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    Mechanisms of endotoxin-induced endothelial monolayer disruption: Roles of tyrosine phosphorylation, caspase activation, and the actin-associated adherens junctions

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    Author
    Bannerman, Douglas Donald
    Advisor
    Goldblum, Simeon E.
    Date
    1999
    Type
    dissertation
    
    Metadata
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    Abstract
    Endothelial cell injury and/or dysfunction contributes to a variety of complications associated with Gram-negative septicemia including systemic vascular collapse, disseminated intravascular coagulation, and vascular leak syndromes. Endotoxin or bacterial lipopolysaccharide, a component of the outer membrane of Gram-negative bacteria, directly provokes endothelial injury in vitro and in vivo. Specifically, endotoxin in the presence of serum induces F-actin depolymerization, opening of the paracellular pathway, and increased endothelial monolayer permeability to macromolecules. We have identified lipid A as the bioactive moiety of bacterial lipopolysaccharide responsible for inducing an array of endothelial cell responses including increased protein tyrosine phosphorylation, actin depolymerization, increased monolayer permeability, and apoptosis. We have also found that the influence of endotoxin on endothelial cell actin organization and barrier function is mediated, in part, through a signaling pathway that is dependent on tyrosine phosphorylation events. Protein tyrosine kinase inhibition, which blocks endotoxin-induced tyrosine phosphorylation of the focal adhesion protein paxillin, protects against downstream endothelial responses including actin depolymerization, intercellular gap formation, and loss of barrier function. Further, we have studied the effect that caspase-mediated cleavage of adherens junction proteins has on mediating endotoxin-induced changes in cell-cell and cell-matrix adhesion. Endotoxin-provoked increments in transendothelial albumin flux and endothelial cell detachment occur at doses and times which are compatible with endotoxin-induced caspase activation and apoptosis. Proteins associated with the zonula adherens and focal adhesions, which mediate cell-cell and cell-matrix adhesion, respectively, are targets of caspase proteolysis. Cleavage of focal adhesion kinase leads to its dissociation from paxillin, a substrate for focal adhesion kinase tyrosine phosphorylation. The time-dependent cleavage of focal adhesion kinase and its dissociation from paxillin parallels a decrease in the phosphotyrosine content of paxillin. Caspase inhibition blocks focal adhesion kinase cleavage, decrements in paxillin phosphotyrosine content, and endothelial cell detachment, but fails to protect against endotoxin-induced endothelial barrier dysfunction. Protein tyrosine kinase inhibition, however, fails to block proteolysis but does protect against increased monolayer permeability. These findings suggest a bifurcation in the pathways through which endotoxin influences cell-cell adhesion and opening of the paracellular pathway versus endothelial cell adhesion to and detachment from the underlying extracellular matrix.
    Description
    University of Maryland, Baltimore. Pathology. Ph.D. 1999
    Keyword
    Biology, Molecular
    Biology, Cell
    Biology, Animal Physiology
    Health Sciences, Pathology
    Gram-Negative Bacteria
    Endothelial Cells--microbiology
    Endotoxins--adverse effects
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/1289
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    Theses and Dissertations All Schools
    Theses and Dissertations School of Medicine

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