Airway wall remodelling in chronic allergic airway disease

Allergic asthma is the result of an immune-inflammatory response directed against common environmental aeroallergens with concomitant remodeling of the airway wall, and ultimately leads to abnormal lung function. However, the relative contribution of various aspects of the asthmatic response on lung dysfunction are currently unclear, and the underlying immunological and biochemical causes of this pathology have not been fully elucidated. The experiments undertaken in this thesis utilize an experimental mouse model of chronic asthma to investigate: (1) the immunological, structural and functional consequences of sustained respiratory exposure to house dust mite extract (HDM), a pervasive environmental aeroallergen; (2) the importance of Th2-polarized inflammation in the development of airway remodeling and bronchial hyperreactivity; (3) the ability of currently available pharrnacotherapy strategies to ameliorate the structural and functional changes associated with allergic airways disease.; The findings presented here demonstrate that chronic respiratory exposure to HDM in Balb/c mice results in sustained Th2-polarized inflammation of the airways which reaches a plateau after three weeks of exposure, followed by significant changes to the structure of the airway wall and lung dysfunction with continued allergen exposure for up to seven weeks. Considering that asthma affects only a small proportion of the population, the importance of the type of immune response directed against aeroallergens in the development of allergic airway disease was investigated in mice that develop a Th1-polarized immune-inflammatory response to HDM, due to a genetic deficiency in IL-4. This study demonstrated the requirement for a Th2-polarized immune-inflammatory response directed against HDM for the elaboration of the structural and functional changes to the airway characteristic of asthma. Finally, we demonstrated that pharmacological intervention with currently available phamiatherapies could result in an improvement in airway pathology, but only when delivered in the context of withdrawal of the inciting allergen.; The data presented in this thesis provide insight into the impact of chronic inflammation on airway structural cells, and the downstream functional consequences of sustained allergen exposure to the respiratory mucosa. It is hoped that further studies employing common aeroallergens to drive allergic airway disease will not only broaden our understanding of the etiology of asthma, but also provide direction in the search for novel targets in the management of this disorder.