Adenosine receptors and asthma

Abstract

The pathophysiological processes underlying respiratory diseases like asthma are complex, resulting in an overwhelming choice of potential targets for the novel treatment of this disease. Despite this complexity, asthmatic subjects are uniquely sensitive to a range of substances like adenosine, thought to act indirectly to evoke changes in respiratory mechanics and in the underlying pathology, and thereby to offer novel insights into the pathophysiology of this disease. Adenosine is of particular interest because this substance is produced endogenously by many cells during hypoxia, stress, allergic stimulation, and exercise. Extracellular adenosine can be measured in significant concentrations within the airways; can be shown to activate adenosine receptor (AR) subtypes on lung resident cells and migrating inflammatory cells, thereby altering their function, and could therefore play a significant role in this disease. Many preclinical in vitro and in vivo studies have documented the roles of the various AR subtypes in regulating cell function and how they might have a beneficial impact in disease models. Agonists and antagonists of some of these receptor subtypes have been developed and have progressed to clinical studies in order to evaluate their potential as novel antiasthma drugs. In this chapter, we will highlight the roles of adenosine and AR subtypes in many of the characteristic features of asthma: airway obstruction, inflammation, bronchial hyperresponsiveness and remodeling. We will also discuss the merit of targeting each receptor subtype in the development of novel antiasthma drugs.

Fig. 1

Metabolism of adenosine. Adenosine is generated mainly by two enzymatic systems: intra/extracellularly localized nucleotidases and cytoplasmic S-adenosylhomocysteine hydrolase (SAHH). In response to hypoxia/cellular damage or other stressful/inflammatory stimuli, ATP is rapidly dephosphorylated by combined effects of adenylate cyclase (AC), phosphodiesterases (PDE) and nucleotidases to form intra/extracellular adenosine. Ecto-5′-nucleotidase (ecto-5′-NT) is one such enzyme that plays an important role in regulating local adenosine production for receptor signaling. Extracellular adenosine can interact with adenosine receptors (AR) that are coupled to heterotrimeric G proteins, which, in turn, couple AR activation to various effector molecules that can regulate second-messenger systems to influence cell and tissue function. Adenosine can also be deaminated to inosine by adenosine deaminase (ADA) that can exist intra- or extracellularly, or it can be transported into and out of the cells via membrane-associated nucleoside transporters. Intracellular adenosine is generated from the dephosphorylation of AMP by a cytosolic form of nucleotidase (cyto-5′-NT) or the hydrolysis of S-adenosylhomocysteine by SAHH. Adenosine can also be phosphorylated back to AMP by adenosine kinase (AK). AMP can also be directly deaminated to inosine monophosphate (IMP) by AMP deaminase. The reaction of phosphorylation predominates when adenosine occurs at a low physiological concentration (<1 µM), whereas ADA is activated at higher concentrations of the substrate (>10 µM). Hypoxanthine is formed after the removal of ribose from inosine by the actions of purine nucleoside phosphorylase (PNP) PNP has only negligible activity towards adenosine and degrades mainly inosine. Hypoxanthine can be salvaged back to IMP by hypoxanthine phosphoribosyltransferase (HPRT), which is again converted to AMP through the purine nucleotide cycle (PNC). Hypoxanthine can also enter the xanthine oxidase (XO) pathway to form xanthine and uric acid sequentially as byproducts

Fig. 2

Adenosine receptors and pathophysiology of asthma. By acting on adenosine receptors (ARs), A₁, A_2A, A_2B, and A₃ ARs, adenosine released under conditions of cellular stress as seen in asthmatic airways produces bronchoconstriction and inflammation. The net effect of adenosine on ARs will depend on the relative expression of these receptors on different cell types in asthmatic airways, and is concentration-dependent, as adenosine frequently exhibits opposing effects through the activation of AR subtypes expressed on the same cells coupled to different G proteins and signaling pathways. By acting on A₁ARs on bronchial smooth muscle cells and afferent sensory airway nerves, adenosine produces bronchoconstriction. By acting on A₁ARs on inflammatory leukocytes such as neutrophils, monocytes, macrophages, and lymphocytes, adenosine produces proinflammatory effects. Activation of A_2AARs on the inflammatory cells suppresses the release of proinflammatory cytokines and mediators. Activation of A_2AARs coupled to G_s and adenylate cyclase may also lead to bronchial smooth muscle relaxation via the cAMP–PKA (cyclic adenosine monophosphate–protein kinase A) pathway. Activation of A_2BARs coupled to G_s and adenylate cyclase induce cytokine release from human bronchial epithelial and smooth muscle cells. Activation of A_2BARs on murine bone marrow-derived mast cells (BMMCs) regulates the release of cytokines. The effect of adenosine on A₃ARs is species dependent. In mice, rats, and guinea pigs, activation of A₃ARs by adenosine produces bronchoconstriction, airway inflammation, mast cell degranulation, and mucus hyperplasia. In humans, activation of A₃ARs by adenosine produces anti-inflammatory effects, inhibition of chemotaxis and degranulation of eosinophils and cytokine release from monocytes. Circled times denote inhibition