The contribution of histamine as a mediator in asthma
The contribution of histamine as a mediator in asthma
Histamine was identified at the turn of the century and subsequently associated with allergic disease. Its pro-inflammatory actions and ability to cause bronchoconstriction in asthmatic subjects suggest a role in asthma. This thesis attempts to identify the role of histamine in asthma more precisely.
The effect of histamine on airway epithelial permeability was studied in the upper airways. Histamine challenge increased epithelial permeability, causing increased concentrations of total protein and albumin in nasal lavage. These were ablated by H4-receptor blockade but attenuated to a much lesser extent by H2-receptor blockage. There was little change in airflow measurements, which could reflect a non-specific effect of histamine mediated via airway irritant receptors.
In a comparative study the new H1-receptor antagonists, astemizole, terfenadine and cetirizine were more effective than older drugs, with a lesser adverse effect profile. They were 5-15 times more effective in protecting against the bronchoconstrictor effect of inhaled histamine in asthmatics. Terfenadine was highly specific with no anti-methacholine, prostaglandin D2 or leukotriene D4 effects in asthmatic airways. It is thus ideally suited to use as a pharmacological tool for the study of histamine in asthma. In a controlled trial terfenadine did not confer any significant benefit in the treatment of chronic asthma.
In a laboratory model of asthma, allergen inhalation by atopic asthmatics caused immediate histamine release, demonstrated by increased plasma concentrations measured using a sensitive and specific radio-immunoassay. Similar concentration changes were found in normal subjects after inhalation of histamine sufficient to cause profound bronchoconstriction in asthmatics, implying not all systemic histamine contributes to the early bronchoconstrictor response. This explains the limited reduction of early bronchoconstriction by terfenadine, despite the plasma histamine rise being unchanged. No significant histamine release was demonstrated during the late phase response despite measurement of plasma histamine and urinary Nτ-methylhistamine. Terfenadine did not significantly affect this late response.
Histamine is a minor contributor to the acute bronchoconstrictor response following allergen exposure in asthma but does not play a significant role in the ongoing inflammatory response.
University of Southampton
1994
Wood-Baker, Richard
(1994)
The contribution of histamine as a mediator in asthma.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
Histamine was identified at the turn of the century and subsequently associated with allergic disease. Its pro-inflammatory actions and ability to cause bronchoconstriction in asthmatic subjects suggest a role in asthma. This thesis attempts to identify the role of histamine in asthma more precisely.
The effect of histamine on airway epithelial permeability was studied in the upper airways. Histamine challenge increased epithelial permeability, causing increased concentrations of total protein and albumin in nasal lavage. These were ablated by H4-receptor blockade but attenuated to a much lesser extent by H2-receptor blockage. There was little change in airflow measurements, which could reflect a non-specific effect of histamine mediated via airway irritant receptors.
In a comparative study the new H1-receptor antagonists, astemizole, terfenadine and cetirizine were more effective than older drugs, with a lesser adverse effect profile. They were 5-15 times more effective in protecting against the bronchoconstrictor effect of inhaled histamine in asthmatics. Terfenadine was highly specific with no anti-methacholine, prostaglandin D2 or leukotriene D4 effects in asthmatic airways. It is thus ideally suited to use as a pharmacological tool for the study of histamine in asthma. In a controlled trial terfenadine did not confer any significant benefit in the treatment of chronic asthma.
In a laboratory model of asthma, allergen inhalation by atopic asthmatics caused immediate histamine release, demonstrated by increased plasma concentrations measured using a sensitive and specific radio-immunoassay. Similar concentration changes were found in normal subjects after inhalation of histamine sufficient to cause profound bronchoconstriction in asthmatics, implying not all systemic histamine contributes to the early bronchoconstrictor response. This explains the limited reduction of early bronchoconstriction by terfenadine, despite the plasma histamine rise being unchanged. No significant histamine release was demonstrated during the late phase response despite measurement of plasma histamine and urinary Nτ-methylhistamine. Terfenadine did not significantly affect this late response.
Histamine is a minor contributor to the acute bronchoconstrictor response following allergen exposure in asthma but does not play a significant role in the ongoing inflammatory response.
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Published date: 1994
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Local EPrints ID: 462773
URI: http://eprints.soton.ac.uk/id/eprint/462773
PURE UUID: f03d9f5b-07c2-4264-82a7-0a307f029002
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Date deposited: 04 Jul 2022 19:58
Last modified: 04 Jul 2022 19:58
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Author:
Richard Wood-Baker
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