Asthma is defined as a chronic inflammatory disease of the airways; however, the underlying physiological and immunological processes are not fully understood. Animal models have been used to elucidate asthma pathophysiology, and to identify and evaluate novel therapeutic targets. Several recent review articles (Epstein, 2004; Lloyd, 2007; Boyce and Austen, 2005; Zosky and Sly, 2007) have discussed the potential value of these models. Allergen challenge models reproduce many features of clinical asthma and have been widely used by investigators; however, the majority involve acute allergen challenge procedures. It is recognised that asthma is a chronic inflammatory disease resulting from continued or intermittent allergen exposure, usually via inhalation, and there has been a recent focus on developing chronic allergen exposure models, predominantly in mice. Here, we review the acute and chronic exposure mouse models, and consider their potential role and impact in the field of asthma research.

INTRODUCTION

Human allergic asthma is defined as a chronic inflammatory disorder of the airways and is characterised by airway inflammation, persistent airways hyperresponsiveness (AHR) and intermittent, reversible airways obstruction (GINA, 2006; Bousquet et al., 2000). In addition, structural changes in the airway including subepithelial and airway wall fibrosis, goblet cell hyperplasia/metaplasia, smooth muscle thickening and increased vascularity are observed (Bousquet et al., 2000; Fish, 1999). These changes are termed ‘airway remodelling’ and may be the result of repeated exposure to the allergen, which causes repeated or continuing inflammation in the airways (Zosky and Sly, 2007). Chronic inflammation and structural changes are thought to have functional consequences that contribute to asthma symptoms.

The exact cellular and biochemical processes underlying chronic inflammation and airway remodelling are poorly understood. Although the best approach to investigate these processes, and to identify crucial pathways and potential novel targets for drug therapy, is to perform studies in human asthmatics, the required mechanistic studies are not acceptable owing to ethical reasons. Animal models provide an alternative for investigating disease mechanisms and progression. Because asthma is a complex multifactorial disease, it is unlikely that a single animal model of asthma that replicates all of the morphological and functional features of the chronic human disease will ever be developed. However, we can use animals to model specific features of the disease, and much of our current understanding of disease processes in asthma, and in particular the response to allergens, comes from studies in laboratory animals such as guinea pigs, rats and mice. The mouse is the most widely used species, mainly because of the availability of transgenic animals and because of the wide array of specific reagents that are available for analysis of the cellular and mediator response. This Commentary will, therefore, focus on the development of allergen challenge models in the mouse.

ACUTE ALLERGEN CHALLENGE MODELS

Mice do not spontaneously develop asthma; so, in order to investigate the processes underlying this disease, an artificial asthmatic-like reaction has to be induced in the airways. Mouse models of the acute allergic response to inhaled allergens have been widely used to elucidate the mechanisms underlying the immunologic and inflammatory responses in asthma, and for the identification and investigation of novel targets for controlling allergic inflammation.

A variety of different acute allergen challenge models have been developed in mice and a number of sensitisation and challenge protocols have been employed. Some of these are summarised in Table 1.

Table 1

Mouse models of acute allergic pulmonary inflammation

Gender/strainAllergenSensitisationExposure/challengeResponses to challengeReferences
Female BALB/c OVA OVA/alum (i.p.) on days 0 and 12 OVA aerosol on days 18–23 From day 24: AHR, increased eosinophils in BAL and lung tissue. Remodelling and Th2 cytokine induction Lloyd et al., 2000; McMillan et al., 2002; McMillan et al., 2005  
Female BALB/c OVA OVA + AlOH3 (i.p.) on days 0 and 14 OVA aerosol on days 28–30 From day 32: AHR, increased eosinophils in BAL and lung tissue. Remodelling and Th2 cytokine induction Tomkinson et al., 2001; Hamelmann et al., 1999a  
Male BALB/c OVA OVA (i.p.) on 7 alternate days OVA aerosol for 8 consecutive days(starting on day 27) 24 hours post final OVA challenge: AHR, increased eosinophils in BAL and lung tissue. Th2 cytokine induction Hessel et al., 1995; Janssen et al., 2000  
Female BALB/c OVA OVA + alum (i.p.) on days 0 and 14 OVA (i.n) on days 14, 25, 26 and 27 From day 28: AHR and increased eosinophils in BAL and lung tissue. Remodelling Henderson et al., 1996  
Male BALB/c OVA OVA (i.p.) on 7 alternate days OVA (i.t.) on day 42 for 3 days, each 3 days apart 24 hours post final OVA challenge: increased eosinophils in BAL and lung tissue Blyth et al., 2000  
Male A/J Bla g 2 and Der f 1 OVA + AlOH3 (i.p.) on days 0 and 7 Allergen (oro-tracheal) on day 14 From day 17: AHR (only to Bla g 2) and increased eosinophils in BAL and lung tissue Sarpong et al., 2003  
Male C57BL/6 HDM Der p 1 + AlOH3 (i.p.) on day 0 HDM (aerosol) on day 14 for 7 consecutive days AHR and BAL and lung tissue inflammation at 24 hours post final challenge Tournoy et al., 2000  
Female BALB/c OVA OVA + alum (i.p.) on days 0 and 14 OVA aerosol on days 28–30 and 72 days after last challenge AHR and BAL eosinophilia on days 32, 37, 44 and 74 Kanehiro et al., 2001  
Male BALB/c OVA OVA + AlOH3 (i.p.) on days 0 and 5 2×OVA inhalations, each 4 hours apart on day 17 Following OVA challenge: AHR, EAR and LAR observed Fernandez-Rodriguez et al., 2008  
Male BALB/c OVA OVA + AlOH3 (i.p.) on day 0 and OVA i.p. on day 10 OVA aerosol on days 17 and 24 Following OVA challenge: EAR and LAR. Increased inflammatory cells in BAL and lung tissue Choi et al., 2005  
Gender/strainAllergenSensitisationExposure/challengeResponses to challengeReferences
Female BALB/c OVA OVA/alum (i.p.) on days 0 and 12 OVA aerosol on days 18–23 From day 24: AHR, increased eosinophils in BAL and lung tissue. Remodelling and Th2 cytokine induction Lloyd et al., 2000; McMillan et al., 2002; McMillan et al., 2005  
Female BALB/c OVA OVA + AlOH3 (i.p.) on days 0 and 14 OVA aerosol on days 28–30 From day 32: AHR, increased eosinophils in BAL and lung tissue. Remodelling and Th2 cytokine induction Tomkinson et al., 2001; Hamelmann et al., 1999a  
Male BALB/c OVA OVA (i.p.) on 7 alternate days OVA aerosol for 8 consecutive days(starting on day 27) 24 hours post final OVA challenge: AHR, increased eosinophils in BAL and lung tissue. Th2 cytokine induction Hessel et al., 1995; Janssen et al., 2000  
Female BALB/c OVA OVA + alum (i.p.) on days 0 and 14 OVA (i.n) on days 14, 25, 26 and 27 From day 28: AHR and increased eosinophils in BAL and lung tissue. Remodelling Henderson et al., 1996  
Male BALB/c OVA OVA (i.p.) on 7 alternate days OVA (i.t.) on day 42 for 3 days, each 3 days apart 24 hours post final OVA challenge: increased eosinophils in BAL and lung tissue Blyth et al., 2000  
Male A/J Bla g 2 and Der f 1 OVA + AlOH3 (i.p.) on days 0 and 7 Allergen (oro-tracheal) on day 14 From day 17: AHR (only to Bla g 2) and increased eosinophils in BAL and lung tissue Sarpong et al., 2003  
Male C57BL/6 HDM Der p 1 + AlOH3 (i.p.) on day 0 HDM (aerosol) on day 14 for 7 consecutive days AHR and BAL and lung tissue inflammation at 24 hours post final challenge Tournoy et al., 2000  
Female BALB/c OVA OVA + alum (i.p.) on days 0 and 14 OVA aerosol on days 28–30 and 72 days after last challenge AHR and BAL eosinophilia on days 32, 37, 44 and 74 Kanehiro et al., 2001  
Male BALB/c OVA OVA + AlOH3 (i.p.) on days 0 and 5 2×OVA inhalations, each 4 hours apart on day 17 Following OVA challenge: AHR, EAR and LAR observed Fernandez-Rodriguez et al., 2008  
Male BALB/c OVA OVA + AlOH3 (i.p.) on day 0 and OVA i.p. on day 10 OVA aerosol on days 17 and 24 Following OVA challenge: EAR and LAR. Increased inflammatory cells in BAL and lung tissue Choi et al., 2005  

Bla g 2, recombinant Blatella germanica 2 (cockroach allergen); Der f 1, Dermatophagoides farinae 1 (house dust mite allergen); BAL, bronchoalveolar lavage; EAR, early asthmatic response; LAR, late asthmatic response.

The nature of the acute inflammatory model may be influenced by the choice of mouse strain, the allergen, and the sensitisation and challenge protocol (Zosky and Sly 2007; Kumar et al., 2008). The most commonly used strain of mouse for antigen challenge models is BALB/c as they develop a good T helper cell 2 (Th2)-biased immunological response (Boyce and Austen, 2005). However, other strains (C57BL/6 and A/J) have been used successfully in allergen challenge studies (Kumar et al., 2008). Ovalbumin (OVA) derived from chicken egg is a frequently used allergen that induces a robust, allergic pulmonary inflammation in laboratory rodents. A review of OVA challenge models has recently been published by Kumar et al. (Kumar et al., 2008). OVA, however, is seldom implicated in human asthma, and other groups have used alternative allergens that may have greater clinical relevance, for example house dust mite (HDM) and cockroach extracts (Johnson et al., 2004; Sarpong et al., 2003).

Although many different sensitisation and challenge protocols have been used, the basic model is consistent. Acute sensitisation protocols usually require multiple systemic administration of the allergen in the presence of an adjuvant. Adjuvants such as aluminium hydroxide (AlOH3) are known to promote the development of the Th2 phenotype by the immune system when it is exposed to an antigen. Adjuvant-free protocols have also been described (Blyth et al., 1996), but these usually require a greater number of exposures to achieve suitable sensitisation. Sensitisation solely via the airways has also been attempted using both OVA and HDM. With OVA models, success has been limited and only modest pulmonary inflammation and mild AHR have been observed. This might be because tolerance can develop when model protein antigens are delivered via inhalation without systemic sensitisation. Inhaled delivery of HDM has been more successful, possibly because of the intrinsic enzymatic activity of this allergen. After the sensitisation period (usually 14–21 days), the animal is challenged with the allergen via the airway, usually over a period of several days. Allergen may be inhaled as a nebulised formulation (aerosol), or administered by intratracheal (i.t.) or intranasal (i.n.) instillation of an aqueous formulation.

The acute challenge mouse models reproduce many key features of clinical asthma, for example elevated levels of IgE, airway inflammation, goblet cell hyperplasia, epithelial hypertrophy, AHR to specific stimuli and, in some models, early- and late-phase bronchoconstriction in response to allergen challenge. However, there are also some major differences. In acute challenge models, the pattern and distribution of pulmonary inflammation is different from that observed in individuals with asthma (Kumar and Foster, 2002). For example, bronchoalveolar lavage and histology studies indicate that the influx of inflammatory cells is dominated by eosinophils. Because of the short-term nature of the acute models, many of the lesions observed in chronic human asthma, such as chronic inflammation of the airway wall, and airway remodelling changes are absent. Furthermore, many of the key features appear to be short-lived and, in some models, airways inflammation and AHR have been shown to resolve within a few weeks after the final allergen challenge (McMillan and Lloyd, 2004).

Despite these apparent shortcomings, acute allergen challenge models have been successfully used to investigate disease processes, in particular the relationship between cells and inflammatory mediators, and how they orchestrate the inflammatory processes in the lung. Evidence supporting the hypothesis that asthma is a Th2-mediated disease, the role of the T cell in the allergic response, and the role of the eosinophil and its involvement in the development of AHR came from studies in the acute challenge models.

A wide range of cellular and molecular targets have been identified, and subsequently evaluated, in the acute challenge models. These include anti-cytokine approaches, specific mediator antagonists, monoclonal antibodies and specific enzyme inhibitors. With a number of these targets, efficacy has been demonstrated in the acute challenge models, but not in clinical trials in patients. Anti-IL-5 therapy is one of the most frequently discussed examples. IL-5 appears to have a key role in allergen-induced inflammatory responses and the development of AHR in mice. IL-5 knockout mice were protected both from acute allergic inflammation, AHR (Foster et al., 1996) and chronic airway remodelling (Cho, et al., 2004). However, IL-5 antagonists have been evaluated in both mild acute and chronic severe asthma, and have failed to show clinical benefit (Leckie et al., 2000; Kips et al., 2003). There are other examples of drugs that have shown efficacy in acute challenge models but not in clinical studies; these include VLA4 antagonists (Norris et al., 2005), PAF antagonists (Hozawa et al., 1995) and IL-4 antagonists (Riffo-Vasquez and Spina, 2002; Borish et al., 1999). One possible explanation for the contrasting data from the mouse and human studies is that in mouse acute challenge models it is only possible to assess the affect on the development of allergic responses; whereas with clinical studies, potential suppression of established inflammatory disease is investigated.

Thus, although the acute challenge models have been useful for investigating the process underlying acute airway inflammation and AHR, there are concerns relating to the suitability of acute challenge models for both the investigation of disease processes associated with chronic asthma, and assessing potential novel treatments that may slow, or reverse, the changes of airway inflammation and remodelling, and its effect on lung function.

CHRONIC ALLERGEN CHALLENGE MODELS

In order to address some of the issues associated with acute challenge models, several research groups have investigated chronic allergen exposure in mice. The key aims were to reproduce more of the features of clinical asthma, such as airway remodelling and persistent AHR, and to enable novel therapies to be evaluated in a therapeutic setting rather than a prophylactic setting, i.e. evaluating the effect of a novel drug in an established pulmonary inflammation setting. A number of different chronic challenge models have been developed by increasing the number of allergen challenges, some examples are shown in Table 2. Kumar et al. and Lloyd have discussed some of these models in recent review articles (Kumar et al., 2008; Lloyd, 2007).

Table 2

Mouse models of chronic allergic pulmonary inflammation

Mouse gender/strainAllergenSensitisationExposure/challengeResponses post final allergen challengeReference
Female BALB/c OVA OVA + alum (i.p.) on days -7 and -21 OVA for 6/8 weeks (3 days/week) Intraepithelial eosinophilia, infiltration of lamina propria by mononuclear cells, remodelling, Th2 cytokine induction and AHR Temelkovski et al., 1998  
Female BALB/c OVA OVA + alum (i.p.) on days 0 and 14 OVA (i.n.) on days 14, 27, 28, 47, 61 and 73–75 Eosinophilic and mononuclear cell inflammation; goblet cell hyperplasia and mucus occlusion of airways; widespread deposition of subepithelial collagen Henderson et al., 2002  
Female BALB/c OVA OVA + aluminium potassium sulphate(i.p.) on days 1 and 11 OVA (i.n.) on days 11, 19, 20, 33, 34, 47, 48, 61, 62, 75, 76, 89 and 90 Increased eosinophilia, remodelling, Th2 cytokine induction and AHR Leigh et al., 2002a  
Female BALB/c OVA OVA + alum (i.p.) on days 0 and 12 OVA aerosol on days 18–23 and then 3 days/week for5/8 weeks starting on day 26 Inflammation, remodelling, Th2 cytokine induction and AHR; TGF-β induction McMillan et al., 2005  
Female BALB/c HDM extract − HDM (i.n.) 5 days/week for up to 7 weeks Eosinophilic inflammation, remodelling, Th2 cytokine induction and AHR Johnson et al., 2004  
Female BALB/c HDM extract − HDM (i.n.) 5 days/week for up to 5 weeks Eosinophilic inflammation, lung tissue inflammatory gene expression Ulrich et al., 2008  
Male BALB/c OVA OVA + AlOH3 on days 0 and 5 OVA aerosol, starting day17, 3 days/week for 6 weeks Eosinophilic inflammation, AHR, and early and late asthmatic responses Fernandez-Rodriguez et al., 2008  
Female BALB/c OVA OVA and alum (s.c.) on days 0, 7, 14 and 21 OVA (i.n.) on days 27, 29 and 31, and then twice a week for 3 months Eosinophilic inflammation, remodelling and TGF-β induction Lee et al., 2008  
Mouse gender/strainAllergenSensitisationExposure/challengeResponses post final allergen challengeReference
Female BALB/c OVA OVA + alum (i.p.) on days -7 and -21 OVA for 6/8 weeks (3 days/week) Intraepithelial eosinophilia, infiltration of lamina propria by mononuclear cells, remodelling, Th2 cytokine induction and AHR Temelkovski et al., 1998  
Female BALB/c OVA OVA + alum (i.p.) on days 0 and 14 OVA (i.n.) on days 14, 27, 28, 47, 61 and 73–75 Eosinophilic and mononuclear cell inflammation; goblet cell hyperplasia and mucus occlusion of airways; widespread deposition of subepithelial collagen Henderson et al., 2002  
Female BALB/c OVA OVA + aluminium potassium sulphate(i.p.) on days 1 and 11 OVA (i.n.) on days 11, 19, 20, 33, 34, 47, 48, 61, 62, 75, 76, 89 and 90 Increased eosinophilia, remodelling, Th2 cytokine induction and AHR Leigh et al., 2002a  
Female BALB/c OVA OVA + alum (i.p.) on days 0 and 12 OVA aerosol on days 18–23 and then 3 days/week for5/8 weeks starting on day 26 Inflammation, remodelling, Th2 cytokine induction and AHR; TGF-β induction McMillan et al., 2005  
Female BALB/c HDM extract − HDM (i.n.) 5 days/week for up to 7 weeks Eosinophilic inflammation, remodelling, Th2 cytokine induction and AHR Johnson et al., 2004  
Female BALB/c HDM extract − HDM (i.n.) 5 days/week for up to 5 weeks Eosinophilic inflammation, lung tissue inflammatory gene expression Ulrich et al., 2008  
Male BALB/c OVA OVA + AlOH3 on days 0 and 5 OVA aerosol, starting day17, 3 days/week for 6 weeks Eosinophilic inflammation, AHR, and early and late asthmatic responses Fernandez-Rodriguez et al., 2008  
Female BALB/c OVA OVA and alum (s.c.) on days 0, 7, 14 and 21 OVA (i.n.) on days 27, 29 and 31, and then twice a week for 3 months Eosinophilic inflammation, remodelling and TGF-β induction Lee et al., 2008  

Chronic allergen challenge models involve repeated exposure of the airways to low levels of allergen for periods of up to 12 weeks. Different allergens have been employed and co-administration of an adjuvant is not always required. A number of investigators, for example Temelkovski et al., Fernandez-Rodriguez et al. and Wegman have used OVA to establish a chronic exposure (Temelkovski et al., 1998; Fernandez-Rodriguez et al., 2008; Wegmann, 2008). Others have used environmentally relevant allergens such as HDM extract or grass pollen (Johnson et al., 2004; Kim et al., 2006). One anticipated problem with chronic allergen exposure, in particular with model protein antigens such as OVA, was that long-term challenge might lead to the development of tolerance and downregulation of inflammation and AHR (Jungsuwadee et al., 2004; Kumar et al., 2008). Both the strain of mouse and route of allergen administration are factors that may influence the induction of tolerance (McMillan and Lloyd, 2004; Shinagawa and Kojima, 2003). Kumar et al. suggested that tolerance might be related to the high mass concentrations of the aerosolised allergen used, which could overwhelm the clearance mechanisms (Kumar et al., 2008). This group successfully developed a model in which sensitised animals were exposed to inhalation of controlled mass concentrations of aerosolised antigen to minimise parenchymal inflammation and tolerance.

Chronic allergen exposure in mice has been shown to reproduce some of the hallmarks of human asthma including allergen-dependent sensitisation, a Th2-dependent allergic inflammation characterised by eosinophilic influx into the airway mucosa, and AHR. In addition, in some models, there is evidence of airway remodelling with goblet cell hyperplasia, epithelial hypertrophy, and either subepithelial or peribronchiolar fibrosis. Importantly, some of the key features of the chronic allergen exposure models have been shown to persist after the final challenge. After cessation of allergen challenge, some features of airway remodelling have been shown to persist in a number of models (Johnson et al., 2004; Macmillan and Lloyd, 2004; Kumar et al., 2004a). In these models, the persistence of AHR and lung inflammation varies depending on the exposure protocols employed (Lloyd, 2007).

There are limitations associated with the chronic models. In some cases, features peculiar to the mouse are observed that are not seen in human asthma. For example, in the mouse, inflammation is not restricted to the conducting airways, whereas it is in humans, and both lung parenchymal and vascular inflammation/remodelling are observed (Wenzel and Holgate, 2006). Large increases in airway smooth muscle, which is a characteristic feature of chronic asthma (Carroll et al., 1993), either does not appear to occur (Wenzel and Holgate, 2006) or, if it does, only after high level challenge (Shinagawa and Kojima, 2003; McMillan and Lloyd, 2004). Furthermore, there is little or no recruitment of mast cells into the airway wall or epithelium (Boyce and Austen, 2005), which may reflect the paucity of mast cells in the airways of mice (Kumar and Foster, 2002).

Despite these issues, using repetitive allergen provocation in mice has been shown to mimic important features of the human disease and would appear to represent an improvement over the acute challenge models.

IMPACT OF CHRONIC ALLERGEN CHALLENGE MODELS ON ASTHMA RESEARCH

Chronic allergen exposure in mice appears to now be the model of choice for studying the role of specific cell types and inflammatory cytokines and mediators in the processes involved in chronic inflammation and, in particular, some of the structural changes to the airways. For example, Humbles et al. have used a chronic challenge model to investigate the role of the eosinophil in airway remodelling (Humbles et al., 2004), and Kumar et al. and McMillan et al. have investigated the role of TGF-β in the development of airway remodelling in their chronic challenge model (Kumar et al., 2004a; McMillan et al., 2005). In addition, Yang et al. have used chronic models to investigate the role of IL-13 in regulating chronic inflammatory changes to the airway (Yang et al., 2005). These, and future, studies will add to our understanding of the mechanisms of chronic inflammation and airway remodelling and their contribution to asthma symptoms.

Chronic models may also provide a more suitable system for the preclinical evaluation of novel therapeutic agents. Unlike acute challenge models, the chronic challenge model enables investigations to be carried out in a setting of established airway inflammation and AHR and, therefore, more closely reflects most of the experimental studies undertaken in the clinic. A number of groups are using chronic models to profile established and novel pharmacological treatments for asthma. These studies might provide an insight into the predictive nature of the chronic models with regard to clinical outcome. A summary of some of the compounds that have been evaluated in mouse acute and chronic allergen challenge models and in human asthma trials is provided in Table 3. A number of anti-inflammatory agents are being profiled in chronic models, and reports of efficacy with corticosteroids (Macmillan et al., 2005), leukotriene receptor antagonists (Henderson et al., 2002) and phosphodiesterase 4 (PDE4) inhibitors (Herbert, et al., 2008) are emerging. Preliminary data suggest that certain chronic models might reproduce sensitivity to drug therapy in the clinic. However, further studies using a wider range of molecules, including examples that have demonstrated positive and negative outcomes in the clinic, are required. These studies will enable investigators to judge whether the chronic models might better reflect clinical outcome and represent an improvement over the acute challenge models.

Table 3

Compounds developed, or in development, for the treatment of respiratory disease: profile in preclinical mouse models and in clinical studies

Compound class/mechanismProfile in acute modelReferenceProfile in chronic modelReferenceProfile in clinical studiesReference
Corticosteroid(dexamethasone, budesonide, FP) Inhibited inflammation, AHR and subepithelial fibrosis Blyth et al., 2000  Inhibits airway inflammation and remodelling Kumar et al., 2003  Improved lung function (FEV1) and caused significant improvement in asthma symptom scores Pearlman et al., 1997  
Inhibited AHR, pulmonary inflammation and ameliorated remodelling Yang et al., 2005  Attenuated the maximal, late asthmatic response and protected against AHR and sputum eosinophilia Leigh et al., 2002b  
Calcineurin inhibitor(cyclosporine A) Attenuated BALF eosinophilia and inhibited AHR Nagai et al., 1996  Inhibited eosinophilia in BAL and lung; AHR was also attenuated Lee et al., 2006  Increased morning PEF; improved FEV1 and reduced exacerbations Alexander et al., 1992  
Thromboxane antagonists Reduced total cell numbers and eosinophils in BALF Shi et al., 1998  No published data − No significant improvement in FEV1 Stenton et al., 1992  
Partially blocked the induction of AHR Richter et al., 2007  
Platelet activating factor (PAF) PAF-acetylhydrolase reduced airway eosinophilia, mucus hypersecretion and AHR Henderson et al., 2000a  No published data − PAF antagonist did not protect against antigen-induced early- and late-phase response Townley et al., 1994  
5-lipoxygenase(Zileuton) Blocked airway mucus release and infiltration of eosinophils into airway; no effect on AHR Henderson et al., 1996  No published data − Reduced corticosteroid requirement, improved FEV1 and improved quality of life Israel et al., 1996  
Leukotriene antagonist(Montelukast) Reduced airway eosinophilia and AHR Eum et al., 2003  Reduced airway eosinophilia, mucus plugging, smooth muscle hyperplasia and subepithelial fibrosis Henderson et al., 2002  Improved FEV1; reduced β-agonist use and nocturnal awakenings Reiss et al., 1996  
Anti-IgE Reduced OVA-specific IgE, no effect on eosinophilia in BAL or lung, no effect on AHR Hamelmann et al., 1999b  No published data − Reduced exacerbations and steroid and β-agonist use Busse et al., 2001  
Reduced use of rescue medication; improved asthma-related symptoms; reduced steroid use and improved quality of life. Holgate et al., 2004  
Improved FEV1 and morning PEF; reduced exacerbation rate. Humbert et al., 2005  
Anti-IL-5 Inhibited eosinophilia, lung inflammation and AHR Hamelmann et al., 1999a  Inhibited eosinophilic inflammation and remodelling but had no effect on AHR Kumar et al., 2004b  Prevented blood eosinophilia but had no effect on LAR or AHR to histamine Leckie et al., 2000  
Anti-IL-4 IL-4 receptor antagonist reduced airway eosinophilia and AHR Tomkinson et al., 2001  IL-4−/− mice protected from AHR and aspects of remodelling Leigh et al., 2004a  Soluble IL-4R attenuated drop in FEV1 and inhibited increase in asthma symptom score Borish et al., 2001  
Soluble IL-4 receptor reduced inflammation and mucus hypersecretion; no effect on AHR Henderson et al., 2000b  
Anti-IL-13 Soluble IL-13 receptor suppressed AHR Leigh et al., 2004b  Suppressed pulmonary inflammation; partially suppressed changes in remodelling and had limited effect on AHR Kumar et al., 2004b  Human anti-IL-13 monoclonal antibody inhibited allergen- induced EAR and LAR Gauvreau et al., 2008  
Soluble IL-13 receptor had no effect on AHR or remodelling Leigh et al., 2004b  IL-4 mutein targeting inhibition of IL-4 and IL-13 reduced the FEV1 decreases in response to allergen challenge Wenzel et al., 2007  
VLA-4 Anti-VLA-4 antibody prevented changes in RL and inhibited cell infiltration in BAL Kanehiro et al., 2000  No published data − Antagonist had no effect on EAR or LAR; no effect on AHR Ravensberg et al., 2006  
Phosphodiesterase -4 inhibitor(rolipram, roflumilast) Prevented changes in RL and Cdyn, and reduced inflammation, goblet cell hyperplasia and IL-4 and -5 levels in BALF Kanehiro et al., 2001  Inhibited eosinophil infiltration and ameliorated remodelling; AHR was slightly reduced Kumar et al., 2003  Inhibited both EAR and LAR Van Schalkwyk et al., 2005  
Attenuated AHR and reduced the decrease in FEV1 during late asthmatic response Louw et al., 2007  
Anti-CD4/8 Anti-CD4/8 treatment inhibited AHR and inflammation Leigh et al., 2004c  Anti-CD4/8 treatment did not inhibit AHR in chronic protocol; remodelling was unaffected Leigh et al., 2004a  High dose anti-CD4 monoclonal antibody associated with an improvement of PEF; FEV1 was unchanged from placebo control; non-significant improvement in symptom score Kon et al., 1998  
Inhibited AHR, remodelling and lung plasma cells; moderate reduction in inflammation; no reduction in intraepithelial eosinophilia and eotaxin expression Foster et al., 2002  
Anti-TNF-α Reduced BAL neutrophilia and BAL/lung eosinophilia; BALF cytokines reduced Deveci et al., 2008  No published data − Improved asthma symptoms, lung function and bronchial hyperresponsiveness. Howarth et al., 2005  
Inhibited late asthma response without affecting early response; reduced airway eosinophilia and inflammation Choi et al., 2005  
Compound class/mechanismProfile in acute modelReferenceProfile in chronic modelReferenceProfile in clinical studiesReference
Corticosteroid(dexamethasone, budesonide, FP) Inhibited inflammation, AHR and subepithelial fibrosis Blyth et al., 2000  Inhibits airway inflammation and remodelling Kumar et al., 2003  Improved lung function (FEV1) and caused significant improvement in asthma symptom scores Pearlman et al., 1997  
Inhibited AHR, pulmonary inflammation and ameliorated remodelling Yang et al., 2005  Attenuated the maximal, late asthmatic response and protected against AHR and sputum eosinophilia Leigh et al., 2002b  
Calcineurin inhibitor(cyclosporine A) Attenuated BALF eosinophilia and inhibited AHR Nagai et al., 1996  Inhibited eosinophilia in BAL and lung; AHR was also attenuated Lee et al., 2006  Increased morning PEF; improved FEV1 and reduced exacerbations Alexander et al., 1992  
Thromboxane antagonists Reduced total cell numbers and eosinophils in BALF Shi et al., 1998  No published data − No significant improvement in FEV1 Stenton et al., 1992  
Partially blocked the induction of AHR Richter et al., 2007  
Platelet activating factor (PAF) PAF-acetylhydrolase reduced airway eosinophilia, mucus hypersecretion and AHR Henderson et al., 2000a  No published data − PAF antagonist did not protect against antigen-induced early- and late-phase response Townley et al., 1994  
5-lipoxygenase(Zileuton) Blocked airway mucus release and infiltration of eosinophils into airway; no effect on AHR Henderson et al., 1996  No published data − Reduced corticosteroid requirement, improved FEV1 and improved quality of life Israel et al., 1996  
Leukotriene antagonist(Montelukast) Reduced airway eosinophilia and AHR Eum et al., 2003  Reduced airway eosinophilia, mucus plugging, smooth muscle hyperplasia and subepithelial fibrosis Henderson et al., 2002  Improved FEV1; reduced β-agonist use and nocturnal awakenings Reiss et al., 1996  
Anti-IgE Reduced OVA-specific IgE, no effect on eosinophilia in BAL or lung, no effect on AHR Hamelmann et al., 1999b  No published data − Reduced exacerbations and steroid and β-agonist use Busse et al., 2001  
Reduced use of rescue medication; improved asthma-related symptoms; reduced steroid use and improved quality of life. Holgate et al., 2004  
Improved FEV1 and morning PEF; reduced exacerbation rate. Humbert et al., 2005  
Anti-IL-5 Inhibited eosinophilia, lung inflammation and AHR Hamelmann et al., 1999a  Inhibited eosinophilic inflammation and remodelling but had no effect on AHR Kumar et al., 2004b  Prevented blood eosinophilia but had no effect on LAR or AHR to histamine Leckie et al., 2000  
Anti-IL-4 IL-4 receptor antagonist reduced airway eosinophilia and AHR Tomkinson et al., 2001  IL-4−/− mice protected from AHR and aspects of remodelling Leigh et al., 2004a  Soluble IL-4R attenuated drop in FEV1 and inhibited increase in asthma symptom score Borish et al., 2001  
Soluble IL-4 receptor reduced inflammation and mucus hypersecretion; no effect on AHR Henderson et al., 2000b  
Anti-IL-13 Soluble IL-13 receptor suppressed AHR Leigh et al., 2004b  Suppressed pulmonary inflammation; partially suppressed changes in remodelling and had limited effect on AHR Kumar et al., 2004b  Human anti-IL-13 monoclonal antibody inhibited allergen- induced EAR and LAR Gauvreau et al., 2008  
Soluble IL-13 receptor had no effect on AHR or remodelling Leigh et al., 2004b  IL-4 mutein targeting inhibition of IL-4 and IL-13 reduced the FEV1 decreases in response to allergen challenge Wenzel et al., 2007  
VLA-4 Anti-VLA-4 antibody prevented changes in RL and inhibited cell infiltration in BAL Kanehiro et al., 2000  No published data − Antagonist had no effect on EAR or LAR; no effect on AHR Ravensberg et al., 2006  
Phosphodiesterase -4 inhibitor(rolipram, roflumilast) Prevented changes in RL and Cdyn, and reduced inflammation, goblet cell hyperplasia and IL-4 and -5 levels in BALF Kanehiro et al., 2001  Inhibited eosinophil infiltration and ameliorated remodelling; AHR was slightly reduced Kumar et al., 2003  Inhibited both EAR and LAR Van Schalkwyk et al., 2005  
Attenuated AHR and reduced the decrease in FEV1 during late asthmatic response Louw et al., 2007  
Anti-CD4/8 Anti-CD4/8 treatment inhibited AHR and inflammation Leigh et al., 2004c  Anti-CD4/8 treatment did not inhibit AHR in chronic protocol; remodelling was unaffected Leigh et al., 2004a  High dose anti-CD4 monoclonal antibody associated with an improvement of PEF; FEV1 was unchanged from placebo control; non-significant improvement in symptom score Kon et al., 1998  
Inhibited AHR, remodelling and lung plasma cells; moderate reduction in inflammation; no reduction in intraepithelial eosinophilia and eotaxin expression Foster et al., 2002  
Anti-TNF-α Reduced BAL neutrophilia and BAL/lung eosinophilia; BALF cytokines reduced Deveci et al., 2008  No published data − Improved asthma symptoms, lung function and bronchial hyperresponsiveness. Howarth et al., 2005  
Inhibited late asthma response without affecting early response; reduced airway eosinophilia and inflammation Choi et al., 2005  

BALF, bronchoalveolar lavage fluid; BAL, bronchoalveolar lavage; RL, lung resistance; Cdyn, dynamic compliance; PEF, peak expiratory flow; EAR, early asthmatic response; LAR, late asthmatic response; FEV, forced expiratory volume.

CONCLUSIONS

Mouse allergen challenge models are a basic, and frequently used, tool for asthma research. Because of the complexity and diverse nature of the disease, it is unlikely that a mouse model that is truly representative of clinical asthma will be developed. Efforts are focusing on modelling specific disease phenotypes rather than trying to reproduce all features of asthma in a single model. Acute allergen challenge models have been extensively used to investigate pulmonary inflammation and AHR, but their use is limited, in particular when relating findings to chronic asthma. Chronic allergen challenge models appear to reproduce some of the features of chronic asthma and might enable key questions, relating to both the pathogenesis of asthma and potential approaches to novel therapy, to be addressed. Both acute and chronic allergen challenge models have limitations that need to be taken into account when extrapolating findings from the animal model to the human disease.

It is important that mouse models are valid and reflect clinical asthma as closely as possible. Studies are ongoing to refine and improve existing models in order to enhance their utility. For example, asthma exacerbations account for the majority of asthma-related hospital visits and this is becoming a focus of research. Mouse models are being developed to model asthma exacerbations, and investigators are using acute and chronic allergen challenge models as a background for superimposing additional, higher intensity allergen challenge (Siegle et al., 2006; Ito et al., 2008) or viral infection (Bartlett et al., 2008).

A combination of improved animal models, which more closely reflect asthma, and use of relevant human systems will broaden our knowledge of the disease and help identify and evaluate new therapeutic targets.

Acknowledgements

Deposited in PMC for immediate release.

REFERENCES

Alexander
A. G.
,
Barnes
N. C.
,
Kay
A. B.
(
1992
).
Trial of cyclosporin in corticosteroid-dependent chronic severe asthma
.
Lancet
339
,
324
328
.
Bartlett
N. W.
,
Walton
R. P.
,
Edwards
M. R.
,
Aniscenko
J.
,
Caramori
G.
,
Zhu
J.
,
Glanville
N.
,
Choy
K. J.
,
Jourdan
P.
,
Burnet
J.
, et al. 
(
2008
).
Mouse models of rhinovirus-induced disease and exacerbation of allergic airway inflammation
.
Nat. Med.
14
,
199
204
.
Blyth
D. I.
,
Pedrick
M. S.
,
Savage
T. J.
,
Hessel
E. M.
,
Fattah
D.
(
1996
).
Lung inflammation and epithelial changes in a murine model of atopic asthma
.
Am. J. Respir. Cell Mol. Biol.
14
,
425
438
.
Blyth
D. I.
,
Wharton
T. F.
,
Pedrick
M. S.
,
Savage
T. J.
,
Sanjar
S.
(
2000
).
Airway subepithelial fibrosis in a murine model of atopic asthma, suppression by dexamethasone or anti-IL-5 antibody
.
Am. J. Respir. Cell Mol. Biol.
23
,
241
246
.
Borish
L. C.
,
Nelson
H. S.
,
Lanz
M. J.
,
Claussen
L.
,
Whitmore
J. B.
,
Agosti
J. M.
,
Garrison
L.
(
1999
).
Interleukin-4 receptor in moderate atopic asthma: a phase I/II randomized, placebo controlled trial
.
Am. J. Respir. Crit. Care Med.
160
,
1816
1823
.
Borish
L. C.
,
Nelson
H. S.
,
Corren
J.
(
2001
).
Efficacy of soluble IL-4 receptor for the treatment of adults with asthma
.
J. Allergy Clin. Immunol.
107
,
963
970
.
Bousquet
J.
,
Jeffery
P. K.
,
Busse
W. W.
,
Johnson
M.
,
Vignola
A. M.
(
2000
).
Asthma: from bronchoconstriction to airways inflammation and remodelling
.
Am. J. Respir. Crit. Care Med.
161
,
1720
1745
.
Boyce
J. A.
,
Austen
K. F.
(
2005
).
No audible wheezing: nuggets and conundrums from mouse asthma models
.
J. Exp. Med.
201
,
1869
1873
.
Busse
W.
,
Corren
J.
,
Lanier
B. Q.
,
McAlary
M.
,
Fowler-Taylor
A.
,
Cioppa
G. D.
,
van As
A.
,
Gupta
N.
(
2001
).
Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma
.
J. Allergy Clin. Immunol.
108
,
184
190
.
Carroll
N. G.
,
Elliot
J.
,
Morton
A. R.
,
James
A. L.
(
1993
).
The structure of large and small airways in nonfatal and fatal asthma
.
Am. Rev. Respir. Dis.
147
,
405
410
.
Cho
J. Y.
,
Miller
M.
,
Baek
K. J.
,
Han
J. W.
,
Nayar
J.
,
Lee
S. Y.
,
McElwain
K.
,
McElwain
S.
,
Friedman
S.
,
Broide
D. H.
(
2004
).
Inhibition of airway remodeling in IL-5 deficient mice
.
J. Clin. Invest.
13
,
551
560
.
Choi
I. W.
,
Sun-Kim Kim
Y. S.
,
Ko
H. M.
,
Im
S. Y.
,
Kim
J. H.
,
You
H. J.
,
Lee
Y. C.
,
Lee
J. H.
,
Park
Y. M.
, et al. 
(
2005
).
TNF-a induces the late-phase airway hyperresponsiveness and airway inflammation through cytosolic phospholipase A2 activation
.
J. Allergy Clin. Immunol.
116
,
537
543
.
Deveci
F.
,
Muz
M. H.
,
Ilhan
N.
,
Kirkil
G.
,
Turgut
T.
,
Akpolat
N.
(
2008
).
Evaluation of the anti-inflammatory effect of infliximab in a mouse model of acute asthma
.
Respirology
13
,
488
497
.
Epstein
M. M.
(
2004
).
Do mouse models of allergic asthma mimic clinical disease?
Int. Arch. Allergy Immunol.
133
,
84
100
.
Eum
S. Y.
,
Maghni
K.
,
Hamid
Q.
,
Campbell
H.
,
Eidelman
D. H.
,
Martin
J. G.
(
2003
).
Involvement of the cysteinyl-leukotrienes in allergen-induced airway eosinophilia and hyperresponsiveness in the mouse
.
Am. J. Respir. Cell Mol. Biol.
28
,
25
32
.
Fernandez-Rodriguez
S.
,
Ford
W. R.
,
Broadley
K. J.
,
Kidd
E. J.
(
2008
).
Establishing the phenotype in novel acute and chronic murine models of allergic asthma
.
Int. Immunopharmacol.
8
,
756
763
.
Fish
J. E.
,
Peters
S. P.
(
1999
).
Airway remodelling and persistent airways obstruction in asthma
.
J. Allergy Clin. Immunol.
104
,
509
516
.
Foster
P.
,
Hogan
S.
,
Ramsay
A.
,
Matthaei
K.
,
Young
I.
(
1996
).
Interleukin-5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model
.
J. Exp. Med.
183
,
195
201
.
Foster
P. S.
,
Yang
M.
,
Herbert
C.
,
Kumar
R. K.
(
2002
).
CD4(+) T-lymphocytes regulate airway remodeling and hyper-reactivity in a mouse model of chronic asthma
.
Lab. Invest.
82
,
455
462
.
Gauvreau
G. M.
,
Boulet
L.-P.
,
Fitzgerald
J. M.
,
Durn
B.
,
Zhou
S.
,
Burt
D.
,
Watson
R. M.
,
Duong
M.
,
Killian
K. J.
,
Carlsten
C.
, et al. 
(
2008
).
The effects of IMA-638 on allergen induced airway responses in subjects with mild atopic asthma. European Respiratory Society Meeting, Berlin
.
Eur. Resp. J.
Abstract 827S. (in press).
Global initiative for asthma (GINA)
.
2006
. http://www.ginaasthma.com
Hamelmann
E.
,
Cieslewicz
G.
,
Schwarze
J.
,
Ishizuka
T.
,
Joetham
A.
,
Heusser
C.
,
Gelfand
E. W.
(
1999a
).
Anti-IL-5 but not anti-IgE prevents airway inflammation and airway hyperresponsiveness
.
Am. J. Respir. Crit. Care Med.
160
,
934
941
.
Hamelmann
E.
,
Tadeda
K.
,
Oshiba
A.
,
Gelfand
E. W.
(
1999b
).
Role of IgE in the development of allergic airway inflammation and airway hyperresponsiveness – a murine model
.
Allergy
54
,
297
305
.
Henderson
W. R.
 Jr
,
Lewis
D. B.
,
Albert
R. K.
,
Zhang
Y.
,
Lamm
W. J.
,
Chianf
G. K.
,
Jones
F.
,
Eriksen
P.
,
Tien
Y. T.
,
Jonas
M.
, et al. 
(
1996
).
The importance of leukotrienes in airway inflammation in a mouse model of asthma
.
J. Exp. Med.
184
,
1483
1494
.
Henderson
W. R.
 Jr
,
Lu
J.
,
Poole
K. M.
,
Dietsch
G. N.
,
Chi
E. Y.
(
2000a
).
Recombinant human platelet-activating factor-acetylhydrolase inhibits airway inflammation and hyperreactivity in mouse asthma model
.
J. Immunol.
164
,
3360
3367
.
Henderson
W. R.
 Jr
,
Chi
E. Y.
,
Maliszewski
C. R.
(
2000b
).
Soluble IL-4 receptor inhibits airway inflammation following allergen challenge in a mouse model of asthma
.
J. Immunol.
164
,
1086
1095
.
Henderson
W. R.
,
Tang
L.
,
Chu
S.
,
Tsao
S. M.
,
Chiang
G. K.
,
Jones
F.
,
Jonas
M.
,
Pae
C.
,
Wang
H.
,
Chi
E. Y.
(
2002
).
A role for cysteinyl leukotrienes in airway remodelling in a mouse asthma model
.
Am. J. Respir. Crit. Care Med.
165
,
108
116
.
Herbert
C.
,
Hettiaratchi
A.
,
Webb
D. C.
,
Thomas
P. S.
,
Foster
P. S.
,
Kumar
R. K.
(
2008
).
Suppression of cytokine expression by roflumilast and dexamethasone in a model of chronic asthma
.
Clin. Exp. Allergy
38
,
847
856
.
Hessel
E. M.
,
Zwart
A.
,
Oostveen
E.
,
Van Oosterhout
A. J.
,
Blyth
D. I.
,
Nijkamp
F. P.
(
1995
).
Repeated measurement of respiratory function and bronchoconstriction in unanesthetised mice
.
J. Appl. Physiol.
79
,
1711
1716
.
Holgate
S. T.
,
Chuchalin
A. G.
,
Hébert
J.
,
Lötvall
J.
,
Persson
G. B.
,
Chung
K. F.
,
Bousquet
J.
,
Kerstjens
H. A.
,
Fox
H.
,
Thirlwell
J.
, et al. 
(
2004
).
Efficacy and safety of a recombinant anti-immunoglobulin E antibody (omalizumab) in severe allergic asthma
.
Clin. Exp. Allergy
34
,
632
638
.
Howarth
P. H.
,
Babu
K. S.
,
Arshad
H. S.
,
Lau
L.
,
Buckley
M.
,
McConnell
W.
,
Becket
P.
,
Al Ali
M.
,
Chauhan
A.
,
Wilson
S. J.
, et al. 
(
2005
).
Tumour necrosis factor (TNFalpha) as a novel therapeutic target in symptomatic corticosteroid dependent asthma
.
Thorax
60
,
1012
1018
.
Hozawa
S.
,
Hiruta
Y.
,
Ishioka
S.
,
Yamakido
M.
(
1995
).
Effects of a PAF antagonist, Y-24180 on bronchial hyperresponsiveness in patients with asthma
.
Am. J. Respir. Crit. Care Med.
152
,
1198
1202
.
Humbert
M.
,
Beasley
R.
,
Ayres
J.
,
Slavin
R.
,
Hébert
J.
,
Bousquet
J.
,
Beeh
K. M.
,
Ramos
S.
,
Canonica
G. W.
,
Hedgecock
S.
, et al. 
(
2005
).
Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE
.
Allergy
60
,
309
316
.
Humbles
A. A.
,
Lloyd
C. M.
,
McMillan
S. J.
,
Friend
D. S.
,
Xanthou
G.
,
McKenna
E. E.
,
Ghiran
S.
,
Gerard
N. P.
,
Yu
C.
,
Orkin
S. H.
, et al. 
(
2004
).
A critical role for eosinophils in allergic airways remodeling
.
Science
305
,
1776
1779
.
Israel
E.
,
Cohn
J.
,
Dubé
L.
,
Drazen
J. M.
(
1996
).
Effect of treatment with zileuton, a 5-lipoxygenase inhibitor, in patients with asthma: a randomized controlled trial
. Zileuton Clinical Trial Group.
JAMA
275
,
931
936
.
Ito
K.
,
Herbert
C.
,
Siegle
J. S.
,
Vuppusetty
C.
,
Hansbro
N.
,
Thomas
P.
,
Foster
P.
,
Barnes
P.
,
Kumar
R.
(
2008
).
Steroid-resistant neutrophilic inflammation in a mouse model of an acute exacerbation of asthma
.
Am. J. Respir. Crit. Care Med.
(in press).
Janssen
E. M.
,
van Oosterhout
A. J. M.
,
Nijkamp
F. P.
,
van Eden
W.
,
Wauben
M. H.
(
2000
).
The efficacy of immunotherapy in an experimental murine model of allergic asthma is related to the strength and site of T cell activation during immunotherapy
.
J. Immunol.
165
,
7207
7214
.
Johnson
J. R.
,
Wiley
R. E.
,
Fattouh
R.
,
Swirski
F. K.
,
Gajewska
B. U.
,
Coyle
A. J.
,
Guttierrez-Ramos
J. C.
,
Ellis
R.
,
Inman
M. D.
,
Jordana
M.
(
2004
).
Continuous exposure to house dust mite elicits chronic airway inflammation and structural remodelling
.
Am. J. Respir. Crit. Care Med.
169
,
378
385
.
Jungsuwadee
P.
,
Benkovsky
M.
,
Dekan
G.
,
Stingl
G.
,
Epstein
M. M.
(
2004
).
Repeated aerosol allergen exposure suppresses inflammation in B-cell deficient mice with established allergic asthma
.
Int. Arch. Allergy Immunol.
133
,
126
134
.
Kanehiro
A.
,
Takeda
K.
,
Joetham
A.
,
Tomkinson
A.
,
Ikemura
T.
,
Irvin
C. G.
,
Gelfand
E. W.
(
2000
).
Timing of administration of anti-VLA-4 differentiates airway hyperresponsiveness in the central and peripheral airways in mice
.
Am. J. Respir. Crit. Care Med.
162
,
1132
1139
.
Kanehiro
A.
,
Ikemura
T.
,
Mäkelä
M. J.
,
Lahn
M.
,
Joetham
A.
,
Dakhama
A.
,
Gelfand
E. W.
(
2001
).
Inhibition of PDE4 attenuates airway hyperresponsiveness and airway inflammation in a model of secondary allergen challenge
.
Am. J. Respir. Crit. Care Med.
163
,
173
184
.
Kim
C. H.
,
Ahn
J. H.
,
Kim
S. J.
,
Lee
S. Y.
,
Kim
Y. K.
,
Kim
K. H.
,
Moon
H. S.
,
Song
J. S.
,
Park
S. H.
,
Kwon
S. S.
(
2006
).
Co-administration of vaccination with DNA encoding T-cell epitope on the Der p and BCG inhibited airway remodelling in a murine model of chronic asthma
.
J. Asthma
43
,
345
353
.
Kips
J. C.
,
O’Connor
B. J.
,
Langley
S. J.
,
Woodcock
A.
,
Kerstjens
H. A.
,
Postma
D. S.
,
Danzig
M.
,
Cuss
F.
,
Pauwels
R. A.
(
2003
).
Effect of SCH55700, a humanized anti-human interleukin-5 antibody, in severe persistent asthma; a pilot study
.
Am. J. Respir. Crit. Care Med.
167
,
1655
1659
.
Kon
O. M.
,
Sihra
B. S.
,
Compton
C. H.
,
Leonard
T. B.
,
Kay
A. B.
,
Barnes
N. C.
(
1998
).
Randomised, dose-ranging, placebo-controlled study of chimeric antibody to CD4 (keliximab) in chronic severe asthma
.
Lancet
352
,
1109
1113
.
Kumar
R. K.
,
Foster
P. S.
(
2002
).
Modeling allergic asthma in mice: pitfalls and opportunities
.
Am. J. Respir. Cell Mol. Biol.
27
,
267
272
.
Kumar
R. K.
,
Herbert
C.
,
Thomas
P. S.
,
Wollin
L.
,
Beume
R.
,
Yang
M.
,
Webb
D. C.
,
Foster
P. S.
(
2003
).
Inhibition of inflammation and remodeling by roflumilast and dexamethasone in murine chronic asthma
.
J. Pharmacol. Exp. Ther.
307
,
349
355
.
Kumar
R. K.
,
Herbert
C.
,
Kasper
M.
(
2004a
).
Reversibility of airway inflammation and remodelling following cessation of antigenic challenge in a model of chronic asthma
.
Clin. Exp. Allergy
34
,
1796
1802
.
Kumar
R. K.
,
Herbert
C.
,
Webb
D. C.
,
Li
L.
,
Foster
P. S.
(
2004b
).
Effects of anticytokine therapy in a mouse model of chronic asthma
.
Am. J. Respir. Crit. Care Med.
170
,
1043
1048
.
Kumar
R. K.
,
Herbert
C.
,
Foster
P. S.
(
2008
).
The ‘classical’ ovalbumin challenge model of asthma in mice
.
Curr. Drug Targets
9
,
485
494
.
Leckie
M. J.
,
ten Brinke
A.
,
Khan
J.
,
Diamant
Z.
,
O’Connor
B. J.
,
Walls
C. M.
,
Mathur
A. K.
,
Cowley
H. C.
,
Chung
K. F.
,
Djukanovic
R.
, et al. 
(
2000
).
Effects of interleukin-5 blocking monoclonal antibody on eosinophils, airways hyerresponsiveness, and the late asthmatic response
.
Lancet
356
,
2144
2148
.
Lee
S. Y.
,
Kim
J. S.
,
Lee
J. M.
,
Kwon
S. S.
,
Kim
K. H.
,
Moon
H. S.
,
Song
J. S.
,
Park
S. H.
,
Kim
Y. K.
(
2008
).
Inhaled corticosteroid prevents the thickening of airway smooth muscle in murine model of chronic asthma
.
Pulm. Pharmacol. Ther.
21
,
14
19
.
Lee
Y. C.
,
Kim
S. H.
,
Seo
Y. B.
,
Rho
S. S.
,
Lee
J. C.
(
2006
).
Inhibitory effects of Actinidia polygama extract and cyclosporine A on OVA-induced eosinophilia and bronchial hyperresponsiveness in a murine model of asthma
.
Int. Immunopharmacol
.
6
,
703
713
.
Leigh
R.
,
Ellis
R.
,
Wattie
J.
,
Southam
D. S.
,
De Hoogh
M.
,
Gauldie
J.
,
O’Byrne
P. M.
,
Inman
M. D.
(
2002a
).
Dysfunction and remodeling of the mouse airway persist after resolution of acute allergen-induced airway inflammation
.
Am. J. Respir. Cell Mol. Biol.
27
,
526
535
.
Leigh
R.
,
Vethanayagam
D.
,
Yoshida
M.
,
Watson
R. M.
,
Rerecich
T.
,
Inman
M. D.
,
O’Byrne
P. M.
(
2002b
).
Effects of montelukast and budesonide on airway responses and airway inflammation in asthma
.
Am. J. Respir. Crit. Care Med.
166
,
1212
1217
.
Leigh
R.
,
Ellis
R.
,
Wattie
J. N.
,
Hirota
J. A.
,
Matthaei
K. I.
,
Foster
P. S.
,
O’Byrne
P. M.
,
Inman
M. D.
(
2004a
).
Type 2 cytokines in the pathogenesis of sustained airway dysfunction and airway remodeling in mice
.
Am. J. Respir. Crit. Care Med
.
169
,
860
867
.
Leigh
R.
,
Ellis
R.
,
Wattie
J.
,
Donaldson
D. D.
,
Inman
M. D.
(
2004b
).
Is interleukin-13 critical in maintaining airway hyperresponsiveness in allergen-challenged mice?
Am. J. Respir. Crit. Care Med.
170
,
851
856
.
Leigh
R.
,
Southam
D. S.
,
Ellis
R.
,
Wattie
J. N.
,
Sehmi
R.
,
Wan
Y.
,
Inman
M. D.
(
2004c
).
T-cell-mediated inflammation does not contribute to the maintenance of airway dysfunction in mice
.
J. Appl. Physiol.
97
,
2258
2265
.
Lloyd
C. M.
(
2007
).
Building better mouse models of asthma
.
Curr. Allergy Asthma Rep.
7
,
231
236
.
Lloyd
C. M.
,
Gonzalo
J.
,
Nguyen
T.
,
Delaney
T.
,
Tian
J.
,
Oettgen
H.
,
Coyle
A. J.
,
Gutierrez-Ramos
J. C.
(
2000
).
Resolution of bronchial hyperresponsiveness and pulmonary inflammation is associated with IL-13 and tissue leukocyte apoptosis
.
J. Immunol.
166
,
2033
2040
.
Louw
C.
,
Williams
Z.
,
Venter
L.
,
Leitchtl
S.
,
Schmid-Wirlitsch
C.
,
Bredenbroker
D.
,
Bardin
P. G.
(
2007
).
Roflumilast, a phosphodiesterase 4 inhibitor, reduces airway hyperresponsiveness after allergen challenge
.
Respiration
74
,
411
417
.
McMillan
S. J.
,
Lloyd
C. M.
(
2004
).
Prolonged allergen challenge in mice leads to persistent airway remodelling
.
Clin. Exp. Allergy
34
,
497
507
.
McMillan
S. J.
,
Bishop
B.
,
Townsend
M. J.
,
McKenzie
A. N.
,
Lloyd
C. M.
(
2002
).
The absence of IL-9 does not affect the development of allergen-induced pulmonary inflammation nor airway hyperreactivity
.
J. Exp. Med.
195
,
51
57
.
McMillan
S. J.
,
Xanthou
G.
,
Lloyd
C. M.
(
2005
).
Therapeutic administration of Budesonide ameliorates allergen-induced airway remodelling
.
Clin. Exp. Allergy
35
,
388
396
.
Nagai
H.
,
Yamaguchi
S.
,
Tanaka
H.
(
1996
).
The role of interleukin-5 in allergic airway hyperresponsiveness in mice
.
Ann. N. Y. Acad. Sci.
796
,
91
96
.
Norris
V.
,
Choong
L.
,
Tran
D.
,
Corden
Z.
,
Boyce
M.
,
Arshad
H.
,
Holgate
S.
,
O’Connor
B.
,
Millet
S.
,
Miller
B.
, et al. 
(
2005
).
Effect of IVL745, a VLA-4 antagonist on allergen-induced bronchoconstriction in patients with asthma
.
J. Allergy Clin. Immunol.
116
,
761
767
.
Pearlman
D. S.
,
Noonan
M. J.
,
Tashkin
D. P.
,
Goldstein
M. F.
,
Hamedani
A. G.
,
Kellerman
D. J.
,
Schaberg
A.
(
1997
).
Comparative efficacy and safety of twice daily fluticasone propionate powder versus placebo in the treatment of moderate asthma
.
Ann. Allergy Asthma Immunol.
78
,
356
362
.
Ravensberg
A. J.
,
Luijk
B.
,
Westers
P.
,
Hiemstra
P. S.
,
Sterk
P. J.
,
Lammers
J. W.
,
Rabe
K. F.
(
2006
).
The effect of a single inhaled dose of a VLA-4 antagonist on allergen-induced airway responses and airway inflammation in patients with asthma
.
Allergy
61
,
1097
1103
.
Reiss
T. F.
,
Altman
L. C.
,
Chervinsky
P.
,
Bewtra
A.
,
Stricker
W. E.
,
Noonan
G. P.
,
Kundu
S.
,
Zhang
J.
(
1996
).
Effects of montelukast (MK-0476), a new potent cysteinyl leukotriene (LTD4) receptor antagonist, in patients with chronic asthma
.
J. Allergy Clin. Immunol.
98
,
528
534
.
Richter
M.
,
Cloutier
S.
,
Sirois
P.
(
2007
).
Endothelin, PAF and thromboxane A2 in allergic pulmonary hyperreactivity in mice. Prostaglandins Leukot
.
Essent. Fatty Acids
76
,
299
308
.
Riffo-Vasquez
Y.
,
Spina
D.
(
2002
).
Role of cytokines and chemokines in bronchial hyperresponsiveness and airway inflammation
.
Pharmacol. Ther.
94
,
185
211
.
Sarpong
S. B.
,
Zhang
L.
,
Kleeberger
S. R.
(
2003
).
A novel mouse model of experimental asthma
.
Int. Arch. Allergy Immunol.
132
,
346
354
.
Shi
H.
,
Yokoyama
A.
,
Kohno
N.
(
1998
).
Effect of thromboxane A2 inhibitors on allergic pulmonary inflammation in mice
.
Eur. Respir. J.
11
,
624
629
.
Shinagawa
K.
,
Kojima
M.
(
2003
).
Mouse model of airway remodelling: strain differences
.
Am. J. Respir. Crit. Care Med.
68
,
959
967
.
Siegle
J. S.
,
Hansbro
N.
,
Herbert
C.
,
Yang
M.
,
Foster
P. S.
,
Kumar
R. K.
(
2006
).
Airway hyperreactivity in exacerbation of chronic asthma is independent of eosinophilic inflammation
.
Am. J. Resp. Cell Mol. Biol.
35
,
565
570
.
Stenton
S. C.
,
Young
C. A.
,
Harris
A.
,
Palmer
J. B.
,
Hendrick
D. J.
,
Walters
E. H.
(
1992
).
The effect of GR32191 (a thromboxane receptor antagonist) on airway responsiveness in asthma
.
Pulm. Pharmacol.
5
,
199
202
.
Temelkovski
J.
,
Hogan
S. P.
,
Shepherd
D. P.
,
Foster
P. S.
,
Kumar
R. K.
(
1998
).
An improved murine model of asthma: selective airway inflammation, epithelial lesions and increased methacholine responsiveness following chronic exposure to aerosolised allergen
.
Thorax
53
,
849
856
.
Tomkinson
A.
,
Duez
A.
,
Cieslewicz
G.
,
Pratt
J. C.
,
Joetham
A.
,
Shanafelt
M. C.
,
Gundel
R.
,
Gelfand
E. W.
(
2001
).
A murine IL-4 receptor antagonist that inhibits IL-4- and IL-13-induced responses prevents antigen-induced airway eosinophilia and airway hyperresponsiveness
.
J. Immunol.
166
,
5792
5800
.
Tournoy
K. G.
,
Kips
J. C.
,
Schou
C.
,
Pauwels
R. A.
(
2000
).
Airway eosinophilia is not a requirement for allergen-induced airway hyperresponsiveness
.
Clin. Exp. Allergy
30
,
79
85
.
Townley
R. G.
,
Eda
R.
,
Hopp
R. J.
,
Bewtra
A. K.
,
Gillen
M. S.
(
1994
).
The effect of RP 59227, a platelet-activating factor antagonist, against antigen challenge and eosinophil and neutrophil chemotaxis in asthmatics
.
J. Lipid Mediat. Cell Signal.
10
,
345
353
.
Ulrich
K.
,
Hincks
J. S.
,
Walsh
R.
,
Wetterstrand
E. M.
,
Fidock
M. D.
,
Sreckovic
S.
,
Lamb
D. J.
,
Douglas
G. J.
,
Yeadon
M.
,
Perros-Huguet
C.
, et al. 
(
2008
).
Anti-inflammatory modulation of chronic airway inflammation in the murine house dust mite model
.
Pulm. Pharmacol. Ther.
21
,
637
647
.
Van Schalkwyk
E.
,
Strydom
K.
,
Williams
Z.
,
Venter
L.
,
Leichtl
S.
,
Schmid-Wirlitsch
C.
,
Bredenbröker
D.
,
Bardin
P. G.
(
2005
).
Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, attenuates allergen-induced asthmatic reactions
.
J. Allergy Clin. Immunol.
116
,
292
298
.
Wegmann
M.
(
2008
).
Animal models of chronic experimental asthma-strategies for the identification of new therapeutic targets
.
J. Occup. Med. Toxicol.
3
,
S4
.
Wenzel
S.
,
Holgate
S. T.
(
2006
).
The mouse trap: it still yields few answers in asthma
.
Am. J. Respir. Crit. Care Med.
174
,
1173
1175
.
Wenzel
S.
,
Wilbraham
D.
,
Fuller
R.
,
Getz
E. B.
,
Longphre
M.
(
2007
).
Effect of an Interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies
.
Lancet
370
,
1422
1431
.
Yang
G.
,
Li
L.
,
Volk
A.
,
Emmell
E.
,
Petley
T.
,
Giles-Komar
J.
,
Rafferty
P.
,
Lakshminarayanan
M.
,
Griswold
D. E.
,
Bugelski
P. J.
, et al. 
(
2005
).
Therapeutic dosing with an anti-interleukin-13 monoclonal antibody inhibits asthma progression in mice
.
J. Pharmacol. Exp. Ther.
313
,
8
15
.
Zosky
G. R.
,
Sly
P. D.
(
2007
).
Animal models of asthma
.
Clin. Exp. Allergy
37
,
973
988
.

COMPETING INTERESTSThe authors declare no competing financial interests.