Airway structural remodelling in asthma: Functional relevance and suitability as a target for therapy

Airway remodelling (AR) in asthma, a collective term describing all the airway microscopic structural changes, has long been known; however, its functional relevance is poorly understood. The lack of non-invasive methods for assessing AR contributes to this scarcity of studies on AR. First, this thesis describes the association of AR with physiological markers of airflow obstruction. This was coupled with attempting to assess the link between proximal and small airway qualitative computed tomography (QCT)-derived markers and AR. Furthermore, to further study the relevance of AR, we describe the effects of fevipiprant, a novel prostaglandin D2 (PGD2) receptor 2 (DP2) antagonist, and bronchial thermoplasty (BT) on various asthma domains including AR. We found that airway smooth muscle (ASM) mass and airway vascularity was closely related to airflow obstruction. Additionally, we have demonstrated that ASM, vascularity and epithelial thickness was associated with QCT-measured proximal airway morphometry changes whereas increased vascularity and goblet cells hyperplasia was related to air trapping. Coupled with improvements is eosinophilic inflammation, asthma symptoms and lung function, we have shown that DP2 antagonism in a randomised controlled trial, resulted in improvement in epithelial integrity and reduction of ASM. Finally, we have shown that while BT treatment did not affect ASM mass, subepithelial fibrosis or lung function, it did improve epithelial integrity and reduced smooth muscle actin expression. Whether these changes contribute to the benefits seen in BT studies needs further research. This thesis has contributed to the development of fevipiprant as a new treatment for asthma, validated methods to assess AR, demonstrated how AR relates to asthma outcomes and shown how fevipiprant and BT impact AR. Further longitudinal studies are also needed to explore the heterogeneity of AR in various asthma phenotypes especially in the context of clinical trials of new therapies using novel non-invasive methods of measuring AR.