Date of Award
Doctor of Philosophy (PhD)
Physiology and Pharmacology
Asthma is a chronic respiratory disease which is characterized by reversible bronchoconstriction, airway hyperresponsiveness, and airway inflammation. Allergen inhalation by sensitized atopic asthmatics enhances airway hyperresponsiveness and inflammation, providing a model to study mild asthma exacerbation. Airway inflammation can be measured non-invasively from airway secretions by sputum induction. Prior to starting this thesis, information on allergen-induced inflammation measured from sputum was limited. Furthermore, the pro- or anti-inflammatory effects of asthma therapies had not been investigated using this model of allergen-induced airway inflammation. The aim of this thesis was to first characterize the allergen-induced changes in sputum inflammatory cells and determine the repeatability of measurements of sputum inflammatory cells following allergen inhalation challenge. In addition, this thesis was aimed to investigate the pro- or anti-inflammatory effects of asthma therapies on allergen-induced airway inflammation. Inflammatory cells considered to be important in asthma, such as eosinophils and mast cells, were measured from induced sputum following allergen inhalation challenge. These cells remained significantly elevated in sputum for 7d following inhalation of allergen, compared to diluent control. Cytokines associated with the activation and chemotaxis of eosinophils such as IL-5, eotaxin and RANTES, were also significantly elevated following allergen inhalation challenge. We examined the repeatability of allergen-induced airway inflammation assessed by induced sputum, and calculated the subject sample sizes required to demonstrate significant attenuation of sputum eosinophilia in placebo-controlled crossover studies. Measurement of sputum inflammatory cells, particularily eosinophils, following allergen inhalation challenge were found to reflect the pro- or anti-inflammatory effects of asthma therapies. Inhaled budesonide and PGE 2 are known to protect against allergen-induced early and late asthmatic responses and allergen-induced airway hyperresponsiveness. We demonstrated that regular treatment with inhaled budesonide, and that inhalation of PGE2 immediately before allergen inhalation challenge attenuated the allergen-induced early and late asthmatic responses, and the allergen-induced increase in airway hyperresponsiveness and inflammatory cells. In contrast, regular treatment with an inhaled β2 -agonist, an asthma therapy known to enhance the allergen-induced late asthmatic response, also enhanced the allergen-induced increase in sputum eosinophils during the late asthmatic response. These findings indicate that the measurements of airway eosinophils from induced sputum following allergen inhalation challenge reflect the allergen-induced late asthmatic response and airway hyperresponsiveness. Furthermore, allergen-induced sputum eosinophilia is a sensitive indicator of the pro- or anti-inflammatory effects of asthma therapies in mild atopic asthma.
Gauvreau, Gail M., "Pharmacological modulation of allergen-induced airway inflammation" (1998). Open Access Dissertations and Theses. Paper 2507.