In order to mount an effective host defense, human neutrophils are armed with the ability to adhere to the endothelium, to migrate between interendothelial cell junctions and to penetrate the underlying basement membrane. Once the cells have penetrated the vessel wall they proceed to locate and destroy microbial invaders, and to participate in the dissolution of surrounding damaged tissues. However, these invasive, microbicidal and proteolytic capabilities also imbue the neutrophil with the ability to exert tissue-destructive effects against the endothelium and its surrounding structures in a diverse array of disease states. Indeed, neutrophil-dependent vascular damage has been implicated in pathologic states ranging from immune vasculitis and respiratory distress syndromes to atherosclerotic disease and myocardial reperfusion injury. Nonetheless, the ability of pathophysiologic stimuli to mediate neutrophildependent vascular damage in a biologically relevant model of the vessel wall is largely uncharacterized and the destructive mechanisms involved remain controversial. In an attempt to resolve these issues four aims are described. First, to develop an in vitro, three-dimensional model of the human blood vessel wall wherein the endothelium, interendothelial cell junctions and basal lamina have in vivo-like characteristics; second to use this model to examine neutrophil adherence, chemotaxis and functional responses to host and pathogen-derived stimuli; third, to determine the triggered neutrophil's ability to initiate endothelial cell detachment and lysis, and to degrade basement membrane as well as perivascular tissue components; and fourth, to determine and identify the role of neutrophil-derived oxygen metabolites and lysosomal proteinases in vessel wall damage. An understanding of neutrophil-endothelial cell interactions will not only provide specific information concerning the pathogenesis of vascular injury, but will also provide new insights into the biochemistry of the inflammatory process. Utilizing this information, therapeutic interventions may be designed that are able to attenuate inflammatory tissue damage in a diverse array of pathological states.
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