Structure function relationships in adult asthma

Airway hyperresponsiveness (AHR) is a central feature of the asthma paradigm. Non Asthmatic Eosinophilic Bronchits (EB) has emerged as a powerful disease control model to study the immunopathological mechanisms of AHR in asthma. EB is characterised by cough, AHR is absent despite ongoing eosinophilic airway inflammation. This thesis compares features of structural and cellular remodeling in the airway wall in asthma and EB as well as the static geometry of proximal conducting airways in these two polar conditions. We have demonstrated for the first time that structural remodeling, notably increased airway smooth muscle (ASM) mass, vascular remodeling and the expression of VEGF, number of submucosal glands and collagen 3 deposition; occur to similar degrees in both asthma and EB. None of these structural components were associated with AHR in asthma. In contrast we found that the number of mast cells within the ASM independently correlated with the degree of AHR. Coupled with these findings, asthma was characterised by reduced patency of the proximal airway lumen due to airway wall thickening and the degree of thickening correlated with the degree of AHR. In contrast EB was characterised by maintained proximal airway luminal patency despite an increase in the area of the airway wall. Our findings suggest that AHR is dissociated from airway wall structural remodeling in asthma and associated with mast cell infiltration of the ASM. Finally we have shown that fibrocytes are present in the ASM in asthma in contrast to EB and may contribute to the increased ASM mass seen in asthma. Future studies should explore the mechanisms that promote reduced luminal patency in asthma and preserve luminal patency in EB, as well as the functional impact of mast cell infiltration of the ASM and fibrocytes in asthma upon ASM dynamics.EThOS - Electronic Theses Online ServiceGBUnited Kingdo