THE UNCOUPLING OF THE INFLAMMATORY AND STRUCTURAL COMPONENTS OF AIRWAY HYPERRESPONSIVENESS

Airway hyperresponsivess (AHR) is a characteristic feature of asthma. However, the mechanisms underlying AHR are complex and likely to be multi-factoriaL A number of animal models have focused on understanding the mechanisms of transient airway inflammation and the associated transient airway dysfunction that occur following brief allergen exposure. While much has been learned about the role of acute inflammation in this brief allergen-induced response, a limitation of these studies is that the airway dysfunction is not fully representative of the AHR present in asthma. For example, we have shown that effective anti-inflammatory treatment results in only a modest reduction in AHR, indicating that AHR is usually sustained in asthma. This suggests that other mechanisms, including airway remodeling, likely play an important role in the pathophysiology of AHR. The subsequent focus of this thesis has been firstly, to demonstrate that sustained airway dysfunction develops in mice chronically exposed to allergen, and secondly, to explore the potential mechanisms and associations underlying this phenomenon. By subjecting sensitized mice to either brief or chronic periods of allergen exposure, we have developed a novel model in which chronic allergen exposur