Pathologists of the 19th century were aware that leukocytes migrate from the blood across the wall of microvessels and accumulate in inflamed tissue. The purpose of this migration, a process called diapedesis, remained enigmatic until the discoveries of Elias Metchnikoff in 1901. He demonstrated that leukocytes attack and kill bacteria, and he recognized diapedesis as a fundamental mechanism of host defense (1). Indeed, any immune response relies on the well-coordinated trafficking of leukocytes from the circulation into lymphoid tissue (homeostatic immune surveillance) and sites of tissue injury (inflammation). The emerging model is that leukocyte adhesion and extravasation are guided by a series of well choreographed interactions between leukocytes and endothelial cells (ECs). These interactions are supported by temporally controlled and spatially restricted engagement of receptor–ligand pairs between cell types. This triggers bidirectional signaling events that lead to changes in cellular phenotype and function. The extravasation of a specific subset of leukocytes at selective sites during inflammation is achieved through expression of specific adhesion molecules and cell-type–selective chemoattractants (2,3).

The function of recruited neutrophils is to control and eliminate infection and to promote tissue repair. To achieve these ends during an inflammatory response, the lifespan of transmigrated neutrophils is extended, compared to circulating counterparts, partially through endothelial-derived factors. The endothelium also provides cues to those phagocytes that result in their locally contained release of cytokines, chemokines, growth factors, proteinases, and reactive oxygen species (ROS). Clark and Clark (4) recognized the importance of changes in the “consistency” of the endothelium in initiating an inflammatory response. Furthermore, they noted that a spatially localized and graded physiologic response to inflammatory stimuli was important for maintaining the integrity of the endothelium (4).