Events at the Vascular Wall: The Molecular Basis of Inflammation

Under normal conditions, leukocytes in the bloodstream flow past endothelial cells. However, as the initial step in the inflammatory response, for example during an infection, leukocytes must adhere to the endothelium and then emigrate into the tissues. This process must be regulated precisely—both in time and space—because when activation occurs in the blood vessels, inflammatory mediators can escape into the circulating blood and activate leukocytes systemically, with potentially devastating outcomes. In addition, if activation occurs in the bloodstream, leukocytes may fail to adhere where they were needed and rather lodge downstream in the lung capillaries. Clinical consequences of such dysregulation include acute lung injury, ischemia-reperfusion, and multiorgan failure after sepsis. When we began our studies in the mid-1980s, the prevailing view regarding the initiation of inflammation was that the process began when an agent produced in the affected tissue generated a chemotactic gradient of attractant. Leukocytes in the bloodstream activated by the attractant were thought to migrate up the gradient to sites where they were needed. We hypothesized that endothelial cells must be key participants, because a chemotactic gradient would be dissipated at the endothelia-blood interface. Thus, we proposed that achieving spatial specificity of inflammation initiation must involve activation of the endothelial cells that form the junction between the tissues and the blood. This review centers on one aspect of inflammation: the activation of endothelial cells and responding cells in the inflammation response. It also describes our current understanding of the activation process (see additional reviews1,2). The steps of activation have formed a focus for the attention of both basic researchers interested in cell biology and clinicians interested in treating inflammatory responses. ### Physiological Mechanisms for Initiation of Inflammation Our work has demonstrated that endothelial cell activation occurs as part of the inflammatory response in an experimental system where cultured human endothelial cells are exposed to …