The inflammatory response is a critical component of the host reaction to injury following surgical intervention, trauma, and burns. A fundamental property of inflammation is the adherence of leukocytes to endothelium before the recruitment of leukocyte-endothelial interactions in the emigration of leukocytes from the bloodstream. Conversely, neutrophil adherence to endothelium under some circumstances can be detrimental to the host, such as in ischemia-reperfusion injury. These two extremes of pathological neutrophil-endothelial cell interaction, failure to adhere and endothelial injury, suggest that leukocyte adherence to an endothelial surface is precisely regulated. Although active participation of the endothelium in inflammatory reactions was first postulated by Cohnheim over one hundred years ago, it has only recently been demonstrated that endothelial cells promote the adherence of leukocytes to their surfaces through the expression of cell surface adhesion molecules. Thus, the endothelium participates in guiding leukocytes to sites of active inflammation and tissue injury. It is well established that many inflammatory reactions are mediated by cytokines induced by Gram-negative bacterial lipopolysaccharide (LPS; endotoxin), in particular tumor necrosis factor (TNF) and interleukin-1 (IL-1). The expression of many leukocyte adherence molecules on endothelial cell surfaces can be induced by TNF and IL-1, as well as directly by LPS, suggesting that endothelial adherence molecules may have an important role in local and systemic inflammatory responses. Furthermore, it is now recognized that endothelial cells can be activated by TNF, IL-1 and LPS to express a repertoire of proinflammatory, procoagulant and immunological functions in addition to directing leukocyte adherence. However, the cellular mechanisms of endothelial cell activation are not well defined. In this application we propose to elucidate cellular and molecular mechanisms of endothelial cell activation by examining factors that control a well-described function of activated endothelium, expression of endothelial leukocyte adherence molecule 1 (ELAM-1). We propose to test the hypothesis that the expression of ELAM-1 is dependent on definable and specific molecular mechanisms that are activated in response to inflammatory stimuli. We believe that a fundamental knowledge of these aspects of endothelial cell biology is critical to the development of therapies for destructive inflammatory reactions (e.g., systemic inflammation).
