Treating lung inflammation with agonists of the adenosine A_2A receptor: promises, problems and potential solutions

Abstract

Adenosine A 2A receptor agonists may be important regulators of inflammation. Such conclusions have come from studies demonstrating that, (i) adenosine A 2A agonists exhibit anti-inflammatory properties in vitro and in vivo, (ii) selective A 2A antagonists enhance inflammation in vivo and, (iii) knock outs of this receptor aggravate inflammation in a wide variety of in vivo models. Inflammation is a hallmark of asthma and COPD and adenosine has long been suggested to be involved in disease pathology. Two recent publications, however, suggested that an inhaled adenosine A 2A receptor agonist (GW328267X) did not affect either the early and late asthmatic response or symptoms associated with allergic rhinitis suggesting that the rationale for treating inflammation with an adenosine A 2A receptor agonist may be incorrect. A barrier to fully investigating the role of adenosine A 2A receptor agonists as anti-inflammatory agents in the lung is the side effect profile due to systemic exposure, even with inhalation. Unless strategies can be evolved to limit the systemic exposure of inhaled adenosine A 2A receptor agonists, the promise of treating lung inflammation with such agents may never be fully explored. Using strategies similar to that devised to improve the therapeutic index of inhaled corticosteroids, UK371,104 was identified as a selective agonist of the adenosine A 2A receptor that has a lung focus of pharmacological activity following delivery to the lung in a pre clinical in vivo model of lung function. Lung-focussed agents such as UK371,104 may be suitable for assessing the anti-inflammatory potential of inhaled adenosine A 2A receptor agonists.

Gs-Coupled Adenosine Receptors Differentially Limit Antigen-Induced Mast Cell Activation

“…It is possible that the environment in which the mast cell resides influences adenosine receptor expression and function, accounting for the differences in receptor effects observed between these studies. Although several studies have suggested that A 2A receptors mediate anti-inflammatory effects (Antonioli et al, 2010;Fenster et al, 2000;Harada et al, 2000;Kreckler et al, 2006;Rork et al, 2008;Trevethick et al, 2008), a clinical trial failed to demonstrate efficacy of an A 2A agonist in attenuating allergen-induced early and late reactions, sputum total cell counts and EG21 cell numbers, eosinophil cationic protein levels, or inflammatory cytokine production in asthmatic subjects (Luijk et al, 2008).…”

Purinergic Signaling in the Airways

“…As for asthma, the main purinergic emphasis has been on the role of adenosine receptors in COPD Polosa, 2002; see reviews by Peleg and Schulman, 2002;Blackburn, 2003;van den Berge et al, 2004van den Berge et al, , 2007Caruso et al, 2006;Mohsenin and Blackburn, 2006;Trevethick et al, 2008;Polosa and Blackburn, 2009;Zhou et al, 2009bZhou et al, , 2010. Enprofylline, a xanthine lacking adenosine receptor antagonism, was shown to be a potent bronchodilator in patients with COPD (Lunell et al, 1982).…”

“…Activation of A 2A receptors inhibited inflammatory cell activation in COPD (Bonneau et al, 2006). Inhaled A 2A receptor agonists have been used for the treatment of COPD Trevethick et al, 2008;Thomas et al, 2008). It has been shown that after a 1-year smoking cessation airway inflammation in COPD persisted or was aggravated and that this may be due to an increase in neutrophils expressing A 3 receptors and macrophages expressing A 1 receptors (Versluis et al, 2009).…”

Emerging anti-inflammatory strategies for COPD

“…A key molecular mechanism is the suppression of the nuclear factor (NF)-kB pathway activated by cytokines such as tumour necrosis factor (TNF)-a and interleukin (IL)-1b. The stimulation of A 2a -receptors limits macrophage proinflammatory cytokine production, reduces adhesion molecule expression on endothelial cells, and suppresses the generation of superoxide anion and leukotriene synthesis by neutrophils [20][21][22].…”