Current evidence suggests that activation of the inflammatory cascade can culminate in ARDS. A complex interplay between activating molecules, responding inflammatory cells and vascular endothelial cells forms this inflammatory cascade. Mediators implicated in this response include the cytokines TNFalpha and Il-1, in addition to endotoxin or lipopolysaccharide itself. An essential component is the regulated interplay between activating molecules are currently being defined; the molecules and systems involved in neutrophil diapedesis on EC and extravasation through endothelial cell junctions are less well defined. Recent studies from our laboratory have identified a novel mechanism, or more likely mechanisms, that result in endothelial cell-dependent neutrophil adhesion, activation and migration across the monolayers. Our initial observations were made with the venom of Loxosceles and it now appears that these finding are also relevant to inflammatory cytokines (e.g. TNF, IL-1) that are key mediators of normal and pathologic inflammation. We find these inflammatory mediators induce the surface expression of E- selectin, but that on venom-treated cells this selectin has a markedly altered specificity and recognizes a different leukocyte counter receptor. We also find that cytokines and Loxosceles venom cause a redistribution of PECAM-1, a richly glycosylated (40%) member of the immunoglobulin superfamily of adhesion molecules, from its exclusive localization at endothelial cell intercellular junctions to the apical surface. PECAM-1 (CD31) is a glycosaminoglycan (GAG) binding protein and, as it is related to molecules like N-CAM, it may undergo Ca+2 dependent homotypic (self) association. Neutrophils and some T cells also express PECAM-1, where it is a transmembrane signaling molecule that activates cellular adhesion mechanisms. We find neutrophil and endothelial cell GAG are required for optimal adhesion to venom-treated endothelial cells, but not to cytokine-treated endothelial cells. However, we also find endothelial cell GAG are absolutely required for neutrophil activation and transmigration across cytokine-activated monolayers, showing that GAG receptors on neutrophils play an essential role in events after adhesion. The unanticipated role of GAG in these cellular interactions also implies a role for neutrophil heparinase in modulating these processes. These observations have the potential to provide novel insights, and thereby potentially new therapeutic interventions, into the underlying mechanisms that culminate in ARDS.
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