© 2003 American Thoracic Society
Modeling Airway RemodelingThe Winner by a Nose?Physiology Program Harvard School of Public Health Boston, Massachusetts Asthma is a syndrome characterized by episodes of reversible airway obstruction. Some asthmatics, however, also experience a gradual decline in lung function due to fixed obstruction. This fixed obstruction may be related to the marked airway remodeling that is observed in histologic sections of subjects who died of asthma. Indeed, airway remodeling can be observed in airway biopsies of even mild to moderate asthmatics. The features of asthmatic airway remodeling include subepithelial fibrosis, increased numbers and volume of mucous cells in the epithelium, increased amounts of airway smooth muscle, and increased vascularization of the airway wall (1), and may be related to repeated bouts of inflammation and repair. Given its potential impact on lung function, it is important to understand the etiology of airway remodeling in asthma to develop therapies that arrest or reverse it. Animal models represent a powerful tool for such studies. Many investigators have chosen to try and model the asthmatic phenotype in mice because of the advantages associated with this species, including cost, short breeding periods, availability of inbred strains with known characteristics, good genetic markers, a well-characterized immune system, and the ability to induce genetic modifications. Mice do not spontaneously develop asthma, but a syndrome with some of the features of asthma can be induced in mice upon systemic allergen sensitization and subsequent airway challenge. To date, such models have been used primarily to understand the acute responses to allergen challenge, and have been pivotal in our current understanding of the importance of the T cell in the etiology of asthma (2). One of the challenges associated with using this model is that with repeated allergen challenge, the phenotype becomes attenuated. For example, in this issue of the Journal (pp. 959–967), Shinagawa and Kojima (3) report that mice immunized systemically with ovalbumin and then challenged with daily aerosols of ovalbumin develop airway eosinophilia after 1 to 2 weeks of challenge. With continued challenges over the next 2 weeks, however, the eosinophilia declines. Similarly, airway hyperresponsiveness develops in the first week after chronic ovalbumin aerosol challenge in a similar model but disappears after 3 to 6 weeks of aerosol challenges (4). It has been suggested that immune tolerance accounts for the attenuation of the phenotype with repeated allergen challenge. Perhaps for this reason, and because it takes time and/or repeated challenge for the changes to develop, few investigators have been successful in modeling the airway remodeling of asthma, particularly as regards the airway smooth muscle hyperplasia that is characteristic of the human disease. An exception to this rule is goblet cell hyperplasia that can be observed even after only a few days of allergen challenge (5) and continues to be observed even after four weeks of challenge (3). Shinagawa and Kojima now report (3) that repeated nasal challenge of A/J mice with ovalbumin results in airway eosinophilia and airway hyperresponsiveness that do not decline with time. The data are notable both for the lack of tolerance with repeated allergen challenge and for the observation that the syndrome was induced without the need for systemic immunization, a situation that more closely mimics the way humans become sensitized. There are few if any other mouse models of allergic airway disease in which in vivo airway hyperresponsiveness is observed in the absence of systemic immunization (for review, see Reference 6). Importantly, airway remodeling also occurred. Goblet cell hyperplasia was evident within four weeks of the initiation of repeated nasal challenges, and no further changes were observed with longer durations of challenge. Thickening of the airway smooth muscle layer and increases in the hydroxyproline content of the lungs consistent with increased collagen deposition in the lamina propria were also observed, and importantly, were progressive over time. It is not clear why tolerance failed to develop and airway remodeling was allowed to progress in this model versus the more typical models consisting of systemic allergen sensitization followed by repeated aerosol allergen challenge. It is noteworthy in this report by Shinagawa and Kojima (3), however, that the airway challenges occurred by nasal instillation rather than by aerosol administration. It is possible that the lack of tolerance was the result of the airway versus systemic sensitization. Henderson and coworkers, however, also reported persistent airway eosinophilia, airway hyperresponsiveness, and a twofold increase in the thickness of the airway smooth muscle layer in BALB/c mice after 10 weeks of nasal allergen challenge, even though the mice were systemically immunized (7). It is also possible that nasal challenges, compared with aerosol challenges, result in a much-reduced dose of allergen delivered to the lung. Indeed Kumar and Foster (8) have reported that tolerance can be avoided and progressive airway remodeling and airway hyperresponsiveness can be induced with repeated aerosol allergen challenges, when the aerosol dose is carefully controlled by monitoring and controlling the number and size of aerosol particles. Alternatively, tolerance and consequent limitations to progressive airway remodeling may be observed with repeated aerosol challenge because the aerosol exposure usually involves the whole body and results in substantial deposition of the allergen on the fur. Subsequently, when the animal grooms itself, there may be significant oral ingestion of the allergen leading to the development of tolerance. Shinagawa and Kojima (3) also report that repeated nasal ovalbumin challenge results in chronic airway eosinophilia, chronic airway hyperresponsiveness, and thickening of the airway smooth muscle layer only in A/J mice and not in other strains. The A/J mouse is also more susceptible to allergic airway responses in an acute model of systemic ovalbumin sensitization followed by a single airway challenge (9), likely as a result of a defect in complement signaling in this strain (10). It may be that the increased susceptibility to allergic sensitization conferred by this defect is what allows for the induction of allergic airway responses in the A/J mouse without the need for systemic immunization (3). It might, however, be possible to use systemic immunization in conjunction with repeated nasal challenge to generate in other mouse strains the features apparent in the A/J mice with nasal challenge only. Indeed, persistent airway eosinophilia, airway hyperresponsiveness, and airway remodeling are observed in BALB/c mice using such a strategy (7). The ability to induce chronic airway remodeling in other mouse strains would be extremely exciting because genetically modified mice that might be used to examine the mechanistic basis for this remodeling are not currently available on the A/J background. Mouse models of airway remodeling such as this one (3) may ultimately help establish the relationship between chronic airway inflammation and the decline in lung function that occurs in some individuals with asthma and are clear winners—by more than a nose. FOOTNOTES Conflict of Interest Statement: S.S. was the recipient of a $15,000 grant from Merck to study the effects of interleukin-9 on airway smooth muscle. REFERENCES
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