Purinergic mechanisms in inflammation

Adenosine is now used to treat cardiac arrhythmias and a variety of other potential therapeutic uses for adenosine and its receptor‐specific analogues have been suggested. We will review here the evidence that adenosine may be useful in the treatment of inflammatory diseases although its potential for promotion of inflammation must be taken into account. The antiinflammatory effects of adenosine and its receptor analogues were first suggested in 1983. Originally shown to diminish neutrophil function via interaction with adenosine A 2 receptors, adenosine has a variety of effects on the cells involved in inflammation, which, in general, are antiinflammatory. In this series of reports we will discuss the effects of adenosine, acting at its receptors on macrophage/monocytes, and on the synthesis and secretion of the cytokines that orchestrate inflammation. In previous studies, the paradoxical capacity of adenosine to promote the inflammatory functions of neutrophils has been shown to result from A 1 receptor occupancy. We will discuss here the potential pro‐inflammatory role of adenosine, acting at A 1 receptors, to enhance the adhesive capacity of vascular endothelium, a critical element in recruiting leukocytes to inflamed sites. Although prior studies have focussed on the potential for adenosine receptor‐specific agonists to diminish inflammation it is also possible that endogenously released adenosine plays an antiinflammatory role. We will review the evidence that two commonly used and potent antiinflammatory agents, methotrexate and sulfasalazine, diminish inflammation via promotion of adenosine release. The expansion of the potential therapeutic uses of adenosine to include inflammatory diseases may permit the development of novel pharmacologic agents for the treatment of such diseases as rheumatoid arthritis. Drug Dev. Res. 39:426–435, 1996. © 1997 Wiley‐Liss, Inc.