Adenosine signalling in airways
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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Ambroxol-enhanced ciliary beating via voltage-gated Ca<sup>2+</sup> channels in mouse airway ciliated cells
2023, European Journal of PharmacologyRealising the potential of various inhaled airway challenge agents through improved delivery to the lungs
2018, Pulmonary Pharmacology and TherapeuticsCitation Excerpt :The effects of indirect agents depend on the specific cells and receptors involved [10], but many of the stimuli used are known to activate sensory nerves, for example bradykinin, sulphur dioxide and adenosine (reviewed in Ref. [23]). Some indirect stimuli are endogenous compounds known to be released during airways obstruction, such as adenosine, AMP, tachykinins and bradykinin [24–31]. Another group of indirect-acting stimuli is comprised of sulphur-containing compounds, which originated from the observation that sulphur dioxide, a common air pollutant, and sulphites used as preservatives in food processing, may induce bronchoconstriction in susceptible subjects through activation of sensory neuronal pathways [32,33].
Airway responsiveness to adenosine after a single dose of fluticasone propionate discriminates asthma from COPD
2014, Pulmonary Pharmacology and TherapeuticsCitation Excerpt :The underlying mechanism of this narrowing appears to involve the stimulation of specific mast cell surface adenosine A2b receptors with the subsequent release of mediators and contraction of airway smooth muscle [3,4]. As airway hyperresponsiveness (AHR) to AMP is more closely associated with atopy and allergic airway inflammation than AHR to direct stimuli such as methacholine and histamine [5–7], bronchial provocation test with inhaled AMP may help to improve the diagnostic discrimination between asthma and COPD [8]. Diagnostic uncertainty can arise between COPD and asthma [9].
The role of the adenosinergic system in lung fibrosis
2013, Pharmacological ResearchCitation Excerpt :A2BRs are identified in mast cells, bronchial smooth muscle cells and lung fibroblasts. In these cellular types, adenosine, via activation of A2BRs, increases the release of various inflammatory cytokines and promotes differentiation of lung fibroblasts into myofibroblasts, typical of the fibrotic event [41,45,47]. In lungs of ADA-deficient mice treated with a selective antagonist of A2bRs, the inflammatory and the fibrotic processes as well as airway remodeling decreased [40,48,49].
Hyperresponsiveness to adenosine in sensitized Wistar rats over-expressing A<inf>1</inf> receptor
2012, European Journal of PharmacologyCitation Excerpt :Adenosine is a ubiquitous signaling nucleoside resulting from ATP catabolism, whose extracellular levels strongly increase following cellular damage or stress (Fredholm, 2007). Adenosine plays a role in bronchial asthma; asthmatics present elevated adenosine levels in bronchoalveolar lavage fluids (Caruso et al., 2006; Driver et al., 1993) and bronchoconstriction following inhalation of adenosine or of its precursor, adenosine-5′-monophosphate (Cushley et al., 1983). Interestingly, in humans, bronchial sensitivity to adenosine reflects allergic asthma and bronchial inflammation better than the sensitivity to other agents, such as methacholine or histamine (De Meer et al., 2002; Manso et al., 2011).
Adenosine receptors as targets for therapeutic intervention in asthma and chronic obstructive pulmonary disease
2009, Trends in Pharmacological Sciences