Adenosine receptors and asthma in humans

Abstract

According to an executive summary of the GINA dissemination committee report, it is now estimated that approximately 300 million people (5% of the global population or 1 in 20 persons) have asthma. Despite the scientific progress made over the past several decades toward improving our understanding of the pathophysiology of asthma, there is still a great need for improved therapies, particularly oral therapies that enhance patient compliance and that target new mechanisms of action. Adenosine is an important signalling molecule in human asthma. By acting on extracellular G-protein-coupled ARs on a number of different cell types important in the pathophysiology of human asthma, adenosine affects bronchial reactivity, inflammation and airway remodelling. Four AR subtypes (A 1 , A 2a , A 2b and A 3 ) have been cloned in humans, are expressed in the lung, and are all targets for drug development for human asthma. This review summarizes what is known about these AR subtypes and their function in human asthma as well as the pros and cons of therapeutic approaches to these AR targets. A number of molecules with high affinity and high selectivity for the human AR subtypes have entered clinical trials or are poised to enter clinical trials as anti-asthma treatments. With the availability of these molecules for testing in humans, the function of ARs in human asthma, as well as the safety and efficacy of approaches to the different AR targets, can now be determined.British Journal of Pharmacology (2008) 155, 475-486; doi:10.1038/bjp.2008 Keywords: adenosine; ARs; asthma; A 1 AR; A 2a AR; A 2b AR; A 3 AR Abbreviations: ADA, adenosine deaminase; AMP, adenosine monophosphate; APCs, antigen presenting cells; AR, adenosine receptor; BAL, bronchoalveolar lavage; CFTR, cystic fibrosis transmembrane conductance regulator; CPA, N 6 -cyclopentyladenosine; DPCPX, 1,3-dipropyl-8-cyclopentylxanthine; FEV 1 , forced expiratory volume in one second; GINA, Global Initiative for Asthma; HBECs, human bronchial epithelial cells; HBSMCs, human bronchial smooth muscle cells; ICSs, inhaled corticosteroids; IP(3), inositol trisphosphate; KO, knockout; LABAs, long acting beta 2 agonists; LAMAs, long acting muscarinic antagonists; LTRAs, leukotriene receptor antagonists; MCP, monocyte chemotactic protein; NECA, 5 0 -N-ethylcarboxamidoadenosine; PC 20 for AMP, provocative concentration (PC) of AMP required to reduce FEV 1 by 20%; PDE-IV, phosphodiesterase-IV; RT-PCR, reverse transcription-polymerase chain reaction IntroductionUnmet medical need for new drugs that improve patient compliance and prevent and treat airway remodelling According to an executive summary of the GINA dissemination committee report, it is now estimated that approximately 300 million people (5% of the global population or 1 in 20 persons) have asthma (Masoli et al., 2004). Moreover, according to the World Health Organization, 255 000 people died of asthma in 2005 and asthma is the most common chronic disease among children. Despite the scientific progress made over the past s...

Purinergic Signaling in the Airways

“…The involvement of adenosine in asthma has been the subject of considerable attention over the years, after it was shown that it produced powerful bronchoconstriction in asthma, although it had little effect in healthy lungs; xanthines, antagonists of adenosine receptors, were widely used for treatment of asthma (for reviews, see Persson, 1982;Kawasaki et al, 1983;Holgate et al, 1987Holgate et al, , 1990Feoktistov and Biaggioni, 1996;Fozard and Hannon, 2000;Meade et al, 2001;Fozard and McCarthy, 2002;Holgate, 2002Holgate, , 2005Polosa et al, 2002;Fozard, 2003;Lee et al, 2003;Livingston et al, 2004;Caruso et al, 2006Caruso et al, , 2009Russo et al, 2006;Brown et al, 2008b;Wilson, 2008). It was suggested that the hyper-responsive effects of adenosine in isolated bronchi was due to indirect actions by liberation of histamine and leukotrienes (Björck et al, 1992).…”

Activation of A 1 -Adenosine Receptors Promotes Leukocyte Recruitment to the Lung and Attenuates Acute Lung Injury in Mice Infected with Influenza A/WSN/33 (H1N1) Virus

“…Although DPCPX treatment did not reverse influenza A virusinduced pulmonary edema, the beneficial effects of this drug on arterial oxygenation suggest that A 1 -AdoR antagonists such as DPCPX may be of some value in this regard, either on their own or as adjuncts to other therapeutic agents. Importantly, additional A 1 -AdoR antagonists are in development for other indications, and they appear to be safe and well tolerated in humans (85).…”

Adenosine Receptors and Asthma

“…Adenosine receptors have been described on a number of different cell types that are important in the pathophysiology of asthma, including dendritic, antigen-presenting cells, human airway epithelial and bronchial smooth muscle cells, lymphocytes, mast cells, eosinophils, neutrophils, macrophages, fibroblasts and endothelial cells (Thiel et al 2003; Young et al 2006; Wilson 2008). Activation of ARs on these different cell types is responsible for inducing the release of mediators and cytokines, leading to BHR, inflammation, edema, and airway remodeling.…”