Impact of Chronic Allergic Inflammation on de novo Sensitization and Airway Remodeling in a Mouse Model of Allergic Airway Disease

Abstract

Allergic asthma is a chronic inflammatory disease of the airways. Importantly, the chronic nature of this disease imparts specific additional consequences that would not otherwise be observed in a strictly acute setting. The development ofvarious structural alterations to the airway wall, collectively tem1ed airway remodeling, represents one such example. Decades of research have provided a great deal of insight into the acute allergic asthmatic response and the processes that govern it. However, less is known about the impact of protracted allergen exposure and chronic immune-inflammatory responses. To this end, the research presented in this thesis explores the consequences of chronic allergen exposure and persistent airway inflammation on asthma pathogenesis, using a mouse model of allergic airway disease induced by respiratory exposure to house dust mite (HDM) allergens. Specifically examined are: i) the impact of continuous allergen exposure and the resulting immune-inflammatory response on the development of de nova sensitization to newly encountered allergens (Chapter 2) and, ii) the roles oftransforming growth factor (TGF)-~ and eosinophils, two putatively critical components of the allergic inflammatory response, in the generation of airway remodeling (Chapters 3 and 4). Our data show that chronic exposure to HDM facilitates the development of the full 'asthmatic phenotype' towards an innocuous antigen. Moreover, they demonstrate that, unlike what has been previously observed in ovalbumin-based models, neither TGF-~ nor eosinophils are critically required for remodeling to develop in the context of HDM exposure. These findings highlight the importance of the lung microenvironment in influencing the type of immune response that develops upon initial antigen encounter and, furthermore, underscore the notion that the role of a particular cell type or molecule in the asthmatic response is contextual and not necessarily broadly applicable.