The Quintiles Prize Lecture 2004. The identification of the adenosine A2B receptor as a novel therapeutic target in asthma.
Adenosine is a powerful bronchoconstrictor of asthmatic, but not normal, airways. In vitro studies on isolated human mast cells and basophils revealed that adenosine and selective analogues augmented inflammatory mediator release from mast cells by stimulating A(2) receptors. Pharmacological blockade of mast cell mediator release in vivo also attenuated adenosine-induced bronchoconstriction, as did theophylline, by adenosine A(2) receptor antagonism. Further in vitro studies revealed that the asthmatic response to adenosine is likely to be mediated via the A(2B) subtype which is selectively antagonised by enprofylline. Studies in animal models, especially mice, have shown a close synergistic interaction between adenosine, Th2 and airway remodelling responses. The recent description of A(2B) receptors on human airway smooth muscle cells that mediate cytokine and chemokine release and induce differentiation of fibroblasts into myofibroblasts strengthens the view that adenosine maybe more than an inflammatory mediator in asthma but also participates in airway wall remodelling in this disease. These data have provided a firm basis for developing adenosine A(2B) receptor antagonists as a new therapeutic approach to this disease.
Holgate
Stephen T
ST
Allergy and Inflammation Research, School of Medicine, University of Southampton, Southampton. S.Holgate@soton.ac.uk
D000241:Adenosine / Q000378:metabolism / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001249:Asthma / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D016084:Bronchoconstriction / Q000187:drug effects; D006801:Humans; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism
D058917:Adenosine A2 Receptor Antagonists; D018927:Anti-Asthmatic Agents; D000241:Adenosine