spirin was discovered at the end of the last century; since then, aspirin and more- novel nonsteroidal anti- inflammatory drugs (NSAIDs) have been used profusely and successfully in the symptomatic treatment of both acute and chronic inflammatory disorders. These drugs act by inhibiting prostaglandin synthesis, which provides an explanation for some of the pharmacological actions (anti-pyretic, analgesic and platelet anti-aggregant) and undesirable effects (stomach and renal damage) of NSAIDs. However, the anti- inflammatory mechanism of action of NSAIDs is currently not well understood 1,2 . This article discusses the recently reported prostaglandin-independent effects of NSAIDs that may account for their anti- inflammatory properties through the inhibition of key steps of the leukocyte emigration process. Mechanism of action of NSAIDs In 1971, Vane proposed that inhibition of prostaglandin synthesis is the main mechanism through which aspirin and related drugs inhibit inflammation 3 . Cyclooxygenase (COX) is a key enzyme in prostaglandin synthesis and almost all known NSAIDS are capable of inhibiting this enzyme. Two different forms of this enzyme have been characterized: COX-1 and COX-2. COX-1 is involved in pro- cesses where prostaglandins have a protective effect 4 , such as the production of gastric mucus and the maintenance of renal blood flow, whereas the activity of COX-2, the inducible form of the enzyme 5,6 , has been strongly associated with inflammation 7 . How- ever, several lines of evidence suggest that COX blockade may not be the sole or even the most important anti-inflammatory mechanism of action of NSAIDs. The fact that certain prostaglandins have anti-inflammatory activity in animal models of arthritis 8 sup- ports this contention, as does the failure of some NSAIDs to act as COX inhibitors, despite their anti-inflammatory activity 9 . Further- more, there is no correlation between the small doses of aspirin that inhibit prostaglandin synthesis and the higher doses required to exert an anti-inflammatory effect in vivo 1 . Finally, recent studies have shown that renal development is defective in animals in which the gene encoding COX-2 has been disrupted, but that the inflamma- tory response is largely intact 10,11 . All these data suggest that the importance of prostaglandin inhibition by NSAIDs in the control of the inflammatory response has been overestimated. Alternative anti-inflammatory pathways Some alternative mechanisms have been explored in an attempt to explain the anti- inflammatory activity of NSAIDs. In this regard, it has been reported that different NSAIDs are able in vitro to inhibit certain phenomena associated with neutrophil acti- vation, such as the synthesis of cyclic AMP, the generation of superoxide anions or the release of lysosomal enzymes 1,2,12 . In addition, some NSAIDs appear to inhibit membrane- associated processes, such as the activation of NADPH oxidase and phospholipase C (PLC) enzymatic pathways 1,2 . Recently, it has been demonstrated in vitro that NSAIDs inhibit the expression of inducible nitric oxide synthase 13 , an enzyme clearly associated with inflam- mation and cell damage. On the other hand, it has been suggested that salicylates and aspirin exert some of their effects by inhibiting NF-B (Refs 14, 15), a nuclear factor involved in the gene transcription of sev- eral proinflammatory cytokines and endothelial adhesion molecules. All these data suggest that NSAIDs have anti-inflammatory mecha- nisms of action other than inhibition of prostaglandin synthesis. Clinical evidence indicates that NSAIDs are more effective in acute rather than in chronic inflammatory diseases. Therefore, it is feasible that NSAIDs may interfere with an early step of the in- flammatory response. Furthermore, the high variability in the clini- cal response of patients to NSAIDs suggest that these agents differ in their mechanisms of action 16 . The multistep model of leukocyte emigration to the tissue The accumulation of leukocytes into inflamed tissues occurs as a consequence of endothelial cell (EC) activation and leukocyte VIEWPOINT IMMUNOLOGY TODAY Vol.19 No.4 169 Copyright © 1998 Elsevier Science Ltd. All rights reserved. 0167-5699/98/$19.00 PII: S0167-5699(97)01216-4 APRIL 1998 Inhibition of leukocyte adhesion: an alternative mechanism of action for anti-inflammatory drugs Federico Díaz-González and Francisco Sánchez-Madrid It has been widely accepted that the mechanism of action of nonsteroidal anti-inflammatory drugs (NSAIDs) is the inhibition of prostaglandin synthesis. However, a significant body of evidence suggests that NSAIDs have additional anti-inflammatory mechanisms of action. Here, Federico Díaz-González and Francisco Sánchez-Madrid discuss novel effects of NSAIDs on leukocyte adhesion pathways that may help in the development of new anti-inflammatory agents that selectively block cell adhesion molecules. A