Functional and structural relationships of the peripheral airways in chronic asthma

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It is now considered that airway wall thickening (airway remodeling), a consequence of persistent airway inflammation in asthmatics, significantly contributes to the symptoms and risk of death from asthma. Despite recent advances in the field, there are still many clinically relevant questions that have not been addressed. Some important issues still to be elucidated are: What is the precise sequence of tissue changes in remodeling? Which components of remodeling are reversible in the absence of allergen provocation? At what point does airway remodeling become irreversible? Does early intervention with anti-inflammatory medication have long term benefits in terms of reducing long-term remodeling? As there have been few appropriate models for addressing these types of remodeling issues, we propose to utilise a large animal model for chronic asthma to address these questions. One of the main focuses of this proposal is to identify biomarkers or functional indices of the different stages of remodelling. The sheep model is well placed to achieve these objectives given that the structure, physiology and asthma pathophysiology of sheep airways is similar to human airways. The novel experimental design is to expose four spatially separate lung regions (segments) in individual sheep with different durations of repeated weekly doses of HDM. The strength of the proposal is that lung function and structure of challenged segments from successive stages of remodeling can be assessed in one sheep. A separate experiment will examine how lung structure and function return to normal in chronically HDM-treated lung segments over successive months after exposure to HDM ceases. It is expected that information gained from this research will lead to a greater fundamental understanding of disease mechanisms in chronic asthma. This will increase the chances of improving current treatments, and allows for new strategies to be devised for treating asthma more effectively.