Neutrophils play an important role in pulmonary inflammation. They respond to an inflammatory stimulus by marginating within the microvasculature and adhering to the endothelium. The neutrophils may then either migrate through the vessel wall into the lung parenchyma or remain adherent to the endothelium and secrete mediators which injure the endothelium, altering vascular permeability. The purpose of the proposed studies is to better understand the mechanisms underlying each step in the neutrophil's response. The working hypothesis for these studies is that neutrophil sequestration within the pulmonary microvasculature is caused by a stimulus-induced decrease in deformability that slows the neutrophils and allows specific adhesive interactions to occur between neutrophils and endothelial cells. The specific receptor/ligand-mediated adhesion leads to either endothelial injury or to migration through the vessel wall into an inflammatory focus. The neutrophil sequestration is accompanied by release of additional neutrophils from the bone marrow. The role of deformability will be evaluated in vivo and in vitro by determining the effect of agents which perturb assembly of the cytoskeleton on neutrophil margination. The role of several adhesion systems will be determined by pretreating animals with specific anti-adhesion molecule antibodies which inhibit the function of the molecule. The contribution of deformability and adhesion to sequestration in neutrophil-induced injury will be studied in rabbits given infusions of activated plasma. The mechanism through which inflammatory mediators induce the release of additional neutrophils from a recruitable pool will be investigated by evaluating changes in both the blood flow to the bone marrow and the adhesion molecules involved in the adhesion of neutrophils to bone marrow stroma and sinusoidal endothelial cells. The mechanism of synergism between endotoxin pretreatment and activated plasma will be evaluated by determining the effect of endotoxin on the expression of adhesion molecules. Finally, neutrophil margination and adhesion that occurs in preparation for migration will be studied in animals with focal pneumonia induced by intrabronchial instillation of stimuli. These studies will extend our understanding of the mechanisms through which neutrophils sequester in the pulmonary microvasculature and injure the endothelium, as well as determine the role of several systems of receptor/ligand adhesion in preparation for migration.
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