Airway Remodelling in Response to Novel Asthma Therapies

Airway remodelling encompasses a range of structural changes seen in the airways of asthma patients, and can be assessed in bronchial biopsy samples. However, there is a paucity of data investigating remodelling responses to asthma therapies. The relationships between airways remodelling and airways inflammation are also not fully understood.

In this thesis I present an overview of asthma pathogenesis, including specific mechanisms underlying both airway inflammation and airway remodelling, before investigating the responses to two novel asthma therapies. I firstly examine the changes seen in airway inflammation and airway remodelling following 12 weeks of treatment with an anti-interleukin-13 antibody. Secondly, I investigate the remodelling responses to bronchial thermoplasty. Where remodelling changes are observed in response to therapy I investigate how this relates to clinical outcomes.

Inflammatory and remodelling responses to anti-interleukin-13 were not significantly different to placebo, despite reductions in exhaled nitric oxide and immunoglobulin-E demonstrating engagement with the target receptor. This established that inhibition of interleukin-13 in isolation does not lead to significant remodelling or inflammatory changes in moderate-to-severe asthma.

Bronchial thermoplasty led to significant improvements in airway remodelling (airway smooth muscle mass, reticular basement membrane thickness and epithelial integrity), although direct relationships between these changes and clinical improvements appear weak or absent. Data from a small number of patients suggests that improvements in epithelial integrity may be more important to clinical benefits than reductions in airway smooth muscle mass, but further investigation is needed.

This thesis contributed new data to the understanding of remodelling and inflammatory pathways in asthma. It also reports the largest study undertaken examining remodelling changes, and their relationships to clinical outcomes, in response to bronchial thermoplasty. Finally, it has provided new evidence of significant epithelial repair after thermoplasty, which may be a key contributor to clinical improvements.