Adenosine receptors: therapeutic aspects for inflammatory and immune diseases

Top Cited Papers
Publisher Website
Google Scholar
Abstract
Adenosine is a key endogenous molecule that is released from cells and regulates tissue function via activating four G-protein-coupled adenosine receptors: A1, A2A, A2B and A3. These receptors are abundantly expressed on the surface of immune cells as well as on endothelial, smooth muscle, epithelial cells, fibroblasts and cardiomyocytes. Adenosine serves as an endogenous modulator of inflammatory and immune processes. Its release can be triggered from almost all cell types by ischaemia, hypoxia, inflammation and oxidative/nitrosative stress. Adenosine receptors can be targeted for the treatment of various inflammatory diseases. In asthma and chronic obstructive pulmonary disease, A2A receptor agonists prevent inflammatory cell infiltration into the lung. A2B receptor antagonists prevent mast-cell degranulation and the overproduction of pro-inflammatory mediators in the lung. In ischaemia, A2A receptor agonists potently down-regulate inflammatory cell infiltration into tissues, production of deleterious free radicals and pro-inflammatory cytokines. In arthritis, A2A receptor agonists have a wide range of anti-inflammatory effects in the inflamed joint. A3 receptor agonists decrease tumour necrosis factor-a production by monocytes and synoviocytes. In sepsis, A1 receptor agonists can prevent inflammation-mediated organ injury in animal models. A2A receptor antagonists are beneficial in sepsis by boosting the eradication of bacteria. In inflammatory bowel disease, A2A receptor agonists attenuate inflammatory cell sequestration in the gut and increase the activity of regulatory T cells thereby ameliorating the course of disease. A2B receptor antagonists prevent intestinal epithelial-cell-mediated inflammatory events and thereby prevent mucosal inflammation. Topical administration of A2A receptor agonists increases the rate of wound healing in part by stimulating angiogenesis in the skin. Thus, A2A receptor agonists are good candidates for the treatment of diabetic foot ulcer. In the clinic, A2A receptor agonists are being tested as therapeutic agents in wound healing and asthma. A2B receptor agonists have shown promise in clinical trials in patients with asthma and A3 receptor agonists improve symptoms in patients with rheumatoid arthritis.