An investigation into the mechanisms driving the late asthmatic response

Asthma is a disease with increasing global prevalence and patients typically suffer from symptoms such as wheezing, breathlessness, chest tightness and cough. In allergic asthma, exposure to allergen can lead to episodes of bronchoconstriction known as the late asthmatic response (LAR).Despite this being a facet of asthma that patients find debilitating and the fact that this feature of asthma is often used in clinical research as an end point to study new therapeutic options, the mechanisms driving the LAR remain unclear. The aim of this thesis was to study the LAR. Initial studies utilised genetically modified (GM) mice missing key allergic effector cells. The data showed that CD4+ and CD8+T cells are central to the aetiology of the LAR. Further studies into the role of the B-cell – mast cell– IgE axis in the murine model indicated that an alternative model was required. In a rat model, it was found that a mast cell stabiliser Disodium Cromoglycate (DSCG), but not a mast cell degranulator, compound 48/80, suppressed the LAR. This suggested that DSCG may be inhibiting LAR independently of its activity on mast cells. As previous data has shown a role for airway sensory nerves and the TRPA1 ion channel in the LAR, the impact of DSCG on sensory nerve activity was investigated. The data indicated that DSCG can inhibit TRPA1 responses in airway sensory nerves and further investigations demonstrated that this was via its actions on the G-protein coupled receptor, GPR35. Overall, this body of work provides new insights into the driving mechanisms behind the LAR and may have uncovered the mystery of the mechanism of action of DSCG. From this, new therapeutic options for asthmatics may become available in the future.Open Acces