Adenosine signalling in airways

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Current research endeavours indicate that adenosine elicits strong inflammatory responses in the lung and might be involved in the pathogenic mechanisms of chronic inflammatory disorders of the airways such as asthma and chronic obstructive pulmonary disease (COPD). The contribution of adenosine-associated effector mechanisms to the initiation, persistence and progression of the inflammatory response is highly heterogeneous and is dictated by the expression pattern of four different adenosine receptors. Selective activation or blockade of these sites can therefore be exploited in an attempt to generate novel therapies for asthma and COPD. In addition, an important development is the use of adenosine (or AMP) as a diagnostic test for discriminating asthma from COPD, and as an accurate biomarker to monitor corticosteroid requirements in asthma. It is likely that therapies interfering with adenosine signalling in the airways will offer a considerable advance in the management of asthma and COPD.

Introduction

The purine nucleoside adenosine is normally present in human tissues at low concentrations, but in response to metabolic stress, such as that encountered in the course of inflammatory events or during tissue hypoxia, a rapid increase in adenosine tissue levels takes place [1]. Once generated, adenosine elicits its biological activities by interacting with at least four adenosine receptor subtypes belonging to a G-protein-coupled- receptor family: A1, A2A, A2B and A3 adenosine receptors [2].

A role for adenosine in pulmonary disease was first suggested in the late 1970s when it was found that adenosine and related synthetic analogues were potent enhancers of IgE-dependent mediator release from isolated rodent mast cells [3]. A few years later, adenosine administered by inhalation was shown to be a powerful bronchoconstrictor of asthmatic but, importantly, not of normal airways [4]. Further work showed that both allergic and non-allergic asthmatics responded in a similar way and that the effect was also seen with adenosine 5′-monophosphate (AMP), ADP and, more recently, ATP [5, 6, 7].

In addition to its well-known effect as a bronchoconstrictor, a growing body of evidence has emphasized the importance of adenosine in the initiation, progression and control of chronic inflammation and remodeling of the airways [8, 9].

This review addresses the evidence for a pathophysiological role of adenosine receptor signalling in inflammatory airway diseases (e.g. asthma and chronic obstructive pulmonary disease [COPD]) and the notion that selective activation or blockade of adenosine receptors leads to therapeutic benefit in the management of pulmonary diseases. The distinctive airway responses to inhaled adenosine have been recently exploited in the clinical and research setting to improve asthma management and to identify innovative diagnostic applications for asthma and COPD.

Section snippets

A role for endogenous adenosine signalling

Elevated levels of adenosine are present in chronically inflamed airways; they have been observed both in the bronchoalveolar lavage fluid [10] and the exhaled breath condensate [11] of patients with asthma. Adenosine levels are also increased after allergen exposure [5] and during exercises in atopic individuals [12]. The observed increase in tissue levels of adenosine suggests that adenosine signaling could regulate important features of chronic inflammatory disorders of the airways,

Rationale for interfering with adenosine signalling

Many cell types that play important roles in the pathogenesis of chronic inflammatory airway disease are known to express adenosine receptors. These cell types include various inflammatory cells, such as mast cells, eosinophils, lymphocytes, neutrophils and macrophages, and structural cells in the lung, such as bronchial epithelial cells, smooth muscle cells, lung fibroblasts and endothelial cells. In addition, numerous animal models have been used to assess the contribution of adenosine and

A role for exogenous adenosine signalling

An important development in the field of adenosine research is the use of adenosine (or AMP) as a diagnostic test for discriminating asthma from COPD. For clinical and research purposes, airway responsiveness is commonly measured by bronchial provocation testing with inhaled methacholine or histamine. However, the bronchoconstrictive stimulus AMP has been recently proposed as a useful diagnostic test for asthma by virtue of its specificity and sensitivity towards allergic airway inflammation [30

Conclusions and future directions

Over the past 20 years, the initial observation of the bronchoconstrictive effect of inhaled adenosine has evolved to provide the basis for a new asthma therapy, as well as a new diagnostic test. Recognition of the potential role of adenosine receptor signalling in the pathogenesis of chronic airway inflammatory diseases advocates the principle that modulating adenosine receptor signalling is likely to constitute a considerable advance in the management of asthma and COPD. Clinical evaluation

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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