The role of bone marrow progenitor cells in allergen-induced airway hyperresponsiveness and airway inflammation

Abstract

<p>Asthma is a disease characterised by reversible bronchoconstriction, airway hyperresponsiveness (AHR) and airway inflammation. Inhalation of allergen by sensitized subjects is an important cause of asthma, and results in an increase in the numbers of inflammatory cells, more specifically the eosinophil, in the airways. An important aspect of allergic inflammatory responses is the induction of increases in inflammatory cell progenitors, which contribute to disease through the continued production of inflammatory cells. Higher numbers of circulating eosinophil/basophil progenitors are demonstrable in the blood of atopic subjects compared with normals, and in asthmatic subjects following allergen inhalation. In addition, there are increases in bone marrow progenitor cells following allergen inhalation in a canine model of allergen-induced AHR. Although these studies suggest that inflammatory cell progenitors in the blood arise from the bone marrow, this had not been shown in humans. The aim of this thesis was to examine the role of bone marrow inflammatory cell progenitors in allergen-induced AHR and airway inflammation, with respect to increased production and trafficking of these cells. In addition, the effect of therapeutic intervention with inhaled glucocorticosteroids was investigated. We demonstrated, for the first time, that increases in bone marrow-derived eosinophil/basophil progenitors occurred 24 hours following allergen inhalation in mild asthmatic subjects through up-regulation of the IL-5 receptor on progenitors, and that the degree of responsiveness of these cells was associated with the magnitude of the eosinophilic response in the airways. In addition, we demonstrated an increase in the trafficking of inflammatory cell progenitors, from the bone marrow through the circulation, into the airways, suggesting that the increased production of these cells can contribute to the ongoing inflammatory response. Finally, we showed that inhalation of the glucocorticosteroid, budesonide, was able to specifically suppress the baseline numbers of bone marrow inflammatory cell progenitors, but was unable to inhibit the allergen-induced increases in these cells. In summary, the findings in this thesis suggest that inflammatory cell progenitors in the bone marrow are affected by inhalation of allergen, with increased production and trafficking to the airways. In addition, while budesonide may have an inhibitory effect on the steady state turnover of eosinophil/basophil progenitors, it has no effect on the allergen-driven events occurring in the bone marrow, suggesting that the inhibitory effects of budesonide inhalation on inflammation and airway responses may not be via inhibition of allergen-induced increases in eosinophil production.</p>