Faculty Bibliography

Nonsteroidal anti-inflammatory drugs (NSAIDs) have anti-inflammatory, analgesic, and antipyretic properties. Although most NSAIDs inhibit prostaglandin synthesis, these agents also have important pharmacologic actions unrelated to their effects on prostaglandins. This review examines the evidence for diverse mechanisms of action of NSAIDs and their use in sports injuries

In mammalian species and in the oldest of multicellular animal forms, NSAIDs inhibit cell activation, apparently in the absence of effects on PG biosynthesis. Thus, an alternative hypothesis can be proposed to account for the antiinflammatory effects of these drugs. Clearly, at low doses aspirin and most of the newer NSAIDs inhibit the biosynthesis of PGs from arachidonic acid, and stable PGs have been shown to mediate fever, hyperalgesia, vasodilation (edema), and several interleukin-1-dependent responses. At high doses, however, aspirin, sodium salicylate, and the newer NSAIDs (at antiinflammatory doses) inhibit non-PG-dependent processes, such as the activity of a variety of enzymes, proteoglycan synthesis by chondrocytes, transmembrane ion fluxes, and chemoattractant binding. These effects are most likely due to the capacity of aspirin-like drugs to insert into the lipid bilayer of plasma membranes, where they disrupt normal signaling events and protein-protein interactions. The ability of NSAIDs to thereby inhibit the activation of inflammatory cells such as the neutrophil may contribute to the antiinflammatory properties of this class of drugs

The iC3b receptor (CR3) is required for neutrophil adhesive functions, including homotypic aggregation. Because stimuli that enhance neutrophil adhesion also induce up-regulation of surface CR3, it is widely held that these two responses are causally related. We have dissociated CR3 display (immunofluorescence) from CR3 function (aggregation). Neutrophils isolated at 4 degrees C and rewarmed to 37 degrees C up-regulated surface CR3 twofold, but did not aggregate. The kinetics of FMLP-induced CR3 up-regulation were discordant with those of aggregation. In the absence of extracellular divalent cations, CR3 expression increased twofold after exposure to FMLP, but neutrophils did not aggregate. FMLP elicited 3.5-fold more aggregation than the ionophore A23187, yet less than one-half as much CR3 up-regulation. 3 mM sodium salicylate inhibited aggregation 55 +/- 4%, but had no effect on CR3 up-regulation. Conversely, 1 mM tetracaine completely inhibited CR3 up-regulation, while significantly enhancing aggregation. Neutroplasts expressed CR3, but did not up-regulate the receptor; in contrast, FMLP induced CR3-dependent aggregation of neutroplasts. We conclude that, although constitutive surface CR3 is required for neutrophil aggregation, the up-regulation of CR3 is neither necessary nor sufficient to promote cell-cell adhesion