Interferon-gamma and pulmonary macrophages contribute to the mechanisms underlying prolonged airway hyperresponsiveness.
BACKGROUND
Airway hyperresponsiveness (AHR) in asthmatics includes a variable component that persists following an allergen challenge. This may be dissociated from inflammatory cell recruitment, implying a role for resident pulmonary cells in regulating the response.


OBJECTIVE
Using improved methods of assessing AHR in a mouse model of allergic airway disease, to investigate the basis of the development of prolonged AHR.


METHODS
BALB/c mice were systemically sensitized and then challenged with aerosolized ovalbumin (OVA). Airway and tissue responsiveness were measured at baseline and at 1 day, and 1, 2 and 3 weeks after the last OVA challenge. Inflammatory cell numbers in BALF and levels of mRNA for eotaxin-1 and -2, IFN-gamma, IL-5 and -13 in the lung were measured at each time-point. In further experiments, the roles of IFN-gamma and of CCR3(+) and CD4(+) cells in the development of prolonged AHR were assessed by blockade or depletion with monoclonal antibodies. The role of pulmonary macrophages was assessed by selective chemical depletion of these cells.


RESULTS
Airway responsiveness was increased above baseline at 1 day after the last OVA challenge, and this was sustained for 1 week. In contrast, tissue-specific responsiveness was only significantly increased above baseline at 1 day. Development of prolonged AHR was inhibited by neutralization of IFN-gamma or by depletion of pulmonary macrophages, but not by depletion of either CD4(+) T cells or CCR3(+) eosinophils.


CONCLUSIONS
An interaction between IFN-gamma and pulmonary macrophages contributed to the prolongation of airway hyperresponsiveness. In contrast, T cells and eosinophils did not contribute to prolongation of AHR. These findings emphasize the importance of the innate host response in the development of manifestations of asthma, as well as its potential relevance as a target for therapeutic intervention.
Yang
M
M
Centre for Asthma and Respiratory Disease, School of Biomedical Sciences, Faculty of Health, University of Newcastle and Hunter Medical Research Institute, Callaghan, NSW 2300, Australia. ming.yang@newcastle.edu.au
Kumar
R K
RK
Foster
P S
PS
D000485:Allergens / Q000276:immunology*; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000276:immunology*; D004195:Disease Models, Animal; D007114:Immunization; D007371:Interferon-gamma / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology
D000485:Allergens; D007371:Interferon-gamma; D010047:Ovalbumin