Trends in Pharmacological Sciences
ReviewAdenosine receptors as targets for therapeutic intervention in asthma and chronic obstructive pulmonary disease
Introduction
Chronic airway diseases such as asthma and chronic obstructive pulmonary disease (COPD) are prevalent inflammatory disorders of the lung that are poorly managed, and for which few new drugs have been developed (see Text Box). Pharmaceutical companies and research institutions are addressing the substantial potential for the development of novel therapeutic agents that modulate adenosine signaling with significant clinical advantage for chronic inflammatory airway diseases [1].
Extracellular adenosine levels are elevated in response to cellular stress and injury through pathways that involve the release of adenine nucleotides and their subsequent dephosphorylation to adenosine [2]. The production of extracellular adenine nucleotides and adenosine can regulate cell function by engaging purinergic type II or type I receptors respectively. This review will focus on the type I or adenosine receptors. These receptors are expressed on various inflammatory and stromal cells and have well characterized anti-inflammatory and wound healing activities that demonstrate the importance of these signalling pathways in tissue protection [3] (Figure 1). In some situations, however, adenosine generation and receptor engagement have pro-inflammatory and tissue destructive activities [4] that serve to amplify tissue injury (Figure 2). This appears to be the case with inflammatory lung diseases such as asthma and COPD. Much evidence suggests that adenosine is playing a detrimental role in these and perhaps other chronic disorders of the airways (Table 1). The observations summarized in Table 1 suggest that adenosine signaling has a potentially pathophysiological role in chronic inflammatory disorders of the airways. These important observations have driven research efforts to develop selective agonists or antagonists for adenosine receptor subtypes for use as novel therapies for asthma and COPD.
Here we review proposed mechanisms of action of adenosine receptors in preclinical studies and describe molecules with high affinity and selectivity for the human adenosine receptor subtypes that are under investigation at preclinical and clinical levels as treatments for respiratory diseases. Findings in preclinical studies suggest there may be efficacy in the use of A1R, A3R and A2BR antagonists in the treatment of key features of asthma and COPD, and A2AR agonist may also prove beneficial. However, the results from clinical trials testing such hypotheses are limited and without firm conclusions.
Section snippets
Targeting adenosine receptor subtypes
Adenosine levels are elevated in the lungs of individuals with asthma and COPD, and adenosine receptors are known to be expressed on most if not all inflammatory and stromal cell types involved in the pathogenesis of these diseases. Extracellular adenosine elicits its effects by interacting with four receptors: A1R, A2AR, A2BR and A3R (Figure 1) [2]. These receptors are differentially expressed in the human lung [5]. The ability of adenosine, whose levels are raised in many pathophysiological
A1R: Preclinical Studies
As with all of the adenosine receptors, there is evidence that A1R exhibits both pro- and anti- inflammatory activities in cellular and animal models of inflammation [3]. In the context of models directed at human asthma, however, the preponderance of studies suggests that this receptor has a pro-inflammatory role. Attention was drawn to this receptor's role in asthma in studies demonstrating that treatment with A1R antagonists [6] and antisense oligodeoxynecleotides [7] directed against A1R
A1R: Clinical Trials
Elevated expression of A1R has been reported in bronchial biopsy specimens obtained from asthmatic subjects [15], where immunoreactivity appears to be predominantly located in the bronchial epithelium and bronchial smooth muscle. Moreover, the methylxanthine bamiphylline might produce its anti-asthma effects in humans by blocking A1R [19]. Given these findings, and given that activation of A1R on human airway epithelial, bronchial smooth muscle cells, neutrophils, macrophages and fibroblasts
A2AR: Preclinical Studies
Increasing evidence suggests that A2AR mediates potent anti-inflammatory activities on specific cells and in various models of inflammation, which has promoted the development of A2AR agonists for the attenuation of inflammation in many disorders (reviewed in [3]). Given the central role of inflammation in asthma and COPD, there has been substantial preclinical research activity targeted at understanding the function of A2AR in models of airway inflammation.
Among the earliest was a study by
A2AR: Clinical Trials
Detailed characterization of the immunohistochemistry and binding of A2AR in human lung parenchyma of patients with COPD has revealed the presence of this receptor subtype in bronchiolar and alveolar epithelial cells, bronchiolar smooth muscle cells and endothelial cells with a high affinity and density [5]. Because activation of A2AR increases intracellular cAMP similar to other agents that increase intracellular cAMP, for example, PDE-IV inhibitors, beta-2 agonists or theophylline, A2AR
A2BR: Preclinical Studies
The A2BR has the lowest affinity for adenosine, yet this receptor might be important in pathological environments where adenosine levels are elevated such as asthma [30]. In support of this, multiple studies demonstrate the ability of A2BR engagement to promote the expression of pro-inflammatory mediators from various cell types critical to processes seen in chronic lung diseases. This includes the release of IL-8 from HMC-1 cells [31], IL-4 and IL-13 32, 33 from HMC-1 cells and mouse
A2BR: Clinical Trials
Characterization of human lung parenchyma in patients with chronic inflammation of the airways suggests that A2BR might be present on mast cells and macrophages [5]. As compared with control smokers, the affinity and density of these receptors in COPD patients appears to be substantially modified, suggesting adenosine signalling might be important in COPD. Such a role for A2BR signalling in the pathophysiology of asthma receives support from pharmacological studies using the adenosine receptor
A3R: Preclinical Studies
The A3R plays complex roles in inflammation, with both pro- and anti-inflammatory functions being described in multiple cellular and animal models with varying roles being dictated largely by species differences (for review see [53]). This receptor has also received attention in chronic inflammatory disorders of the airways. Transcript levels of A3R are elevated in lung biopsies of patients with asthma or COPD [54], where it is thought to localize to eosinophils. Functions attributed to A3R
A3R: Clinical Trials
As mentioned above, transcript levels of A3R are elevated in lung biopsies of patients with asthma or COPD where it appears to be involved in the inhibition of eosinophil chemotaxis. Because asthmatic inflammation is characterized by extensive infiltration of the airways by activated eosinophils, elevated adenosine concentrations associated with asthma might contribute to eosinophilic trafficking through modulation of A3R. King Pharmaceuticals published a patent application claiming a
Conclusions
The pharmacological arsenal for allergy and asthma is fast growing, and significant endeavors in medicinal chemistry and pharmacology have yielded a number of safer and highly selective compounds directed against the four known adenosine receptor subtypes. Some of these compounds have entered clinical development and may be of assistance in the process of finding better therapies for patients with asthma and COPD (Table 3).
Although adenosine generation and the subsequent engagement of adenosine
Disclosure Statement
Riccardo Polosa has received lecture fees from CV Therapeutics, Merck, GSK, Astra-Zeneca, and Novartis; he has also served as a consultant to CV Therapeutics, Sanofi-Aventis, Merck, and Duska Therapeutics. Michael R. Blackburn has served as a consultant for CV Therapeutics.
Acknowledgements
Riccardo Polosa is full Professor of Internal Medicine and he is supported by the University of Catania, Italy. Research in M. R. Blackburn's laboratory is supported by NIH Grants AI43572 and HL70952.
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