Adenosine receptors as targets for therapeutic intervention in asthma and chronic obstructive pulmonary disease

doi:10.1016/j.tips.2009.07.005

Trends in Pharmacological Sciences

Volume 30, Issue 10, October 2009, Pages 528-535

https://doi.org/10.1016/j.tips.2009.07.005 Get rights and content

Asthma and chronic obstructive pulmonary disease (COPD) are pulmonary disorders characterized by various degrees of inflammation and tissue remodeling. Adenosine is a signaling molecule that is elevated in the lungs of patients with asthma and COPD. Adenosine elicits its actions by engaging cell surface adenosine receptors, and substantial preclinical evidence suggests that targeting these receptors will provide novel approaches for the treatment of asthma and COPD. Studies in animal models of airway disease suggest that there may be clinical benefit to the use of A₁, A₃ and A_2B adenosine receptor antagonists in the treatment of features of asthma and/or COPD, while A_2A agonists may also prove effective. Several adenosine receptor based pharmacologic agents have entered clinical development for the treatment of asthma and COPD; however, the studies have been limited and the efficacy of such approaches is not yet clear.

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 A_2BR antagonists in the treatment of key features of asthma and COPD, and A_2AR 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, A_2AR, A_2BR 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

A_2AR: Preclinical Studies

Increasing evidence suggests that A_2AR mediates potent anti-inflammatory activities on specific cells and in various models of inflammation, which has promoted the development of A_2AR 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 A_2AR in models of airway inflammation.

Among the earliest was a study by

A_2AR: Clinical Trials

Detailed characterization of the immunohistochemistry and binding of A_2AR 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 A_2AR increases intracellular cAMP similar to other agents that increase intracellular cAMP, for example, PDE-IV inhibitors, beta-2 agonists or theophylline, A_2AR

A_2BR: Preclinical Studies

The A_2BR 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 A_2BR 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

A_2BR: Clinical Trials

Characterization of human lung parenchyma in patients with chronic inflammation of the airways suggests that A_2BR 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 A_2BR 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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Trends in Pharmacological Sciences

ReviewAdenosine receptors as targets for therapeutic intervention in asthma and chronic obstructive pulmonary disease

Introduction

Section snippets

Targeting adenosine receptor subtypes

A1R: Preclinical Studies

A1R: Clinical Trials

A2AR: Preclinical Studies

A2AR: Clinical Trials

A2BR: Preclinical Studies

A2BR: Clinical Trials

A3R: Preclinical Studies

A3R: Clinical Trials

Conclusions

Disclosure Statement

Acknowledgements

Trends Pharmacol Sci

Eur J Pharmacol

Curr Opin Pharmacol

Eur J Pharmacol

Pharmacol Ther

J Biol Chem

Trends Pharmacol Sci

Pulm Pharmacol

Pharmacol Ther

Respir Med

Therapeutic potential of adenosine receptor antagonists and agonists

Exp Opin Ther Patents

International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors

Pharmacol Rev

Adenosine receptors: therapeutic aspects for inflammatory and immune diseases

Nat Rev Drug Discov

Alteration of adenosine receptors in patients with chronic obstructive pulmonary disease

Am J Respir Crit Care Med

Adenosine-induced bronchoconstriction and contraction of airway smooth muscle from allergic rabbits with late-phase airway obstruction: evidence for an inducible adenosine A1 receptor

J Pharmacol Exp Ther

Involvement of A1 adenosine receptors and neural pathways in adenosine induced bronchoconstriction in mice

Am J Physiol Lung Cell Mol Physiol

Adenosine up-regulation of the mucin gene, MUC2, in asthma

Faseb J

Adenosine-dependent airway inflammation and hyperresponsiveness in partially adenosine deaminase-deficient mice

J Immunol

Adenosine mediates IL-13-induced inflammation and remodeling in the lung: evidence for an IL-13-adenosine amplification pathway

J Clin Invest.

Adenosine metabolism and murine strain-specific IL-4-induced inflammation, emphysema, and fibrosis

J Clin Invest

Enhanced airway reactivity and inflammation in A2A adenosine receptor-deficient allergic mice

Am J Physiol Lung Cell Mol Physiol

Elevated expression of adenosine A1 receptor in bronchial biopsy specimens from asthmatic subjects

Eur Respir J

A protective role for the A(1) adenosine receptor in adenosine-dependent pulmonary injury

J Clin Invest

Metabolic consequences of adenosine deaminase deficiency in mice are associated with defects in alveogenesis, pulmonary inflammation, and airway obstruction

J Exp Med

Adenosine-dependent pulmonary fibrosis in adenosine deaminase-deficient mice

J Immunol

A novel A1 adenosine receptor antagonist, L-97-1 [3-[2-(4-aminophenyl)-ethyl]-8-benzyl-7-{2-ethyl-(2-hydroxy-ethyl)-amino]- ethyl}-1-propyl-3,7-dihydro-purine-2,6-dione], reduces allergic responses to house dust mite in an allergic rabbit model of asthma

J Pharmacol Exp Ther

Clinical potential of respirable antisense oligonucleotides (RASONs) in asthma

Am J Pharmacogenomics

An inhaled respirable antisense oligonucleotide: RASON

Am J Resp Crit Care Med

Effect of adenosine A2A receptor activation in murine models of respiratory disorders

Am J Physiol Lung Cell Mol Physiol

Genetic removal of the A2A adenosine receptor enhances pulmonary inflammation, mucin production, and angiogenesis in adenosine deaminase-deficient mice

Am J Physiol Lung Cell Mol Physiol

Review
Adenosine receptors as targets for therapeutic intervention in asthma and chronic obstructive pulmonary disease

A₁R: Preclinical Studies

A₁R: Clinical Trials

A_2AR: Preclinical Studies

A_2AR: Clinical Trials

A_2BR: Preclinical Studies

A_2BR: Clinical Trials

A₃R: Preclinical Studies

A₃R: Clinical Trials