To study the mechanisms and kinetics underlying the development of increased airway responsiveness (AR) after allergic sensitization, animal models have been invaluable. Using barometric whole-body plethysmography and increases in enhanced pause (Penh) as an index of airway obstruction, we measured responses to inhaled methacholine in conscious, unrestrained mice after sensitization and airway challenge with ovalbumin (OVA). Sensitized and challenged animals had significantly increased AR to aerosolized methacholine compared with control animals. AR measured as Penh was associated with increased IgE production and eosinophil lung infiltration. In a separate approach we confirmed the involvement of the lower airways in the response to aerosolized methacholine using tracheotomized mice. Increases in Penh values after methacholine challenge were also correlated with increased intrapleural pressure, measured via an esophageal tube. Lastly, mice demonstrating AR using a noninvasive technique also demonstrated increased pulmonary resistance responses to aerosolized methacholine when measured using an invasive technique the following day in the same animals. The increases in Penh values were inhibited by pretreatment of the mice with a beta 2-agonist. These data indicate that measurement of AR to inhaled methacholine by barometric whole-body plethysmography is a valid indicator of airway hyperresponsiveness after allergic sensitization in mice. The measurement of AR in unrestrained, conscious animals provides new opportunities to evaluate the mechanisms and kinetics underlying the development and maintenance of airway hyperresponsiveness and to assess various therapeutic interventions.

Eosinophils play a central role in the inflammatory response associated with bronchial asthma. We studied the involvement of eosinophils in the development of airway hyperresponsiveness (AHR) in a mouse model of allergic airway sensitization. Sensitization of BALB/c mice to OVA via the airways induced allergen-specific T-cell responses, IgE production, immediate cutaneous hypersensitivity (ICH), and increased airway reactivity. Airway sensitization was associated with eosinophil infiltration of the airways and increased production of interleukin-5 (IL-5) in cultures of peribronchial lymph node cells. Treatment of OVA-challenged animals with anti-IL-5 antibody during the sensitization protocol completely abolished the infiltration of eosinophils into the lung tissue and prevented the development of AHR without affecting levels of allergen-specific IgE, cutaneous hypersensitivity and allergen-specific T cell responses. These findings demonstrate that infiltration of lung tissue by eosinophils, triggered by increased IL-5 production, is a major factor in the development of AHR in this mouse model of airway sensitization.

In a proportion of atopic asthmatics, exposure to a relevant antigen is followed by chronic inflammation in the airways leading to altered airway responsiveness (AR). However, the mechanisms underlying the development of airway hyperresponsiveness still remain unclear. To elucidate the relationship between IgE-mediated reactions and airway hyperresponsiveness, a murine model of passive sensitization and airway challenge with ovalbumin (

Role of IgE in the development of allergic airway in¯ammation and airway hyperresponsiveness ± a murine model.Allergy 1999, 54, 297±305.

SummaryTo study the role ofCD8 + T cells in allergic sensitization, we examined the effects of in vivo depletion ofCD8 + T cells prior to sensitization on IgE production, immediate type cutaneous hypersensitivity and development of altered airway responsiveness. BALB/c mice were thymectomized and treated with anti-CD8 antibody resulting in depletion of CD8 + T cells (< 1%) in spleen and lymphoid tissues. In these mice, sensitization to ovalbumin (OVA) via the airways still resulted in IgE anti-OVA responses and immediate cutaneous reactions to OVA, but the animals were unable to develop airway hyperresponsiveness, eosinophil infiltration of the lung parenchyma, or IL-5 production in the local lymph nodes of the airway. Transfer of CD8 + T cells from naive animals during sensitization (on day 8 of the 10-d protocol) fully restored the ability to develop airway hyperresponsiveness and this was accompanied by IL-5 production and eosinophil accumulation in the lung. These data indicate a critical role for CD8 + T cells in the production of IL-5 and the development of altered airway responsiveness after antigen sensitization through the airways.