Targeting adenosine receptors: novel therapeutic targets in asthma and chronic obstructive pulmonary disease
Targeting adenosine receptors: novel therapeutic targets in asthma and chronic obstructive pulmonary disease
Adenosine, an endogenous signaling nucleoside that modulates many physiological processes has been implicated in playing an ever increasingly important role in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). All cells contain adenosine and adenine nucleotides and the cellular production of adenosine is greatly enhanced under conditions of local hypoxia as may occur in inflammatory conditions such as asthma and COPD. In 1983, it was first reported that inhaled adenosine causes dose-related bronchoconstriction in patients with both allergic and non-allergic asthma but not in healthy volunteers. This hyperresponsiveness was also reported in patients with COPD, with those patients who smoked exhibiting a significantly greater response. This bronchoconstrictor effect of adenosine is orchestrated through the stimulation of specific cell membrane receptors and involves an important inflammatory cell, the mast cell.
There is substantial evidence which suggests that mast cell activation is central to this unique response to adenosine. Mast cell mediator release makes a significant contribution towards airflow obstruction and the consequent symptoms in patients with asthma. Over the last two decades, researchers have investigated the effect of mast cell inhibitors as well as mast cell mediator receptor antagonists and their role in attenuating the bronchoconstrictor response to inhaled adenosine 5'-monophosphate (AMP). Promising results have been shown using mast cell stabilizers, histamine H receptor antagonists, selective cysteinyl leukotriene-1 receptor antagonists and inhibitors of 5-lipoxygenase and cyclo-oxygenase. Through these findings, the mast cell has been recognized as being a critical inflammatory cell in the adenosine-induced response in patients with asthma and COPD.
To date, four subtypes (A, A, A, A) of adenosine receptors have been cloned each with a unique pattern of tissue distribution and signal transduction. Activation of these receptors has pro- and anti-inflammatory consequences making the development of agonists and/or antagonists at these receptor sites a novel approach in the treatment of patients with asthma and COPD.
This review highlights the importance of adenosine in the pathophysiology of asthma and COPD, the critical role of the mast cell and the potential to target the adenosine receptor subtype in patients with asthma and COPD. The complete characterization of these adenosine receptor subtypes in terms of their distribution in humans and the development of selective agonists and antagonists, holds the key to our complete understanding of the role of this important mediator in asthma and COPD.
adenosine receptor agonists, adenosine receptor antagonists, pharmacodynamics, asthma, chronic obstructive pulmonary disease
99-105
Rorke, S.
ca4b3d19-8862-40e7-8f33-b20da825b08d
Holgate, S.T.
2e7c17a9-6796-436e-8772-1fe6d2ac5edc
2002
Rorke, S.
ca4b3d19-8862-40e7-8f33-b20da825b08d
Holgate, S.T.
2e7c17a9-6796-436e-8772-1fe6d2ac5edc
Rorke, S. and Holgate, S.T.
(2002)
Targeting adenosine receptors: novel therapeutic targets in asthma and chronic obstructive pulmonary disease.
American Journal of Respiratory Medicine, 1 (2), .
Abstract
Adenosine, an endogenous signaling nucleoside that modulates many physiological processes has been implicated in playing an ever increasingly important role in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). All cells contain adenosine and adenine nucleotides and the cellular production of adenosine is greatly enhanced under conditions of local hypoxia as may occur in inflammatory conditions such as asthma and COPD. In 1983, it was first reported that inhaled adenosine causes dose-related bronchoconstriction in patients with both allergic and non-allergic asthma but not in healthy volunteers. This hyperresponsiveness was also reported in patients with COPD, with those patients who smoked exhibiting a significantly greater response. This bronchoconstrictor effect of adenosine is orchestrated through the stimulation of specific cell membrane receptors and involves an important inflammatory cell, the mast cell.
There is substantial evidence which suggests that mast cell activation is central to this unique response to adenosine. Mast cell mediator release makes a significant contribution towards airflow obstruction and the consequent symptoms in patients with asthma. Over the last two decades, researchers have investigated the effect of mast cell inhibitors as well as mast cell mediator receptor antagonists and their role in attenuating the bronchoconstrictor response to inhaled adenosine 5'-monophosphate (AMP). Promising results have been shown using mast cell stabilizers, histamine H receptor antagonists, selective cysteinyl leukotriene-1 receptor antagonists and inhibitors of 5-lipoxygenase and cyclo-oxygenase. Through these findings, the mast cell has been recognized as being a critical inflammatory cell in the adenosine-induced response in patients with asthma and COPD.
To date, four subtypes (A, A, A, A) of adenosine receptors have been cloned each with a unique pattern of tissue distribution and signal transduction. Activation of these receptors has pro- and anti-inflammatory consequences making the development of agonists and/or antagonists at these receptor sites a novel approach in the treatment of patients with asthma and COPD.
This review highlights the importance of adenosine in the pathophysiology of asthma and COPD, the critical role of the mast cell and the potential to target the adenosine receptor subtype in patients with asthma and COPD. The complete characterization of these adenosine receptor subtypes in terms of their distribution in humans and the development of selective agonists and antagonists, holds the key to our complete understanding of the role of this important mediator in asthma and COPD.
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Published date: 2002
Keywords:
adenosine receptor agonists, adenosine receptor antagonists, pharmacodynamics, asthma, chronic obstructive pulmonary disease
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Local EPrints ID: 27387
URI: http://eprints.soton.ac.uk/id/eprint/27387
PURE UUID: 9ee8f393-9b7a-4061-b554-2074914796e6
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Date deposited: 27 Apr 2006
Last modified: 08 Jan 2022 12:54
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Author:
S. Rorke
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