The contribution of bronchoconstrictor prostanoids to the immediate allergen-induced airways response in asthma
The contribution of bronchoconstrictor prostanoids to the immediate allergen-induced airways response in asthma
This thesis is concerned with the airways effects of the broncho-constrictor prostanoids, and their contribution to the immediate allergen-induced airways response in asthma. The predominant prostanoid released following immunological activation of human lung mast cells in vitro is prostaglandin (PG)D2, which is initially metabolised to form 9α, 11β-PGF2, the 11β-hydroxyl epimer of PGF_2a. Initial experiments investigated the airways effects of 9α, 11β-PGF_2, PGD_2 and PGF_2a when inhaled by asthmatic subjects in vivo. Airways responses were assessed by measurement of specific airways conductance (sGaw), forced expiratory volume in one second (FEV_1) and flow at 30% of vital capacity (Vmax_30). Prostaglandin D_2 and 9α, 11β-PGF_2 were approximately equipotent as bronchoconstrictor agents, having similar activities on central and peripheral airways, and being about 30 times more potent than histamine. Subsequent use of the anticholinergic antagonist ipratropium bromide indicated that a significant component of the bronchoconstriction induced by PGD_2 and 9α, 11β-PGF_2 was mediated by cholinergic mediated mechanisms. In addition to PGD_2, immunological activation of dispersed human lung tissue also generated substantial quantities of thromboxane A_2 and PGF_2a, both of which are also potent contractile agonists of airway smooth muscle. The bronchoconstrictor prostanoids cause airway smooth muscle contraction in vitro through stimulation of thromboxane TP receptors, and the specific and potent TP receptor antagonist GR32191 competitively antagonises prostanoid-induced contraction of airway smooth muscle in vitro. In experiments in asthmatic subjects, pretreatment with oral GR32191 did not affect baseline airway calibre or methacholine-induced bronchoconstriction, but caused significant inhibition of PGD_2-induced bronchoconstriction, displacing the concentration-response curves to the right by > 10-fold. Further experiments in allergic asthmatic subjects demonstrated that GR32191 inhibited allergen-induced bronchoconstriction by about 25%. These studies suggest that the bronchoconstrictor prostanoids contribute to the immediate bronchoconstriction induced by inhaled allergen in allergic asthmatic subjects.
University of Southampton
Beasley, Charles William Richard
1989
Beasley, Charles William Richard
Beasley, Charles William Richard
(1989)
The contribution of bronchoconstrictor prostanoids to the immediate allergen-induced airways response in asthma.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
This thesis is concerned with the airways effects of the broncho-constrictor prostanoids, and their contribution to the immediate allergen-induced airways response in asthma. The predominant prostanoid released following immunological activation of human lung mast cells in vitro is prostaglandin (PG)D2, which is initially metabolised to form 9α, 11β-PGF2, the 11β-hydroxyl epimer of PGF_2a. Initial experiments investigated the airways effects of 9α, 11β-PGF_2, PGD_2 and PGF_2a when inhaled by asthmatic subjects in vivo. Airways responses were assessed by measurement of specific airways conductance (sGaw), forced expiratory volume in one second (FEV_1) and flow at 30% of vital capacity (Vmax_30). Prostaglandin D_2 and 9α, 11β-PGF_2 were approximately equipotent as bronchoconstrictor agents, having similar activities on central and peripheral airways, and being about 30 times more potent than histamine. Subsequent use of the anticholinergic antagonist ipratropium bromide indicated that a significant component of the bronchoconstriction induced by PGD_2 and 9α, 11β-PGF_2 was mediated by cholinergic mediated mechanisms. In addition to PGD_2, immunological activation of dispersed human lung tissue also generated substantial quantities of thromboxane A_2 and PGF_2a, both of which are also potent contractile agonists of airway smooth muscle. The bronchoconstrictor prostanoids cause airway smooth muscle contraction in vitro through stimulation of thromboxane TP receptors, and the specific and potent TP receptor antagonist GR32191 competitively antagonises prostanoid-induced contraction of airway smooth muscle in vitro. In experiments in asthmatic subjects, pretreatment with oral GR32191 did not affect baseline airway calibre or methacholine-induced bronchoconstriction, but caused significant inhibition of PGD_2-induced bronchoconstriction, displacing the concentration-response curves to the right by > 10-fold. Further experiments in allergic asthmatic subjects demonstrated that GR32191 inhibited allergen-induced bronchoconstriction by about 25%. These studies suggest that the bronchoconstrictor prostanoids contribute to the immediate bronchoconstriction induced by inhaled allergen in allergic asthmatic subjects.
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Published date: 1989
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Local EPrints ID: 462037
URI: http://eprints.soton.ac.uk/id/eprint/462037
PURE UUID: 93733b73-cdfd-47ef-8d5b-cd2eb3e498bd
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Date deposited: 04 Jul 2022 19:00
Last modified: 04 Jul 2022 19:00
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Author:
Charles William Richard Beasley
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