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Title: Pharmacological regulation of mast cell mediator release in asthma
Author: Howarth, Peter Hugo
ISNI:       0000 0001 2440 7196
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 1987
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This thesis presents the investigation into the pharmacological regulation of mast cell mediator release in asthma, in vivo. The immediate airway response to inhaled allergen has been used as an in vivo model of mast cell activation in atopic asthma and changes in the circulating levels of histamine in plasma and high molecular weight neutrophil chemotactic activity (NCA) in serum as markers of mast cell activation. Both allergenic reactivity and non-specific bronchial reactivity were found to be determinants of the immediate airway response to allergen, the level of non-specific bronchial reactivity determining the pattern of circulating mediator changes following allergen inhalation challenge. In this respect, changes in serum NCA were more sensitive a marker for mast cell activation than changes in plasma histamine. Changes in plasma histamine were only detectable in patients with relatively unreactive airways to non-specific stimuli, indicative of the greater degree of intrapulmonary mast cell degranulation required in these subjects to produce bronchoconstriction. Plasma histamine changes, when they occurred, were, however, significantly greater outside the variance of the baseline measurements than those changes identified with serum NCA, identifying that plasma histamine changes are a more precise marker of intrapulmonary mast cell activation. These changes in plasma histamine were repeatable both within and between subjects. Although basophil derived histamine was found to be an important determinant of resting plasma histamine levels, basophils were not found to contribute to the immediate increments in histamine following allergen inhalation. Using this model, astemizole, a potent and specific oral H₁-receptor antagonist, attenuated the immediate airway response to allergen, without influencing mast cell degranulation. Both inhaled salbutamol and sodium cromoglycate were found to inhibit mast cell degranulation in vivo and inhaled ipratropium bromide, which produced equivalent bronchodilatation to salbutamol, had no significant effect on either the airway or mediator responses to allergen inhalation. Salbutamol was found to be more active, as an inhibitor of immunologically stimulated mast cell mediator release, but the inhaled rather than the oral route, despite dose equivalents producing comparable effects on non-specific bronchial reactivity, illustrating the importance of the mucosal mast cell in the immediate interaction with allergen. Although dose equivalents were not calculated, by inhalation, salbutamol was at least 100 times more potent than sodium cromoglycate in inhibiting immunologically stimulated mast cell degranulation. The relevance of these findings to the model of allergic asthma are discussed and question the role of the mast cell in the genesis of allergen induced airway inflammation and bronchial hyperreactivity in asthma.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Drug use in asthma