Adenosine : a putative mediator of bronchoconstriction in asthma
Adenosine : a putative mediator of bronchoconstriction in asthma
Adenosine causes bronchoconstriction when inhaled by asthmatic subjects, and is released from lung tissue during hypoxia and antigen challenge in vitro. This thesis investigates the possible role of adenosine in the pathogenesis of asthma. The protective effect of a muscarinic cholinergic antagonist, ipratropium bromide (IB) from inhaled adenosine - and methacholine-induced bronchoconstriction in asthma was studied. Inhaled IB protected from methacholine- but not adenosine-induced bronchoconstriction. Parasympathetically mediated bronchoconstriction is therefore unlikely to account for adenosine's airway effect in asthma. The capacity of theophylline, a bronchodilator and a competative antagonist of adenosine at its cell surface receptors, to protect asthmatic subjects from adenosine- and histamine-induced bronchoconstriction was determined. At therapeutic plasma concentrations theophylline protected against both bronchoconstrictor stimuli but exerted a greater protective effect against adenosine. Thus adenosine may mediate bronchoconstriction by an action on its receptors. Asthmatic airways are infiltrated with inflammatory cells. Human leucocytes prelabelled with (3H)-adenine when activated with the calcium ionophore A23187 released labelled hypoxanthine, inosine and adenosine which was associated with a dose-related release of histamine. The chemotactic peptide of f-MLP whilst inducing histamine release had an inconstant effect on release of label. In four of five experiments f-MLP produced a transient early increase in label release but in the remaining experiment no significant release was observed. Anti-human IgE failed to induce significant label release despite releasing histamine. Activated leucocytes are therefore a potential source of adenosine in asthma. Plasma concentrations of adenosine and inosine in asthmatic subjects during bronchial provocation with antigen and methacholine were measured by HPLC. Following both bronchoconstrictor stimuli adenosine levels rose significantly whereas inosine levels were unchanged. The time-course of the airway and plasma adenosine response differed following each bronchial provocant. Antigen inhalation was associated with both a slower onset of bronchoconstriction and a more rapid increase in plasma adenosine, when compared to methacholine challenge. These studies support the hypothesis that adenosine may contribute as a bronchoconstrictor mediator in asthma.
University of Southampton
1987
Mann, Jonathan Spencer
(1987)
Adenosine : a putative mediator of bronchoconstriction in asthma.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
Adenosine causes bronchoconstriction when inhaled by asthmatic subjects, and is released from lung tissue during hypoxia and antigen challenge in vitro. This thesis investigates the possible role of adenosine in the pathogenesis of asthma. The protective effect of a muscarinic cholinergic antagonist, ipratropium bromide (IB) from inhaled adenosine - and methacholine-induced bronchoconstriction in asthma was studied. Inhaled IB protected from methacholine- but not adenosine-induced bronchoconstriction. Parasympathetically mediated bronchoconstriction is therefore unlikely to account for adenosine's airway effect in asthma. The capacity of theophylline, a bronchodilator and a competative antagonist of adenosine at its cell surface receptors, to protect asthmatic subjects from adenosine- and histamine-induced bronchoconstriction was determined. At therapeutic plasma concentrations theophylline protected against both bronchoconstrictor stimuli but exerted a greater protective effect against adenosine. Thus adenosine may mediate bronchoconstriction by an action on its receptors. Asthmatic airways are infiltrated with inflammatory cells. Human leucocytes prelabelled with (3H)-adenine when activated with the calcium ionophore A23187 released labelled hypoxanthine, inosine and adenosine which was associated with a dose-related release of histamine. The chemotactic peptide of f-MLP whilst inducing histamine release had an inconstant effect on release of label. In four of five experiments f-MLP produced a transient early increase in label release but in the remaining experiment no significant release was observed. Anti-human IgE failed to induce significant label release despite releasing histamine. Activated leucocytes are therefore a potential source of adenosine in asthma. Plasma concentrations of adenosine and inosine in asthmatic subjects during bronchial provocation with antigen and methacholine were measured by HPLC. Following both bronchoconstrictor stimuli adenosine levels rose significantly whereas inosine levels were unchanged. The time-course of the airway and plasma adenosine response differed following each bronchial provocant. Antigen inhalation was associated with both a slower onset of bronchoconstriction and a more rapid increase in plasma adenosine, when compared to methacholine challenge. These studies support the hypothesis that adenosine may contribute as a bronchoconstrictor mediator in asthma.
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Published date: 1987
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Local EPrints ID: 461385
URI: http://eprints.soton.ac.uk/id/eprint/461385
PURE UUID: 0b05fd13-1379-414f-8370-625b3600050a
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Date deposited: 04 Jul 2022 18:45
Last modified: 04 Jul 2022 18:45
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Author:
Jonathan Spencer Mann
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