially in guinea pigs, rats, and mice. These investigations have not only shed light on the immunologic mechanisms underlying allergy, but have also allowed evaluation of potential therapeutic agents. For example, the initial assessment of leukotriene receptor antagonists, now widely accepted in the treatment of asthma, was undertaken in a guinea pig model of allergic asthma-like inflammation (1).
Currently, the most widely used experimental animal is the mouse, in part because of the availability of transgenic and gene-targeted animals, and in part because of the variety of specific reagents available for phenotypic and functional analysis of the cellular and mediator response (2, 3). Murine models of allergic bronchopulmonary inflammation have proved to be extremely useful for examination of the basic mechanisms of allergic inflammation and the underlying immunologic response. The key contribution of CD4+ T-lymphocytes to the pathogenesis of asthmatic inflammation, as well as the potentially crucial roles of so-called Th2 cytokines, has been highlighted by several studies in mice (4–7). In particular, studies on interleukin (IL)-5 (8–10) and IL-13 (11–13) in murine models have led to an understanding of the cellular sources of these mediators and the signaling pathways involved. Other noteworthy mechanistic studies have focused on mediators and adhesion molecules involved in leukocyte recruitment (14–23), IgE-independent mechanisms of allergic inflammation (24–27), the role of eosinophils in the afferent limb of the allergic response (28–30), and the role of Th2 cytokine pathways in the pathogenesis of goblet cell hyperplasia/metaplasia in asthmatic airway epithelium (31–33).
Murine models have also facilitated the investigation of novel options for controlling allergic inflammation. These have included not only conventional pharmacologic approaches, using inhibitors of the synthesis of inflammatory mediators or functional antagonists (34–37), but also radical therapeutic options involving antisense oligonucleotides and DNA immunization (38, 39).
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Variability and Limitations of Short-Term Models
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Notwithstanding the wealth of valuable data that have been obtained from studies in short-term murine models of asthmatic inflammation, the limitations of such models must be recognized. Some of the divergent and conflicting results may be related to the marked variation among murine models with respect to the background strains of the animals used for study, the variety of sensitization and challenge protocols employed, and the different readouts used to assess inflammatory and immunologic responses as well as the timing of these assessments (40, 41). Importantly, although short-term exposure to very high mass concentrations of aerosolized allergen is experimentally convenient, this is quite unlike the recurrent long-term exposure to low mass concentrations of allergen experienced by humans with asthma. High-level exposure triggers acute inflammation in the lung parenchyma, especially perivascular and peribronchiolar inflammation, which is markedly different from the acute-on-chronic inflammation of the airway wall observed in human asthma (42). Moreover, the pattern of acute inflammation differs in several respects from that observed in individuals with asthma. For example, intra-epithelial accumulation of eosinophils, which is characteristic of human asthma, is conspicuously absent, at least in the intrapulmonary airways (26). Furthermore, there appears to be little evidence of classical activation or degranulation of these cells (43, 44).
Because most murine models of asthma are more correctly designated models of allergic bronchopulmonary inflammation, questions arise about the use of such models to investigate mechanisms of airway hyperreactivity (AHR). Whole animal studies may not clearly distinguish between AHR originating from the airways and that due to contractile elements in the lung parenchyma, which is responsible for a significant component of resistance to airflow in the presence of alveolar and peribronchiolar inflammation (45). The issue is complicated by the use of various alternative methods of assessing AHR (or an approximation thereto) in rodents. These include in vitro studies of the contraction of muscle strips in response to agonists, assessment under anesthesia of bronchospasm (the Konzett-Rossler technique), assessment of a range of physiologic parameters by tracheal/esophageal cannulation combined with plethysmography, and whole body plethysmography in conscious, unrestrained animals (46, 47). Although results obtained using these different techniques are often similar, there are sometimes striking discrepancies.
Perhaps the most significant deficiency of the commonly used models of allergic bronchopulmonary inflammation is that, by their very nature, they involve short-term experiments. Thus they do not exhibit many of the lesions that typify chronic human asthma (Figure 1)
. Notably absent are chronic inflammation of the airway wall (48) and changes of airway wall remodeling such as subepithelial fibrosis and epithelial proliferation (49). Because chronic inflammation may be related to AHR, whereas airway wall remodeling may have important consequences with respect to both AHR and development of fixed airflow obstruction (50), there is a need for animal models that facilitate investigation of the chronic lesions of asthma.
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Figure 1. Diagrammatic representation of characteristic abnormalities of the airways in asthma, including acute-on-chronic inflammation and changes of airway wall remodeling.
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Modeling the Lesions of Chronic Asthma
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One approach to developing models of chronic asthma has involved pulmonary overexpression of cytokines in transgenic mice, which has helped to identify the potential contributions of mediators such as IL-9, -11, and -13 to the processes of remodeling (51–53). Similarly, an interesting model of asthma has recently been reported in gene-targeted animals deficient for a transcription factor (54), which developed pulmonary inflammation, peribronchiolar fibrosis, and exaggerated baseline airway responsiveness. However, these models do not involve allergen challenge. There have been relatively few descriptions of satisfactory rodent models of chronic antigenic challenge associated with airway inflammation and remodeling resembling human asthma. Experimental protocols have involved repeated inhalational exposure (55, 56), repeated bolus delivery of antigen intratracheally or intranasally (36, 57), or intratracheal challenge with a persisting microorganism (58). A problem that has bedevilled many such studies is the development of extensive parenchymal inflammation, which may be granulomatous and/or associated with pulmonary fibrosis (36, 57–60). Another difficulty reported by some investigators has been downregulation of inflammatory and immunologic responses, as well as of remodeling and AHR, following prolonged exposure (55, 56, 61, 62).
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An Improved Murine Model of Asthma
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Our studies of the dose–response relationship in silica-induced pulmonary fibrosis (63) established that development of progressive parenchymal lesions depended on exceeding a mass concentration threshold of airborne particles. We speculated that in chronic inhalational challenge models of asthma, high-level exposures might similarly overwhelm mechanisms for clearance of antigen from the airways and/or trigger downregulation of the immunologic response. Therefore, we sought to develop a model of chronic asthma in which sensitized animals were exposed by inhalation to carefully controlled mass concentrations of aerosolized antigen, to minimize the likelihood of eliciting parenchymal inflammation. This approach was successful. BALB/c mice sensitized to ovalbumin were challenged for 30 min/d on 3 d/wk with 10–20 mg/m3 of aerosolized ovalbumin in a whole-body inhalation exposure system. Over a period of up to 8 wk, the animals exhibited progressively increasing airway-specific acute-on-chronic inflammation, changes of remodeling, and AHR (64) (Figure 2)
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Figure 2. Inflammation and fibrosis following chronic exposure. Progressive accumulation of intra-epithelial eosinophils and subepithelial fibrosis in sensitized BALB/c mice, chronically exposed to low mass concentrations of aerosolized antigen over a period of 8 wk. Data summarized from Temelkovski and coworkers (64).
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In further studies, we have established that our model exhibits many of the features of chronic human asthma, including: (i) the presence of numerous intra-epithelial eosinophils; (ii) chronic inflammation in the lamina propria, including evidence of a local Th2-biased humoral immune response; (iii) AHR demonstrable by various techniques; and (iv) changes of remodeling, including epithelial hypertrophy, subepithelial fibrosis, and goblet cell hyperplasia/metaplasia (64–67).
Unlike conventional high-level exposure models, both short- and long-term, there is complete absence of lung parenchymal inflammation in this model. Furthermore, in contrast to what has been reported in some long-term exposure models, there is also no evidence of downregulation of inflammatory and immunologic responses following prolonged antigenic challenge, with AHR and changes of remodeling persisting or increasing through 8 wk of exposure.
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The Very Different Pathobiology of Chronic Asthma
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Our model of chronic low-level inhalational challenge differs in a number of significant ways from conventional short-term high-level exposure models. For example, chronic challenge generates a quite different acute inflammatory environment. Eosinophil recruitment into the airways is much more rapid following antigenic challenge in the setting of chronic exposure, suggesting activation of additional mechanisms not operating in short-term models (67). Conversely, IL-13 deficiency abolishes eosinophil recruitment in the chronic challenge model (68), whereas it fails to do so in a short-term model (69), possibly because the much more florid inflammatory response triggered by exposure to high mass concentrations of antigen upregulates alternative pathways (such as expansion of the pool of IL-5–producing Th2 cells and of the bone marrow population of eosinophil precursors) that are not operative in the chronic low-level challenge model. Another intriguing difference is that unlike short-term models, in which eosinophil recruitment is dependent on CD4+ T-lymphocytes (5, 8, 15), depletion of CD4+ T cells does not abrogate eosinophil recruitment in the setting of chronic challenge (70).
The chronic exposure model also induces a chronic inflammatory response in the lamina propria of the airways. This clearly creates an altered immunologic environment in the airway wall, with evidence of a local humoral immune response, manifested as accumulation of antigen-specific immunoglobulin-secreting plasma cells (66) that exhibit a Th2 bias in their immunoglobulin phenotype (70). These cells are not merely antibody factories, however, because they produce eotaxin in response to antigenic challenge (67) and may contribute to the inflammatory response in other ways; for example, plasma cells have the potential to generate proinflammatory cytokines such as TNF- (71). Interestingly, our studies using gene-targeted mice indicate that at least some Th2 cytokines that are traditionally associated with acute allergic inflammation—notably IL-5 and IL-13—also regulate the accumulation of chronic inflammatory cells in the airway wall (65, 68).
Of course, a chronic exposure model which replicates changes of airway wall remodeling offers a fascinating opportunity to dissect the cellular and molecular mechanisms involved in these processes, which cannot be investigated in short-term models. We have used gene-targeted mice and antibody depletion of specific cell types to examine the pathogenesis of remodeling. As summarized in Table 1, our investigations to date demonstrate that IL-13 is crucial in the induction of both the epithelial changes and subepithelial fibrosis of chronic asthma, as well as revealing a hitherto unrecognized fundamental role for CD4+ T-lymphocytes (68, 70). Conversely, we have shown that IL-4 may be important in the regulation of these changes, because remodeling is significantly enhanced in IL-4-/- mice (65). Our data also highlight that absence of signaling via the IL-4 receptor chain has little impact on either inflammation or subepithelial fibrosis, which, in the context of the lack of remodeling in IL-13-/- mice, implies that IL-13 may be able to signal via a pathway not involving the IL-4R chain (68). This latter finding is in agreement with our results in a short-term model of allergic bronchopulmonary inflammation (13) and has important implications for the proposed therapeutic targeting of the IL-4R chain in human asthma.
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TABLE 1 Effects of cytokine deficiency or depletion of CD4+ T-lymphocytes on inflammation, remodeling, and AHR in chronic asthma
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The chronic challenge model is particularly useful for studying the mechanisms of AHR, because in comparison with a model of allergic bronchopulmonary inflammation, we have been able to demonstrate that long-term low-level exposure elicits AHR that originates from the airways and not the parenchyma (Collins and coworkers, submitted for publication). Our results to date have established the dependence of AHR in this model on CD4+ T-lymphocytes and on IL-5 (Table 1). The latter finding is in contrast to observations in BALB/c mice in short-term models (72, 73), presumably because alternative pathways for AHR are activated in response to short-term high-level exposure, whereas in the absence of these alternative mechanisms IL-5 becomes critical. Also in contrast to findings in short-term models, we have demonstrated enhanced AHR in IL-4-/- mice (65). An interesting observation has been that AHR and remodeling can be dissociated in this model, with absent AHR and persistent remodeling in IL-5-/- mice (65) but the converse in IL-13-/- mice (68). This is noteworthy in the context of the apparent linkage between AHR and remodeling demonstrated in human studies (74–76).
Another interesting observation to emerge from our investigations has been that, in contrast to the response to short-term high-level exposure, virtually no airway lesions or AHR could be elicited in sensitized C57BL/6 mice chronically exposed to low levels of aerosolized antigen (unpublished data). Our results highlight the importance of the mouse strain used for development of an experimental model. A technical point of interest has been the choice of appropriate experimental controls, especially in the context of measurement of AHR. Animals that have not been systemically sensitized but have been subjected to chronic inhalational challenge with antigen turn out not to be a "zero response" control, in contrast to the situation with short-term models, because of eventual development of sensitization via the airways. In these animals, for reasons that are unclear, there is evidence of AHR by the Konzett-Rossler method (64), but not by other techniques (65, and Collins and coworkers, submitted for publication).
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Some Unanswered Questions
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The availability of a realistic model of chronic human asthma offers additional opportunities to address a number of key questions relating both to pathogenetic mechanisms of human asthma and to potential novel approaches to therapy. Issues that might be of interest include the following:- Do inflammatory or epithelial cells drive deposition of collagen by myofibroblasts in the airway wall?
- Which growth factors are important in remodeling? How are they regulated?
- What is the role of epithelial "activation" in chronic asthma? How is this most appropriately assessed?
- Does therapeutic efficacy in chronic asthma depend on inhibition of specific cytokines, e.g., IL-5 or IL-13?
- What is the role of non-Th2 cytokines such as TNF- and IFN-
 in asthmatic inflammation, remodeling, and AHR?
This model also provides a very useful system for assessment of novel therapeutic agents, both conventional drugs and immunomodulatory treatments. We believe that it is in this respect that a valid model is most likely to realize its potential. However, we recognize the limitations of murine models for the study of chronic asthma. For example, there is little if any evidence of recruitment of mast cells into the airway wall or epithelium (66), which may reflect the paucity of mast cells in the airways of mice; the phenotype of the epithelium of the proximal intrapulmonary airways in mice is markedly different from humans, necessitating assessment of most epithelial responses in the trachea; and there is no increase in airway smooth muscle mass in this species (77). Nevertheless, the advantages of the improved model considerably outweigh its disadvantages and should facilitate the translation of basic research on the immunobiology of allergic asthma into clinical practice.
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Acknowledgments
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Work in the authors' laboratories has been supported by the National Health and Medical Research Council of Australia, Asthma New South Wales, and the Human Frontiers Science Program.
Received in original form July 22, 2002
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Abstract
Introduction