Purinergic signalling in the lung: important in asthma and COPD?
Introduction
Several recent studies have provided convincing evidence that purines, especially ATP and the product of its enzymatic breakdown, adenosine, have potent effects on multiple lung cell types that are believed to be involved in the pathophysiology of asthma and chronic obstructive pulmonary disease (COPD; for reviews, see 1.•, 2., 3.••, 4.), including mast cells, lymphocytes, eosinophils, neutrophils, dendritic cells, airway epithelial cells [5] and neurons [6••]. It is well known that, unlike healthy individuals, asthmatic and COPD patients react to adenosine challenge with an enhanced hyperresponsiveness, reflected by a marked airway obstruction, and that the bronchoalveolar lavage fluid of most of these patients shows elevated levels of adenosine.
Despite the fact that the mechanisms underlying these pulmonary diseases are multiple and obviously interact with each other, roughly two groups of key players can be distinguished: cell types involved in immune and inflammatory responses, and autonomic neurones and (neuroendocrine) epithelial cells.
The pulmonary sources from which significant amounts of purines are released — thrombocytes, red blood cells, vascular endothelium, smooth muscle, neurones, epithelial cells [3••] and neuroepithelial bodies (NEBs) — and the ways in which these substances can affect lung function under pathological conditions are extremely diverse. Furthermore, the generalisation of particular hypothesised mechanisms by which these purines act is hampered by clear species differences both in the expression patterns of the distinct purinoreceptors and in their respective functions in the airways, not to mention interspecies differences in the characteristics of the intermediary inflammatory cells involved [7]. The complexity of the mechanisms underlying these lung pathologies is further reflected in the fact that purines are capable of exerting completely opposite actions through different receptors; for example, it is now generally accepted that these substances elicit contraction of vascular and non-vascular smooth muscle via activation of ion-gated P2X purinoceptors, whereas their relaxant effects are mediated by G-protein-coupled P2Y receptors 8., 9..
Section snippets
Involvement of intermediary inflammatory cells in the purinergic pathways in asthma and COPD
One mechanism by which extracellular purines can cause bronchospasm in asthma and COPD is indirect, through activation of purinoceptors present on the surface of inflammatory cells — the most important of which are undoubtedly mast cells (see below).
Although the detailed mechanisms remain to be elucidated, it has also been shown that ATP is capable of modulating the function of allergen-carrying dendritic cells and eosinophils by activating P2 receptors on the surface of both cell types,
Involvement of pulmonary autonomic innervation and neuroendocrine system in the purinergic pathways in asthma and COPD
It is generally accepted that under normal conditions several purinoceptor subtypes are involved in the central control of cardiovascular and respiratory networks [20], and that P2X receptors containing the P2X2 subunit play a pivotal role both in carotid body function and in mediating ventilatory responses to hypoxia [21]. The notion, proposed more than 30 years ago, that under several pathological conditions pulmonary side effects, such as dyspnea, commonly accompany the clinical use of
Conclusions
Data reviewed here clearly indicate that purines play a pivotal role in both the inflammatory and neurogenic pathways associated with the pathophysiology of obstructive pulmonary diseases. Given the multitude of players involved, the future challenge will be to design appropriate experiments to elucidate the effects of target-related agonists and antagonists, and reveal the complex interplay between immune and neural components.
Update
Very recent work — combining retrograde tracing and electrophysiological recordings from nodose and jugular vagal ganglia in an ex-vivo, vagally innervated lung preparation — described the presence of two distinct populations of vagal C-fibres in lungs, of which only the nodose population responded with action potential discharge to the P2X receptor-selective agonist α,β-methylene-ATP [48]. This evidence supports the idea that vagal afferent purinergic signalling may be involved in the
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
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of special interest
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of outstanding interest
Acknowledgements
We are grateful to Professor G Burnstock (Director of the Autonomic Neuroscience Institute, Royal Free and University College Medical School) for his invaluable input in our ATP receptor studies. This work was supported by the following research grants: Fund for Scientific Research-Flanders (G.0155.01); NOI-BOF (to DA) from the University of Antwerp.
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