Leukocytes and the trafficking processes that direct these cells to their tissue sites of function, represent mainstays in the mammalian armamentarium against microbial pathogens. Trafficking processes are equally relevant to recruitment of immune cells which engage in functions that include localized immune response and tissue remodeling activities. The remarkable vigor with which leukocytes seek out and destroy pathogens, pathogen-infected cells, and dead cells and their products has come at a price; evolution has been incompletely successful in elaborating an immune system capable of perfectly discriminating between circumstances where potent destructive powers must be applied, and where restraint must be exercised. Leukocytes and their trafficking processes, for example, are occasionally prone to unleashing their powers in a tissue-destructive manner. Excessive trafficking of leukocytes to extravascular locations can lead to serious tissue injury and destruction in both acute and chronic circumstances (1), as exemplified by neutrophil-dependent myocardial injury that accompanies cardiac reperfusion injury (2) and by leukocyte infiltration into joints in patients with rheumatoid arthritis (3). In the context of this series,“Cell Adhesion in Vascular Biology,” we review the conceptual basis for intervention in leukocyte trafficking through blockade of selectin-dependent leukocyte adhesion, discuss selected examples in which these strategies have been applied in vivo, and address novel molecular approaches to the development of selectin antagonists. As reviewed in previous articles in this series (4, 5) and elsewhere (6), neutrophil extravasation is enabled by a multistep process initiated by the selectin family of cell adhesion molecules. P-selectin is expressed by activated vascular endothelium and by activated platelets, whereas E-selectin expression is restricted to activated endothelium. L-selectin, by contrast, is expressed constitutively by neutrophils and by other leukocytes. Each of the three selectins maintains an NH2-terminal, extracellular domain with primary sequence similarity to the C-type family of calcium-dependent lectins. This carbohydrate binding domain, or CRD, plays an essential role in glycan-dependent recognition by selectins of their glycoprotein and glycolipid “counter-receptors.”(The term counterreceptor in this context is the complementary molecule that binds to an adhesion molecule in a structurally specific manner.) Neutrophil–endothelial cell interactions mediated via the selectins in the context of vascular shear flow are characterized by transient tethering of the neutrophil, followed by rolling of the neutrophil along the endothelial surface of the vessel wall. Studies in vitro and in vivo indicate that selectin-dependent neutrophil rolling is essential to subsequent events in the transmigration process, including exposure to locally high concentrations of endothelial cell-derived IL-8, platelet activating factor, and other neutrophil activating molecules (6). These molecules, in turn, promote activation of neutrophil ß2 integrins, leading to integrin-dependent firm adhesion to the integrin counter-receptor, ICAM-1, and finally, neutrophil extravasation.

The selectin-dependent rolling phenomenon relevant to neutrophil recruitment can involve endothelial E-and P-selectin recognition of neutrophil counter-receptors. E-and P-selectin counter-receptor activity has been assigned to several specific neutrophil glycoproteins, including one termed P-selectin glycoprotein ligand 1 (PSGL-1), and various neutrophil glycolipids (reviewed in reference 7). These molecules are each posttranslationally modified by specific sialylated, fucosylated lactosamine …